@article{piedrahita_pierce_2023, title={Using Stem Mini-Organs to Find New Cures}, url={https://doi.org/10.52750/572466}, DOI={10.52750/572466}, author={Piedrahita, Jorge and Pierce, Joshua}, year={2023}, month={Aug} }
 @article{pierce_2022, title={Chemistry Drives Solutions to Our Planet’s Largest Problems: COVID-19 and Beyond}, url={https://doi.org/10.52750/565310}, DOI={10.52750/565310}, abstractNote={Imagine a world where a small cut would often lead to death or one in which cancer and diabetes were untreatable. Where every virus creates a pandemic of the likes of COVID-19. Where food supply was extremely limited due to pests and invasive weeds. Imagine a world where LCD screens, solar energy and adhesives were never developed. The world you have imagined is a world without Chemistry -- and it is just scratching the surface of Chemistry’s role in the world around us. Every modern hunter gatherer culture on Earth uses medicines from the wild environment for treatment. The Chacobo in Bolivia, for instance, rely on hundreds of different plant and animal species to treat different maladies. Just as with much of modern Western medicine, a key element of finding such natural medicines has been trial and error. Testing this. Testing that. But the ability to find new drugs has become more refined and dramatically sped up, and the basic sciences including Chemistry and Biology are key to this field. Joshua Pierce, Ph.D. will share his own story as a chemist, and then describe the ways in which new treatments are being discovered. He will highlight both the challenges of new approaches and the benefits, with a specific focus on how one new, potential treatment for COVID-19, a drug with the potential to prevent those with the disease from getting so very sick, was found and what will happen next with its development.}, author={Pierce, Joshua}, year={2022}, month={Jun} }
 @article{moody_brown_massaro_patel_agarwalla_simpson_brown_zheng_pierce_brudno_2022, title={Restoring Carboxylates on Highly Modified Alginates Improves Gelation, Tissue Retention and Systemic Capture}, volume={138}, ISSN={["1878-7568"]}, url={https://doi.org/10.1016/j.actbio.2021.10.046}, DOI={10.1016/j.actbio.2021.10.046}, abstractNote={Alginate hydrogels are gaining traction for use in drug delivery, regenerative medicine, and as tissue engineered scaffolds due to their physiological gelation conditions, high tissue biocompatibility, and wide chemical versatility. Traditionally, alginate is decorated at the carboxyl group to carry drug payloads, peptides, or proteins. While low degrees of substitution do not cause noticeable mechanical changes, high degrees of substitution can cause significant losses to alginate properties including complete loss of calcium cross-linking. While most modifications used to decorate alginate deplete the carboxyl groups, we propose that alginate modifications that replenish the carboxyl groups could overcome the loss in gel integrity and mechanics. In this report, we demonstrate that restoring carboxyl groups during functionalization maintains calcium cross-links as well as hydrogel shear-thinning and self-healing properties. In addition, we demonstrate that alginate hydrogels modified to a high degree with azide modifications that restore the carboxyl groups have improved tissue retention at intramuscular injection sites and capture blood-circulating cyclooctynes better than alginate hydrogels modified with azide modifications that deplete the carboxyl groups. Taken together, alginate modifications that restore carboxyl groups could significantly improve alginate hydrogel mechanics for clinical applications. STATEMENT OF SIGNIFICANCE: Chemical modification of hydrogels provides a powerful tool to regulate cellular adhesion, immune response, and biocompatibility with local tissues. Alginate, due to its biocompatibility and easy chemical modification, is being explored for tissue engineering and drug delivery. Unfortunately, modifying alginate to a high degree of substitution consumes carboxyl group, which are necessary for ionic gelation, leading to poor hydrogel crosslinking. We introduce alginate modifications that restore the alginate's carboxyl groups. We demonstrate that modifications that reintroduce carboxyl groups restore gelation and improve gel mechanics and tissue retention. In addition to contributing to a basic science understanding of hydrogel properties, we anticipate our approach will be useful to create tissue engineered scaffolds and drug delivery platforms.}, journal={ACTA BIOMATERIALIA}, publisher={Elsevier BV}, author={Moody, C. T. and Brown, A. E. and Massaro, N. P. and Patel, A. S. and Agarwalla, P. A. and Simpson, A. M. and Brown, A. C. and Zheng, H. and Pierce, J. G. and Brudno, Y.}, year={2022}, month={Jan}, pages={208–217} }
 @article{onuska_pierce_2022, title={Synthesis provides insight into a traditional medicine}, volume={606}, ISSN={["1476-4687"]}, DOI={10.1038/d41586-022-01740-w}, number={7916}, journal={NATURE}, author={Onuska, Nicholas P. R. and Pierce, Joshua G.}, year={2022}, month={Jun}, pages={869–870} }
 @article{pandit_palvai_massaro_pierce_brudno_2022, title={Tissue-reactive drugs enable materials-free local depots}, volume={343}, ISSN={["1873-4995"]}, DOI={10.1016/j.jconrel.2022.01.023}, abstractNote={Local, sustained drug delivery of potent therapeutics holds promise for the treatment of a myriad of localized diseases while eliminating systemic side effects. However, introduction of drug delivery depots such as viscous hydrogels or polymer-based implants is highly limited in stiff tissues such as desmoplastic tumors. Here, we present a method to create materials-free intratumoral drug depots through Tissue-Reactive Anchoring Pharmaceuticals (TRAPs). TRAPs diffuse into tissue and attach locally for sustained drug release. In TRAPs, potent drugs are modified with ECM-reactive groups and then locally injected to quickly react with accessible amines within the ECM, creating local drug depots. We demonstrate that locally injected TRAPs create dispersed, stable intratumoral depots deep within mouse and human pancreatic tumor tissues. TRAPs depots based on ECM-reactive paclitaxel (TRAP paclitaxel) had better solubility than free paclitaxel and enabled sustained in vitro and in vivo drug release. TRAP paclitaxel induced higher tumoral apoptosis and sustained better antitumor efficacy than the free drug. By providing continuous drug access to tumor cells, this material-free approach to sustained drug delivery of potent therapeutics has the potential in a wide variety of diseases where current injectable depots fall short.}, journal={JOURNAL OF CONTROLLED RELEASE}, author={Pandit, Sharda and Palvai, Sandeep and Massaro, Nicholas P. and Pierce, Joshua G. and Brudno, Yevgeny}, year={2022}, month={Mar}, pages={142–151} }
 @article{pierce_qiu_2022, title={Total Synthesis of Bipolamine I}, volume={7}, ISSN={["1520-5126"]}, url={https://doi.org/10.1021/jacs.2c06015}, DOI={10.1021/jacs.2c06015}, abstractNote={Indolizidine alkaloids have been the target of chemical and biological studies for decades, most recently highlighted by the isolation of the curvulamine and bipolamine polypyrrole-containing subclass. Herein we report a stereoselective 15-step synthesis of bipolamine I, a distinct member of the broader family, and through this work develop an intermediate that will serve to access other polypyrrole natural products and key analogues going forward.}, journal={JOURNAL OF THE AMERICAN CHEMICAL SOCIETY}, author={Pierce, Joshua G. and Qiu, Xiang}, year={2022}, month={Jul} }
 @article{natalia gonzalez_mills_maugeri_olaya_laguera_enders_sherman_rodriguez_pierce_jose cazzulo_et al._2021, title={Design, synthesis, and evaluation of substrate - analogue inhibitors of Trypanosoma cruzi ribose 5-phosphate isomerase type B}, volume={32}, ISSN={["1464-3405"]}, url={http://dx.doi.org/10.1016/j.bmcl.2020.127723}, DOI={10.1016/j.bmcl.2020.127723}, abstractNote={Ribose 5-phosphate isomerase type B (RPI-B) is a key enzyme of the pentose phosphate pathway that catalyzes the isomerization of ribose 5-phosphate (R5P) and ribulose 5-phosphate (Ru5P). Trypanosoma cruzi RPI-B (TcRPI-B) appears to be a suitable drug-target mainly due to: (i) its essentiality (as previously shown in other trypanosomatids), (ii) it does not present a homologue in mammalian genomes sequenced thus far, and (iii) it participates in the production of NADPH and nucleotide/nucleic acid synthesis that are critical for parasite cell survival. In this survey, we report on the competitive inhibition of TcRPI-B by a substrate – analogue inhibitor, Compound B (Ki = 5.5 ± 0.1 μM), by the Dixon method. This compound has an iodoacetamide moiety that is susceptible to nucleophilic attack, particularly by the cysteine thiol group. Compound B was conceived to specifically target Cys-69, an important active site residue. By incubating TcRPI-B with Compound B, a trypsin digestion LC-MS/MS analysis revealed the identification of Compound B covalently bound to Cys-69. This inhibitor also exhibited notable in vitro trypanocidal activity against T. cruzi infective life-stages co-cultured in NIH-3T3 murine host cells (IC50 = 17.40 ± 1.055 μM). The study of Compound B served as a proof-of-concept so that next generation inhibitors can potentially be developed with a focus on using a prodrug group in replacement of the iodoacetamide moiety, thus representing an attractive starting point for the future treatment of Chagas’ disease.}, journal={BIOORGANIC & MEDICINAL CHEMISTRY LETTERS}, publisher={Elsevier BV}, author={Natalia Gonzalez, Soledad and Mills, Jonathan J. and Maugeri, Dante and Olaya, Christopher and Laguera, Breana L. and Enders, Jeffrey R. and Sherman, Julian and Rodriguez, Ana and Pierce, Joshua G. and Jose Cazzulo, Juan and et al.}, year={2021}, month={Jan} }
 @misc{valdes-pena_massaro_lin_pierce_2021, title={Leveraging Marine Natural Products as a Platform to Tackle Bacterial Resistance and Persistence}, volume={54}, ISSN={["1520-4898"]}, url={https://doi.org/10.1021/acs.accounts.1c00007}, DOI={10.1021/acs.accounts.1c00007}, abstractNote={Antimicrobial resistance to existing antibiotics represents one of the greatest threats to human health and is growing at an alarming rate. To further complicate treatment of bacterial infections, many chronic infections are the result of bacterial biofilms that are tolerant to treatment with antibiotics because of the presence of metabolically dormant persister cell populations. Together these threats are creating an increasing burden on the healthcare system, and a "preantibiotic" age is on the horizon if significant action is not taken by the scientific and medical communities. While the golden era of antibiotic discovery (1940s-1960s) produced most of the antibiotic classes in clinical use today, followed by several decades of limited development, there has been a resurgence in antibiotic drug discovery in recent years fueled by the academic and biotech sectors. Historically, great success has been achieved by developing next-generation variants of existing classes of antibiotics, but there remains a dire need for the identification of novel scaffolds and/or antimicrobial targets to drive future efforts to overcome resistance and tolerance. In this regard, there has been no more valuable source for the identification of antibiotics than natural products, with 69-77% of approved antibiotics either being such compounds or being derived from them.Our group has developed a program centered on the chemical synthesis and chemical microbiology of marine natural products with unusual structures and promising levels of activity against multidrug-resistant (MDR) bacterial pathogens. As we are motivated by preparing and studying the biological effects of these molecules, we are not initially pursuing a biological question but instead are allowing the observed phenotypes and activities to guide the ultimate project direction. In this Account, our recent efforts on the synoxazolidinone, lipoxazolidinone, and batzelladine natural products will be discussed and placed in the context of the field's greatest challenges and opportunities. Specifically, the synoxazolidinone family of 4-oxazolidinone-containing natural products has led to the development of several chemical methods to prepare antimicrobial scaffolds and has revealed compounds with potent activity as adjuvants to treat bacterial biofilms. Bearing the same 4-oxazolidinone core, the lipoxazolidinones have proven to be potent single-agent antibiotics. Finally, our synthetic efforts toward the batzelladines revealed analogues with activity against a number of MDR pathogens, highlighted by non-natural stereochemical isomers with superior activity and simplified synthetic access. Taken together, these studies provide several distinct platforms for the development of novel therapeutics that can add to our arsenal of scaffolds for preclinical development and can provide insight into the biochemical processes and pathways that can be targeted by small molecules in the fight against antimicrobial-resistant and -tolerant infections. We hope that this work will serve as inspiration for increased efforts by the scientific community to leverage synthetic chemistry and chemical microbiology toward novel antibiotics that can combat the growing crisis of MDR and tolerant bacterial infections.}, number={8}, journal={ACCOUNTS OF CHEMICAL RESEARCH}, publisher={American Chemical Society (ACS)}, author={Valdes-Pena, M. Alejandro and Massaro, Nicholas P. and Lin, You-Chen and Pierce, Joshua G.}, year={2021}, month={Apr}, pages={1866–1877} }
 @article{massaro_pierce_2021, title={Rapid synthesis of the core scaffold of crinane and haemanthamine through a multi-component approach}, volume={75}, ISSN={["1873-3581"]}, url={https://doi.org/10.1016/j.tetlet.2021.153201}, DOI={10.1016/j.tetlet.2021.153201}, abstractNote={A rapid synthesis of the core structures of crinane and haemanthamine has been developed, enabled by a multicomponent approach. This work constitutes a formal synthesis of crinane and sets the stage for access to both families of natural products and key analogues. A key highlight of the approach is the modularity of the core synthesis, overcoming existing challenges for these scaffolds and providing a path to explore site-selective oxidation to expand the scope of molecules accessible from common intermediates.}, journal={TETRAHEDRON LETTERS}, publisher={Elsevier BV}, author={Massaro, Nicholas P. and Pierce, Joshua G.}, year={2021}, month={Jul} }
 @article{liang_lin_pierce_2021, title={Stereoselective Synthesis of the Spirocyclic gamma-Lactam Core of the Ansalactams}, volume={23}, ISSN={["1523-7052"]}, url={https://doi.org/10.1021/acs.orglett.1c03782}, DOI={10.1021/acs.orglett.1c03782}, abstractNote={Ansalactam A is an ansa macrolide natural product that contains a densely functionalized spiro-γ-lactam core containing three contiguous stereocenters. This unusual motif distinguishes it from other members of this family and represents a significant synthetic challenge. Herein, we report the development of a stereoselective formal [3+2] cycloaddition reaction for the construction of this key spiro-γ-lactam motif for the first time, thereby enabling access to the northern domain of ansalactam A.}, number={24}, journal={ORGANIC LETTERS}, publisher={American Chemical Society (ACS)}, author={Liang, Zhanhao and Lin, You-Chen and Pierce, Joshua G.}, year={2021}, month={Dec}, pages={9559–9562} }
 @inbook{lin_martinez-brokaw_pierce_2020, place={Amsterdam}, title={1,4-Oxazines and their Benzo Derivatives}, DOI={10.1016/b978-008044992-0.00706-9}, abstractNote={The physical and chemical properties, reactivity, synthesis, and applications of 1,4-oxazines, dihydro-1,4-oxazines, tetrahydro-1,4-oxazines, and their benzo derivatives have been reviewed comprehensively from 1982 to 2006. Fundamental research prior to 1982 has been included where it was omitted from CHEC(1984).}, booktitle={Comprehensive Heterocyclic Chemistry IV}, publisher={Elsevier}, author={Lin, Y-C and Martinez-Brokaw, C. and Pierce, J.G.}, year={2020} }
 @article{lin_ribaucourt_moazami_pierce_2020, title={Concise Synthesis and Antimicrobial Evaluation of the Guanidinium Alkaloid Batzelladine D: Development of a Stereodivergent Strategy}, volume={142}, ISSN={["1520-5126"]}, url={https://doi.org/10.1021/jacs.0c04091}, DOI={10.1021/jacs.0c04091}, abstractNote={Herein, we describe a stereodivergent route to (±)-batzelladine D (2), (+)-batzelladine D (2), (-)-batzelladine D (2), and a series of stereochemical analogues and explore their antimicrobial activity for the first time. The concise synthetic approach enables access to the natural products in a sequence of 8-12 steps from readily available building blocks. Highlights of the synthetic strategy include gram-scale preparation of a late stage intermediate, pinpoint stereocontrol around the tricyclic skeleton, and a modular strategy that enables analogue generation. A key bicyclic β-lactam intermediate not only serves as the key controlling element for pyrrolidine stereochemistry but also serves as a preactivated coupling partner to install the ester side chain. The stereocontrolled synthesis allowed for the investigation of the antimicrobial activity of batzelladine D, demonstrating promising activity that is more potent for non-natural stereoisomers.}, number={21}, journal={JOURNAL OF THE AMERICAN CHEMICAL SOCIETY}, author={Lin, You-Chen and Ribaucourt, Aubert and Moazami, Yasamin and Pierce, Joshua G.}, year={2020}, month={May}, pages={9850–9857} }
 @article{frohock_gilbertie_daiker_schnabel_pierce_2020, title={Front Cover: 5‐Benzylidene‐4‐Oxazolidinones Are Synergistic with Antibiotics for the Treatment of Staphylococcus aureus Biofilms (ChemBioChem 7/2020)}, url={https://doi.org/10.1002/cbic.202000168}, DOI={10.1002/cbic.202000168}, abstractNote={By using an expanded set of 5-benzylidene-4-oxazolidinones it was possible to inhibit the formation of Staphylococcus aureus biofilms, disperse preformed biofilms and—in combination with common antibiotics—to significantly reduce the bacterial load in a robust collagen–matrix biofilm model. In addition to traditional resistance mechanisms, most chronic and recurring infections are further made tolerant to antibiotic action by the presence of biofilms and novel strategies to combat these bacterial communities are urgently needed. More information can be found in the communication by J. G. Pierce et al. on page 933 in Issue 7, 2020 (DOI: 10.1002/cbic.201900633).}, journal={ChemBioChem}, author={Frohock, Bram H. and Gilbertie, Jessica M. and Daiker, Jennifer C. and Schnabel, Lauren V. and Pierce, Joshua G.}, year={2020}, month={Apr} }
 @article{griewisch_pierce_elfenbein_2020, title={Genetic Determinants of Salmonella Resistance to the Biofilm-Inhibitory Effects of a Synthetic 4-Oxazolidinone Analog}, volume={86}, ISSN={0099-2240 1098-5336}, url={http://dx.doi.org/10.1128/aem.01120-20}, DOI={10.1128/aem.01120-20}, abstractNote={Biofilms are resistant to killing by disinfectants and antimicrobials. S. enterica biofilms facilitate long-term host colonization and persistence in food processing environments. Synthetic analogs of 4-oxazolidinone natural products show promise as antibiofilm agents. Here, we show that a synthetic 4-oxazolidinone analog inhibits Salmonella biofilm through effects on both motility and biofilm matrix gene expression. Furthermore, we identify three genes that promote Salmonella resistance to the antibiofilm effects of the compound. This work provides insight into the mechanism of antibiofilm effects of a synthetic 4-oxazolidinone analog in Gram-negative bacteria and demonstrates new mechanisms of intrinsic antimicrobial resistance in Salmonella biofilms.}, number={20}, journal={Applied and Environmental Microbiology}, publisher={American Society for Microbiology}, author={Griewisch, K. F. and Pierce, J. G. and Elfenbein, J. R.}, editor={Kivisaar, MaiaEditor}, year={2020}, month={Aug} }
 @article{luckring_parker_hani_grace_lila_pierce_adin_2020, title={In Vitro Evaluation of a Novel Synthetic Bilirubin Analog as an Antioxidant and Cytoprotective Agent for Pancreatic Islet Transplantation}, volume={29}, url={http://dx.doi.org/10.1177/0963689720906417}, DOI={10.1177/0963689720906417}, abstractNote={Bilirubin is a natural cytoprotective agent and physiologic doses have proven to be beneficial in various models of organ and cellular transplantation. Recently, we showed that bilirubin has protective effects in models of pancreatic islet transplantation, preventing cell death associated with islet stress and suppressing the release of damage-associated molecular patterns. Despite these promising therapeutic attributes, the natural bilirubin used in these research studies is animal-derived (porcine), making it unsuitable for clinical application. In the current study, we synthesized two bilirubin analogs that can be produced without the use of animal-derived products. Antioxidant activity for the analogs was measured using the ferric-reducing-ability-of-plasma (FRAP) and 2,2V-azinobis(3-ethylbenzothiazoline-6-sulfonate) (ABTS) assays. Dose-dependent cytotoxicity and cytoprotective effects were then demonstrated in isolated rat islets. Compound 1 showed similar antioxidant activity to natural bilirubin. Dose-dependent cytotoxicity was seen following treatment with Compound 1 and natural bilirubin at doses >40 μM, resulting in significantly increased cell death when compared to control islets ( P < 0.05) or islets treated with doses ≤20 μM ( P < 0.05). Following hypoxic challenge, islet cell death was reduced in islets treated with Compound 1 at 10 μM (17.27% ± 0.26%) compared to natural bilirubin at 10 μM (51.36% ± 0.71%; P < 0.0001) or 20 μM (59.02% ± 0.83%; P < 0.0001) and control islets (36.51% ± 0.44%; P < 0.0001). Compound 1 was found to have promising antioxidant and cytoprotective effects, limiting islet cell death in a model of islet transplantation hypoxic stress. Compound 1 may serve as a synthetic drug lead for clinical islet transplantation and further evaluation of this molecule and its analogs is warranted.}, journal={Cell Transplantation}, publisher={SAGE Publications}, author={Luckring, Emilee J. and Parker, Patrick D. and Hani, Homayoun and Grace, Mary H. and Lila, Mary A. and Pierce, Joshua G. and Adin, Christopher A.}, year={2020}, month={Jan}, pages={096368972090641} }
 @article{cholewczynski_williams_pierce_2020, title={Stereocontrolled Synthesis of (±)-Melokhanine E via an Intramolecular Formal [3 + 2] Cycloaddition}, volume={22}, url={https://doi.org/10.1021/acs.orglett.9b04546}, DOI={10.1021/acs.orglett.9b04546}, abstractNote={A convergent sequence to access the indole alkaloid (±)-melokhanine E in 12-steps (8-step longest linear sequence) and an 11% overall yield is reported. The approach utilizes two cyclopropane moieties as reactive precursors to a 1,3-dipole and imine species to enable stereoselective construction of the core scaffold through a formal [3 + 2] cycloaddition. The natural product was evaluated for its antimicrobial activity based on isolation reports; however, no activity was observed. The reported efforts serve as a synthetic platform to prepare an array of alkaloids bearing this core structural motif.}, number={2}, journal={Organic Letters}, publisher={American Chemical Society (ACS)}, author={Cholewczynski, Anna E. and Williams, Peyton C. and Pierce, Joshua G.}, year={2020}, month={Jan}, pages={714–717} }
 @article{massaro_pierce_2020, title={Stereoselective, Multicomponent Approach to Quaternary Substituted Hydroindole Scaffolds}, volume={22}, ISSN={["1523-7052"]}, url={https://doi.org/10.1021/acs.orglett.0c01650}, DOI={10.1021/acs.orglett.0c01650}, abstractNote={The Amaryllidaceae alkaloids have been a target of synthesis for decades due to their complex architectures and biological activity. A central feature of these natural product cores is a quaternary substituted hydroindole heterocycle. Building off the foundation of our previous multicomponent approach to highly functionalized pyrrolidinones, herein we report a highly convergent, diastereoselective, multicomponent approach to access the hydroindole cores present within crinine, haemanthamine, pretazettine, and various other bioactive alkaloids. These scaffolds are additionally useful as building blocks for druglike molecules and natural product like library generation.}, number={13}, journal={ORGANIC LETTERS}, publisher={American Chemical Society (ACS)}, author={Massaro, Nicholas P. and Pierce, Joshua G.}, year={2020}, month={Jul}, pages={5079–5084} }
 @article{frohock_gilbertie_daiker_schnabel_pierce_2019, title={5-Benzylidene-4-Oxazolidinones Are Synergistic with Antibiotics for the Treatment of Staphylococcus aureus Biofilms}, volume={12}, ISBN={1439-7633}, url={https://doi.org/10.1002/cbic.201900633}, DOI={10.1002/cbic.201900633}, abstractNote={Abstract The failure of frontline antibiotics in the clinic is one of the most serious threats to human health and requires a multitude of novel therapeutics and innovative approaches to treatment so as to curtail the growing crisis. In addition to traditional resistance mechanisms resulting in the lack of efficacy of many antibiotics, most chronic and recurring infections are further made tolerant to antibiotic action by the presence of biofilms. Herein, we report an expanded set of 5‐benzylidene‐4‐oxazolidinones that are able to inhibit the formation of Staphylococcus aureus biofilms, disperse preformed biofilms, and, in combination with common antibiotics, are able to significantly reduce the bacterial load in a robust collagen‐matrix model of biofilm infection.}, journal={CHEMBIOCHEM}, publisher={Wiley}, author={Frohock, Bram H. and Gilbertie, Jessica M. and Daiker, Jennifer C. and Schnabel, Lauren V and Pierce, Joshua G.}, year={2019} }
 @article{frohock_gilbertie_daiker_schnabel_pierce_2019, title={5-Benzylidene-4-Oxazolidinones are Synergistic with Antibiotics for the Treatment of Staphylococcus Aureus Biofilms}, volume={9}, url={http://dx.doi.org/10.26434/chemrxiv.9759302.v1}, DOI={10.26434/chemrxiv.9759302.v1}, abstractNote={<div>The failure of frontline antibiotics in the clinic is one of the most serious threats to human health and requires a multitude of novel therapeutics and innovative treatment approaches to curtail the growing crisis. In addition to traditional resistance mechanisms resulting in the lack of efficacy of many antibiotics, most chronic and recurring infections are further made tolerant to antibiotic action by the presence of biofilms. Herein, we report an expanded set of 5-benzylidene-4-oxazolidinones that are able to inhibit the formation of Staphylococcus aureus biofilms, disperse preformed biofilms and in combination with common antibiotics are able to significantly reduce the bacterial load in a robust collagen-matrix model of biofilm infection.</div>}, publisher={American Chemical Society (ACS)}, author={Frohock, Bram and Gilbertie, Jessica M. and Daiker, Jennifer C. and Schnabel, Lauren V. and Pierce, Joshua}, year={2019}, month={Sep} }
 @article{martinez-brokaw_radke_pierce_ehlers_ekins_wood_maakestad_rymer_tamama_krasowski_2019, title={Accidental intoxications in toddlers: lack of cross-reactivity of vilazodone and its urinary metabolite M17 with drug of abuse screening immunoassays}, volume={19}, ISSN={["1472-6890"]}, DOI={10.1186/s12907-019-0084-9}, abstractNote={Vilazodone is an FDA approved medication used to treat major depressive disorder. The authors describe two cases of accidental vilazodone exposure in toddlers who presented with symptoms similar to amphetamine exposure and also with unexplained positive amphetamine urine immunoassay drug screens. Given a lack of published data on cross-reactivity of vilazodone and its metabolites with drug of abuse screening tests, the authors investigated drug of abuse immunoassay cross-reactivity of vilazodone and metabolites using computational and empirical approaches.To ascertain the likelihood that vilazodone would cross-react with drug of abuse screening immunoassays, the authors assessed the two-dimensional (2D) similarity of the vilazodone parent molecule and known metabolites to an array of antigenic targets for urine immunoassay drug screens. To facilitate studies of the commercially unavailable M17 metabolite, it was prepared synthetically through a novel scheme. Urine and serum were spiked with vilazodone and M17 into urine (200-100,000 ng/mL) and serum (20-2000 ng/mL) samples and tested for cross-reactivity.Computational analysis using 2D similarity showed that vilazodone and metabolites have generally low similarity to antigenic targets of common drug of abuse screening immunoassays, predicting weak or no cross-reactivity. The M17 metabolite had 2D similarity to amphetamines and tricyclic antidepressants in a range similar to some other compounds exhibiting weak cross-reactivity on these immunoassays. Cross-reactivity testing was therefore performed on two different urine amphetamines immunoassays and a serum tricyclic antidepressant immunoassay. However, actual testing of cross reactivity for vilazodone and the M17 metabolite did not detect cross-reactivity for any urine amphetamines screen at concentrations up to 100,000 ng/mL and for a serum tricyclic antidepressants assays at concentrations up to 2000 ng/mL.While the vilazodone metabolite M17 has weak 2D structural similarity to amphetamines and tricyclic antidepressants, the current study did not demonstrate any experimental cross-reactivity with two different urine amphetamines immunoassays and a serum tricyclic antidepressant immunoassay. Vilazodone ingestions in young children present a diagnostic challenge in their similarity to amphetamine ingestions and the lack of routine laboratory tests for vilazodone. Further work is needed to understand the metabolic profile for vilazodone in children versus adults.}, journal={BMC CLINICAL PATHOLOGY}, author={Martinez-Brokaw, Christina D. and Radke, Joshua B. and Pierce, Joshua G. and Ehlers, Alexandra and Ekins, Sean and Wood, Kelly E. and Maakestad, Jon and Rymer, Jacqueline A. and Tamama, Kenichi and Krasowski, Matthew D.}, year={2019}, month={Feb} }
 @article{pierce_lin_2019, title={Concise Synthesis and Antimicrobial Evaluation of the Guanidinium Alkaloid Batzelladine D}, volume={10}, url={https://doi.org/10.26434/chemrxiv.9924692.v1}, DOI={10.26434/chemrxiv.9924692.v1}, abstractNote={A concise synthesis of the tricyclic guanidinium alkaloid batzelladine D has been accomplished in a sequence of 8 steps from readily available building blocks. Highlights of the synthesis include gram-scale preparation of a late stage intermediate, pinpoint stereocontrol around the tricyclic skeleton and a modular strategy that enables analog generation. A key bicyclic b-lactam intermediate serves to not only control stereochemistry, but also serves as a pre-activated coupling partner to install the ester sidechain. The stereo-controlled synthesis allowed for the investigation of the antimicrobial activity of batzelladine D, demonstrating promising activity that is more potent for non-natural stereoisomers.}, publisher={American Chemical Society (ACS)}, author={Pierce, Joshua and Lin, You-Chen}, year={2019}, month={Oct} }
 @article{lin_ribaucourt_moazami_pierce_2019, title={Concise Synthesis and Antimicrobial Evaluation of the Guanidinium Alkaloid Batzelladine D}, url={https://doi.org/10.26434/chemrxiv.9924692.v2}, DOI={10.26434/chemrxiv.9924692.v2}, abstractNote={A concise synthesis of the tricyclic guanidinium alkaloid batzelladine D has been accomplished in a sequence of 8 steps from readily available building blocks. Highlights of the synthesis include gram-scale preparation of a late stage intermediate, pinpoint stereocontrol around the tricyclic skeleton and a modular strategy that enables analog generation. A key bicyclic b-lactam intermediate serves to not only control stereochemistry, but also serves as a pre-activated coupling partner to install the ester sidechain. The stereo-controlled synthesis allowed for the investigation of the antimicrobial activity of batzelladine D, demonstrating promising activity that is more potent for non-natural stereoisomers.}, author={Lin, You-Chen and Ribaucourt, Aubert and Moazami, Yasamin and Pierce, Joshua}, year={2019}, month={Oct} }
 @article{robinson_mills_pierce_2019, title={Expanded Structure-Activity Studies of Lipoxazolidinone Antibiotics}, volume={10}, ISSN={["1948-5875"]}, url={https://doi.org/10.1021/acsmedchemlett.9b00015}, DOI={10.1021/acsmedchemlett.9b00015}, abstractNote={The lipoxazolidinone family of marine natural products, which contains an unusual 4-oxazolidinone core, was found to possess potent antimicrobial activity against methicillin resistant Staphylococcus aureus (MRSA). Herein, we expanded our previous synthetic efforts by preparing selected aryl derivatives of the lipoxazolidinones and further evaluating the potential to expand the activity of this class of molecules to Gram-negative pathogens. With these analogs, we explored the effect of varying the substitution pattern around the aromatic ring, increasing the chain length between the oxazolidinone core and the aryl system, and how altering the position of more polar functional groups affected the antimicrobial activity. Finally, we utilized a TolC knockout strain of E. coli to demonstrate that our compounds are subject to efflux in Gram-negative pathogens, and activity is restored in these knockouts. Together these results provide additional data for the further development of 4-oxazolidinone analogs 5, 20, and 21 for the treatment of infectious disease.}, number={3}, journal={ACS MEDICINAL CHEMISTRY LETTERS}, publisher={American Chemical Society (ACS)}, author={Robinson, Kaylib R. and Mills, Jonathan J. and Pierce, Joshua G.}, year={2019}, month={Mar}, pages={374-+} }
 @article{pierce_cholewczynski_williams_2019, title={Stereocontrolled Synthesis of Melokhanine E via an Intramolecular Formal [3+2] Cycloaddition}, volume={10}, url={http://dx.doi.org/10.26434/chemrxiv.10022858.v1}, DOI={10.26434/chemrxiv.10022858.v1}, abstractNote={A convergent sequence to access the indole alkaloid melokhanine E in 12-steps (8-step longest linear sequence) and an 11% overall yield is reported. The approach utilizes two cyclopropane moieties as reactive precursors to a 1,3-dipole and imine species to enable stereoselective construction of the core scaffold through a formal [3+2] cycloaddition. The natural product was evaluated for its antimicrobial activity based on isolation reports; however, no activity was observed. The reported efforts serve as a synthetic platform to prepare an array of alkaloids bearing this core structural motif.}, publisher={American Chemical Society (ACS)}, author={Pierce, Joshua and Cholewczynski, Anna and Williams, Peyton}, year={2019}, month={Oct} }
 @article{cusumano_pierce_2018, title={3-Hydroxy-1,5-dihydro-2H-pyrrol-2-ones as novel antibacterial scaffolds against methicillin-resistant Staphylococcus aureus}, volume={28}, ISSN={["1464-3405"]}, url={https://doi.org/10.1016/j.bmcl.2018.02.047}, DOI={10.1016/j.bmcl.2018.02.047}, abstractNote={Herein, we report the synthesis and evaluation of 3-hydroxy-1,5-dihydro-2H-pyrrol-2-ones as antibacterial agents against methicillin-resistant S. aureus (MRSA) and methicillin-resistant S. epidermidis (MRSE). Lead compound 38 showed minimum inhibitory concentrations (MICs) of 8 and 4 μg/mL against MRSA and MRSE, respectively. Furthermore, compound 38 displayed a MIC of 8–16 μg/mL against linezolid-resistant MRSA. These molecules, previously underexplored as antibacterial agents, serve as a new scaffold for antimicrobial development.}, number={16}, journal={BIOORGANIC & MEDICINAL CHEMISTRY LETTERS}, author={Cusumano, Alexander Q. and Pierce, Joshua G.}, year={2018}, month={Sep}, pages={2732–2735} }
 @article{parker_ge_pierce_2018, title={Coupling of thioamides with 4-bromocrotonate esters and subsequent conjugate addition for the rapid one-pot synthesis of functionalized thiazolines}, volume={59}, ISSN={0040-4039}, url={http://dx.doi.org/10.1016/J.TETLET.2017.12.043}, DOI={10.1016/J.TETLET.2017.12.043}, abstractNote={An efficient one-pot synthesis of functionalized thiazolines via the coupling of thioamides with 4-bromocrotonate esters is described. A range of aryl- and alkyl-thioamides with various substitutions are well-tolerated. Additionally, the presence of the exocyclic ester functionality provides a convenient handle for the synthesis of more complex thiazoline-containing natural products and biologically-relevant compounds.}, number={3}, journal={Tetrahedron Letters}, publisher={Elsevier BV}, author={Parker, Patrick D. and Ge, Yonghe and Pierce, Joshua G.}, year={2018}, month={Jan}, pages={277–279} }
 @article{gulledge_collette_mackey_johnstone_moazami_todd_moeser_pierce_cech_laster_2018, title={Mast cell degranulation and calcium influx are inhibited by an Echinacea purpurea extract and the alkylamide dodeca-2E,4E-dienoic acid isobutylamide}, volume={212}, ISSN={0378-8741}, url={http://dx.doi.org/10.1016/J.JEP.2017.10.012}, DOI={10.1016/J.JEP.2017.10.012}, abstractNote={Native Americans used plants from the genus Echinacea to treat a variety of different inflammatory conditions including swollen gums, sore throats, skin inflammation, and gastrointestinal disorders. Today, various Echinacea spp. preparations are used primarily to treat upper respiratory infections. The goal of this study was to evaluate the effects of an ethanolic E. purpurea (L) Moench root extract and the alkylamide dodeca-2E,4E-dienoic acid isobutylamide (A15) on mast cells, which are important mediators of allergic and inflammatory responses. Inhibition of mast cell activation may help explain the traditional use of Echinacea. A15 was evaluated for its effects on degranulation, calcium influx, cytokine and lipid mediator production using bone marrow derived mast cells (BMMCs) and the transformed rat basophilic leukemia mast cell line RBL-2H3. Methods included enzymatic assays, fluorimetry, ELISAs, and microscopy. A root extract of E. purpurea, and low and high alkylamide-containing fractions prepared from this extract, were also tested for effects on mast cell function. Finally, we tested A15 for effects on calcium responses in RAW 264.7 macrophage and Jurkat T cell lines. A15 inhibited ß-hexosaminidase release from BMMCs and RBL-2H3 cells after treatment with the calcium ionophore A23187 by 83.5% and 48.4% at 100 µM, respectively. Inhibition also occurred following stimulation with IgE anti-DNP/DNP-HSA. In addition, A15 inhibited 47% of histamine release from A23187-treated RBL-2H3 cells. A15 prevented the rapid rise in intracellular calcium following FcεRI crosslinking and A23187 treatment suggesting it acts on the signals controlling granule release. An E. purpurea root extract and a fraction with high alkylamide content derived from this extract also displayed these activities while fractions with little to no detectable amounts of alkylamide did not. A15 mediated inhibition of calcium influx was not limited to mast cells as A23187-stimulated calcium influx was blocked in both RAW 264.7 and Jurkat cell lines with 60.2% and 43.6% inhibition at 1 min post-stimulation, respectively. A15 also inhibited the release of TNF-α, and PGE2 to a lesser degree, following A23187 stimulation indicating its broad activity on mast cell mediator production. These findings suggest that Echinacea extracts and alkylamides may be useful for treating allergic and inflammatory responses mediated by mast cells. More broadly, since calcium is a critical second messenger, the inhibitory effects of alkylamides on calcium uptake would be predicted to dampen a variety of pathological responses, suggesting new uses for this plant and its constituents.}, journal={Journal of Ethnopharmacology}, publisher={Elsevier BV}, author={Gulledge, Travis V. and Collette, Nicholas M. and Mackey, Emily and Johnstone, Stephanie E. and Moazami, Yasamin and Todd, Daniel A. and Moeser, Adam J. and Pierce, Joshua G. and Cech, Nadja B. and Laster, Scott M.}, year={2018}, month={Feb}, pages={166–174} }
 @article{mills_robinson_zehnder_pierce_2018, title={Synthesis and Biological Evaluation of the Antimicrobial Natural Product Lipoxazolidinone A}, volume={130}, url={https://doi.org/10.1002/ange.201805078}, DOI={10.1002/ange.201805078}, abstractNote={Abstract Natural products have historically been a major source of antibiotics and therefore novel scaffolds are constantly of interest. The lipoxazolidinone family of marine natural products, with an unusual 4‐oxazolidinone heterocycle at their core, represents a new scaffold for antimicrobial discovery; however, questions regarding their mechanism of action and high lipophilicity have likely slowed follow‐up studies. Herein, we report the first synthesis of lipoxazolidinone A, 15 structural analogues to explore its active pharmacophore, and initial resistance and mechanism of action studies. These results suggest that 4‐oxazolidinones are valuable scaffolds for antimicrobial development and reveal simplified lead compounds for further optimization.}, number={28}, journal={Angewandte Chemie}, publisher={Wiley}, author={Mills, Jonathan J. and Robinson, Kaylib R. and Zehnder, Troy E. and Pierce, Joshua G.}, year={2018}, month={Jul}, pages={8818–8822} }
 @article{mills_robinson_zehnder_pierce_2018, title={Synthesis and Biological Evaluation of the Antimicrobial Natural Product Lipoxazolidinone A}, url={https://doi.org/10.26434/chemrxiv.6103607.v1}, DOI={10.26434/chemrxiv.6103607.v1}, abstractNote={The lipoxazolidinone family of marine natural products, with an unusual 4-oxazolidinone heterocycle at their core, represents a new scaffold for antimicrobial discovery; however, questions regarding their mechanism of action and high lipophilicity have likely slowed follow-up studies. Herein, we report the first synthesis of lipoxazolidinone A, 15 structural analogs to explore its active pharmacophore, and initial resistance and mechanism of action studies. These results suggest that 4-oxazolidinones are valuable scaffolds for antimicrobial development and reveal simplified lead compounds for further optimization.}, publisher={American Chemical Society (ACS)}, author={Mills, Jonathan J. and Robinson, Kaylib R. and Zehnder, Troy E. and Pierce, Joshua G.}, year={2018}, month={Apr} }
 @article{mills_robinson_zehnder_pierce_2018, title={Synthesis and Biological Evaluation of the Antimicrobial Natural Product Lipoxazolidinone A}, volume={57}, ISSN={1433-7851}, url={http://dx.doi.org/10.1002/anie.201805078}, DOI={10.1002/anie.201805078}, abstractNote={Abstract Natural products have historically been a major source of antibiotics and therefore novel scaffolds are constantly of interest. The lipoxazolidinone family of marine natural products, with an unusual 4‐oxazolidinone heterocycle at their core, represents a new scaffold for antimicrobial discovery; however, questions regarding their mechanism of action and high lipophilicity have likely slowed follow‐up studies. Herein, we report the first synthesis of lipoxazolidinone A, 15 structural analogues to explore its active pharmacophore, and initial resistance and mechanism of action studies. These results suggest that 4‐oxazolidinones are valuable scaffolds for antimicrobial development and reveal simplified lead compounds for further optimization.}, number={28}, journal={Angewandte Chemie International Edition}, publisher={Wiley}, author={Mills, Jonathan J. and Robinson, Kaylib R. and Zehnder, Troy E. and Pierce, Joshua G.}, year={2018}, month={Jun}, pages={8682–8686} }
 @article{parker_lemercier_pierce_2018, title={Synthesis of Quaternary-Substituted Thiazolines via Halocyclization of S-Allyl Thioimidate Salts}, volume={83}, ISSN={0022-3263 1520-6904}, url={http://dx.doi.org/10.1021/ACS.JOC.7B02299}, DOI={10.1021/ACS.JOC.7B02299}, abstractNote={An efficient synthesis of S-allyl thioimidate hydrobromide salts via coupling of thioamides with allyl bromide derivatives is described. A range of mono-, di-, and trisubstituted olefins as well as alkyl- and arylthioamides with variations in electronics are tolerated. A rapid anti-diastereoselective halocyclization of these salts provides a variety of substituted alkyl- and arylthiazolines. Initial development of an efficient enantioselective synthesis of quaternary-substituted thiazolines through the organo-catalyzed halocyclization of sulfonate thioimidate salts is also described.}, number={1}, journal={The Journal of Organic Chemistry}, publisher={American Chemical Society (ACS)}, author={Parker, Patrick D. and Lemercier, Bérénice C. and Pierce, Joshua G.}, year={2018}, month={Jan}, pages={12–22} }
 @article{edwards_shymanska_pierce_2017, title={5-Benzylidene-4-oxazolidinones potently inhibit biofilm formation in Methicillin-resistant Staphylococcus aureus}, volume={53}, ISSN={1359-7345 1364-548X}, url={http://dx.doi.org/10.1039/C7CC03626D}, DOI={10.1039/C7CC03626D}, abstractNote={Investigation into the biological function of 5-benzylidene-4-oxazolidinones revealed dose-dependent inhibition of biofilm formation in Methicillin-resistant S. aureus (MRSA). This structurally unusual class of small molecules inhibit up to 89% of biofilm formation with IC50 values as low as 0.78 μM, and disperse pre-formed biofilms with IC50 values as low as 4.7 μM. Together, these results suggest that 4-oxazolidinones represent new chemotypes to enable the study of bacterial biofilms with small molecule chemical probes.}, number={53}, journal={Chemical Communications}, publisher={Royal Society of Chemistry (RSC)}, author={Edwards, Grant A. and Shymanska, Nataliia V. and Pierce, Joshua G.}, year={2017}, pages={7353–7356} }
 @article{cusumano_boudreau_pierce_2017, title={Direct Access to Highly Functionalized Heterocycles through the Condensation of Cyclic Imines and alpha-Oxoesters}, volume={82}, ISSN={["0022-3263"]}, url={https://doi.org/10.1021/acs.joc.7b02572}, DOI={10.1021/acs.joc.7b02572}, abstractNote={A facile, gram-scale preparation of 2-hydroxy-5,6,7,7a-tetrahydro-3H-pyrrolizin-3-ones and 2-hydroxy-6,7,8,8a-tetrahydroindolizin-3(5H)-ones from a condensation cyclization of α-oxoesters with five- and six-membered cyclic imines, respectively, is reported. This transformation enables a concise, three-step synthesis of the natural products phenopyrrozin and p-hydroxyphenopyrrozin. Further, biologically relevant scaffolds, such as α-quaternary β-homo prolines and β-lactams, are also prepared in two- to three-steps from the versatile 2-hydroxy-5,6,7,7a-tetrahydro-3H-pyrrolizin-3-one core.}, number={24}, journal={JOURNAL OF ORGANIC CHEMISTRY}, publisher={American Chemical Society (ACS)}, author={Cusumano, Alexander Q. and Boudreau, Matthew W. and Pierce, Joshua G.}, year={2017}, month={Dec}, pages={13714–13721} }
 @article{pierce_2017, title={How Cancer Cells Become Resistant to Cationic Lytic Peptides: It’s the Sugar!}, volume={24}, ISSN={2451-9456}, url={http://dx.doi.org/10.1016/J.CHEMBIOL.2017.01.009}, DOI={10.1016/J.CHEMBIOL.2017.01.009}, abstractNote={In this issue of Cell Chemical Biology, Ishikawa et al., 2017Ishikawa K. Medina S.H. Schneider J.P. Klar A.J.S. Cell Chem. Biol. 2017; 24 (this issue): 149-158Abstract Full Text Full Text PDF PubMed Scopus (18) Google Scholar demonstrate that the loss of cell-surface anionic saccharides can impart resistance toward anticancer peptides. This study provides the first insight into potential resistance mechanisms toward cationic lytic peptides and highlights the important, yet previously unappreciated, role cell-surface glycans can play in cellular resistance mechanisms. In this issue of Cell Chemical Biology, Ishikawa et al., 2017Ishikawa K. Medina S.H. Schneider J.P. Klar A.J.S. Cell Chem. Biol. 2017; 24 (this issue): 149-158Abstract Full Text Full Text PDF PubMed Scopus (18) Google Scholar demonstrate that the loss of cell-surface anionic saccharides can impart resistance toward anticancer peptides. This study provides the first insight into potential resistance mechanisms toward cationic lytic peptides and highlights the important, yet previously unappreciated, role cell-surface glycans can play in cellular resistance mechanisms. The development of cellular resistance to anticancer agents represents a significant hurdle to the long-term use of chemotherapeutics in oncology. Historically, most acquired resistance mechanisms have focused on small-molecule-based drugs that possess intracellular targets and are subject to efflux pumps, increased metabolism, and/or mutation of the target structure. The various mechanisms by which cancer cells can develop resistance to these small molecule treatments have been well explored (Housman et al., 2014Housman G. Byler S. Heerboth S. Lapinska K. Longacre M. Snyder N. Sarkar S. Cancer. 2014; 6: 1769-1792Crossref Scopus (1407) Google Scholar, Gottesman, 2002Gottesman M.M. Annu. Rev. Med. 2002; 53: 615-627Crossref PubMed Scopus (2116) Google Scholar); however, there has been little study into the potential mechanism by which cells could gain resistance to membrane-lytic anticancer peptides (ACPs) that act to disrupt the integrity of the lipid bilayer via a non-stereospecific mechanism. The lack of an intracellular target and membrane-lytic activity of ACPs has led to the perception that resistance is not likely to occur, and therefore detailed studies to evaluate the potential for resistance have not been conducted. Poly-cationic antimicrobial peptides have been employed extensively and are notable for their amphiphilic structures due to the presence of alternating positive charge and hydrophobic residues (Hancock and Sahl, 2006Hancock R.E.W. Sahl H.G. Nat. Biotechnol. 2006; 24: 1551-1557Crossref PubMed Scopus (3095) Google Scholar). More recently, it has been recognized that these charged peptides can selectively target cancer cells over healthy cells, taking advantage of the negatively charged outer leaflet of the cancer cell surface (Hoskin and Ramamoorthy, 2008Hoskin D.W. Ramamoorthy A. Biochim. Biophys. Acta. 2008; 1778: 357-375Crossref PubMed Scopus (978) Google Scholar). Sinthuvanich et al., 2012Sinthuvanich C. Veiga A.S. Gupta K. Gaspar D. Blumenthal R. Schneider J.P. J. Am. Chem. Soc. 2012; 134: 6210-6217Crossref PubMed Scopus (140) Google Scholar developed a novel ACP (SVS-1, KVKVKVKVDPLPTKVKVKVK-NH2) that contains an 18-residue cationic peptide which forms inactive random coils in solution but which upon interaction with a negatively charged cell surface adopts a β-hairpin structure that is capable of disrupting lipid bilayers. It was subsequently demonstrated that SVS-1 is capable of selectively targeting cancer cells, and these studies provided a platform for the further development of ACPs using this general strategy. In their current work published in this issue of Cell Chemical Biology, Ishikawa et al., 2017Ishikawa K. Medina S.H. Schneider J.P. Klar A.J.S. Cell Chem. Biol. 2017; 24 (this issue): 149-158Abstract Full Text Full Text PDF PubMed Scopus (18) Google Scholar explore the potential for eukaryotic cells to develop resistance to cationic oncolytic peptides and uncover the mutations that are responsible for the resistant cell populations. This study not only addresses questions regarding the potential resistance mechanisms toward SVS-1 but is also more broadly relevant for addressing fundamental understandings of how cell populations respond to the action of ACPs. Since there are not existing model systems developed for the study of ACPs in yeast, the authors first demonstrate that fission yeast are in fact suitable model systems, with wild-type yeast forming colonies readily on normal growth media and killed on growth media treated with the model ACP SVS-1. Interestingly, during these initial experiments, spontaneously arising peptide-resistant colonies were identified. Given the lack of understanding of resistance mechanisms for ACPs, this finding raises numerous questions regarding the genetic basis for resistance and the potential extension of this finding to human cancer cells. Typically, resistance toward toxic substances is acquired through genetic mutations, amplification of a gene, or changes in gene expression (Calo et al., 2014Calo S. Shertz-Wall C. Lee S.C. Bastidas R.J. Nicolás F.E. Granek J.A. Mieczkowski P. Torres-Martínez S. Ruiz-Vázquez R.M. Cardenas M.E. Heitman J. Nature. 2014; 513: 555-558Crossref PubMed Scopus (101) Google Scholar). A series of experiments ensued to investigate the mechanism of acquired resistance, and through both whole-genome sequencing of a resistant mutant (identifying the pvg2 gene as the causative mutation) and screening of a yeast transposon library (identifying the uge1 and gms1 genes as causative mutations) it was demonstrated that stable mutations of single genes were responsible for the resistance phenotypes. A highlight of this study by Ishikawa et al., 2017Ishikawa K. Medina S.H. Schneider J.P. Klar A.J.S. Cell Chem. Biol. 2017; 24 (this issue): 149-158Abstract Full Text Full Text PDF PubMed Scopus (18) Google Scholar is that all three identified genes have functional roles in yeast cell wall protein glycosylation. Interestingly, these genes are involved in the installation of negatively charged glycans at the termini of glycan branches on the cell surface. The authors further demonstrate that the overall negative charge on the cell surface is indeed significantly reduced in the resistant mutants and that there is a direct correlation between sub-population’s cell-surface negative charge and their susceptibly toward SVS-1. Taken together, these studies demonstrate three separate single gene mutations that are capable of significantly reducing cell-surface negative charge through glycan modification leading to mutant yeast strains not subject to the action of cationic ACPs. At a molecular level, these initial results raise questions as to whether the dissipation of cell-surface negative charge is directly decreasing the affinity and action of ACPs or whether these mutants are less subject to the action of cationic peptides due to increased cell-cell interactions. It is known that the reduction in negative charge on the yeast cell surface leads to increased flocculation, and it may be possible that this cell aggregation could prevent the action of ACPs on interior cells; however, the authors demonstrate there is no correlation between flocculation and the action of ACPs on yeast. Another highlight of the paper is the extension of these studies to A549 human lung carcinoma cells. Over a 6-month period, an SVS-1-resistant cell line was generated that grew normally in media containing 50 μM of ACP. These A549-resistant cells demonstrated a modest 5-fold resistance toward SVS-1, yet they are the first example of a characterized mutant resistant to ACPs. The clinical relevancy of such resistance is unclear, as there are not yet ACP molecules in the clinic, although similar levels of resistance have proven problematic in other disease areas, such as HIV. Importantly, cells that are resistant to ACPs were demonstrated as sensitive to traditional small-molecule chemotherapeutic agents such as doxorubicin and paclitaxel. These findings point to the likely pursuit of a dual-agent strategy for future clinical applications to limit resistance and adverse side effects observed with high dosing of ACPs. Finally, Ishikawa et al., 2017Ishikawa K. Medina S.H. Schneider J.P. Klar A.J.S. Cell Chem. Biol. 2017; 24 (this issue): 149-158Abstract Full Text Full Text PDF PubMed Scopus (18) Google Scholar demonstrate that changes in sialic acid content on human cancer cells modulate SVS-1 resistance. Sialic acid is a known tumor marker and contains an anionic carboxyl group. It was determined that the resistant mutant to SVS-1 possessed 65% less sialic acid on its cell wall, and this lack of sialic acid was directly correlated to a reduction in susceptibility to the model ACP. Perhaps most significantly, the authors postulate that the basal levels of sialic acid expression may correlate to the cells’ ability to generate resistance to ACPs, with cell lines such as A549 and Jurkat having high expression levels whereas cell lines such as MCF-7 have lower levels of sialic acids and are therefore less prone to developing resistance through this mechanism. In summary, this study explores the potential for acquired resistance to ACPs in yeast and human cancer cells and reveals single gene mutations that can cause resistant phenotypes through modification of the glycans on cell-surface proteins. Although these findings are significant, many questions remain regarding the clinical relevance of such cationic peptides and the impact, if any, of the modest resistance demonstrated in this report. Regardless, awareness of the glycan alterations will allow for careful development of ACPs and combination treatment regimens to potentially avoid resistance and provide innovative clinical candidates for aggressive human cancers. Glycan Alteration Imparts Cellular Resistance to a Membrane-Lytic Anticancer PeptideIshikawa et al.Cell Chemical BiologyJanuary 12, 2017In BriefAlthough resistance toward small-molecule chemotherapeutics has been well studied, the potential of tumor cells to avoid destruction by membrane-lytic compounds remains unexplored. Ishikawa et al. show that alteration of cell-surface glycans impart resistance towards a model oncolytic peptide. Full-Text PDF Open Archive}, number={2}, journal={Cell Chemical Biology}, publisher={Elsevier BV}, author={Pierce, Joshua G.}, year={2017}, month={Feb}, pages={121–122} }
 @article{shymanska_pierce_2017, title={Stereoselective Synthesis of Quaternary Pyrrolidine-2,3-diones and beta-Amino Acids}, volume={19}, ISSN={["1523-7052"]}, url={https://doi.org/10.1021/acs.orglett.7b01185}, DOI={10.1021/acs.orglett.7b01185}, abstractNote={A facile, diastereoselective synthesis of highly substituted pyrrolidine-2,3-diones is reported, along with the one-step conversion of these heterocycles to novel β-amino acids and further functionalized derivatives. This method involves an unusually mild, one-pot, three-component cyclization/allylation followed by a Claisen rearrangement to provide unusual pyrrolidinone products that are densely functionalized and contain an all-carbon quaternary stereocenter. The reported reaction sequence is operationally simple, exquisitely diastereoselective, and provides gram-scale access to valuable heterocyclic scaffolds and β-amino acids not readily accessible via existing approaches.}, number={11}, journal={ORGANIC LETTERS}, publisher={American Chemical Society (ACS)}, author={Shymanska, Nataliia V. and Pierce, Joshua G.}, year={2017}, month={Jun}, pages={2961–2964} }
 @article{shi_moazami_pierce_2017, title={Structure, synthesis and biological properties of the pentacyclic guanidinium alkaloids}, volume={25}, ISSN={0968-0896}, url={http://dx.doi.org/10.1016/J.BMC.2017.03.015}, DOI={10.1016/J.BMC.2017.03.015}, abstractNote={The pentacyclic guanidinium alkaloids (PGAs) are a family of marine natural products that possess a polycyclic guanidine-containing core and a long alkyl chain tethered spermidine-derived tail that is rarely observed in other natural products. These natural products exhibit potent activities on a wide range of organisms and therefore have attracted the attention of many synthetic chemists; however, the structure-activity relationships and mechanisms of action of PGAs remain largely elusive. Herein we summarize the structure, synthesis, toxicity and mechanisms of action of PGAs and highlight their potential as chemical probes and/or therapeutic leads.}, number={11}, journal={Bioorganic & Medicinal Chemistry}, publisher={Elsevier BV}, author={Shi, Yunlong and Moazami, Yasamin and Pierce, Joshua G.}, year={2017}, month={Jun}, pages={2817–2824} }
 @article{parker_oh_moazami_pierce_loziuk_dean_muddiman_2016, title={Examining ubiquitinated peptide enrichment efficiency through an epitope labeled protein}, volume={512}, ISSN={["1096-0309"]}, DOI={10.1016/j.ab.2016.08.017}, abstractNote={Ubiquitination is a dynamic process that is responsible for regulation of cellular responses to stimuli in a number of biological systems. Previous efforts to study this post-translational modification have focused on protein enrichment; however, recent research utilizes the presence of the di-glycine (Gly-Gly) remnants following trypsin digestion to immuno-enrich ubiquitinated peptides. Monoclonal antibodies developed to the cleaved ubiquitin modification epitope, (tert-butoxycarbonyl) glycylglycine (Boc-Gly-Gly-NHS)(1), are used to identify the Gly-Gly signature. Here, we have successfully generated the Boc-Gly-Gly-NHS modification and showed that when conjugated to a lysine containing protein, such as lysozyme, it can be applied as a standard protein to examine ubiquitinated peptide enrichment within a complex background.}, journal={ANALYTICAL BIOCHEMISTRY}, author={Parker, J. and Oh, Y. and Moazami, Y. and Pierce, J. G. and Loziuk, P. L. and Dean, R. A. and Muddiman, D. C.}, year={2016}, month={Nov}, pages={114–119} }
 @article{shi_pierce_2016, title={Stereocontrolled Synthesis of (+)-Plagiogyrin A}, volume={18}, ISSN={1523-7060 1523-7052}, url={http://dx.doi.org/10.1021/ACS.ORGLETT.6B02629}, DOI={10.1021/ACS.ORGLETT.6B02629}, abstractNote={Plagiogyrin A (1) was first isolated from the fronds of Plagiogyria matsumureana. Structurally, it features an α-ketoaldehyde functional group in its hemiacetal form, fused in a cis-substituted lactone ring. We have successfully synthesized the skeleton of this natural product by employing a stereocontrolled aldol reaction followed by the installation of the α-ketoaldehyde moiety derived from the mild oxidation of an α-diazoketone. Finally, anhydrous acidic conditions released the protected diol and provided the required cyclized hemiacetal.}, number={20}, journal={Organic Letters}, publisher={American Chemical Society (ACS)}, author={Shi, Yunlong and Pierce, Joshua G.}, year={2016}, month={Oct}, pages={5308–5311} }
 @article{pierce_parker_2016, title={Synthesis of 1,2,4-Oxadiazoles via DDQ-Mediated Oxidative Cyclization of Amidoximes}, volume={48}, ISSN={0039-7881 1437-210X}, url={http://dx.doi.org/10.1055/S-0035-1561597}, DOI={10.1055/S-0035-1561597}, abstractNote={An oxidative cyclization of amidoximes to form 1,2,4-oxadiazoles, mediated by 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ), is described. A range of alkyl, aryl, and heteroaryl substrates are tolerated under these conditions. This reaction serves as an alternate approach for the synthesis of functionally diverse oxadiazoles via a rapid and straightforward synthetic procedure.}, number={12}, journal={Synthesis}, publisher={Georg Thieme Verlag KG}, author={Pierce, Joshua and Parker, Patrick}, year={2016}, month={Apr}, pages={1902–1909} }
 @article{lemercier_pierce_2016, title={Thiohydroximic acids: Versatile reagents for organic synthesis}, volume={27}, number={2}, journal={Synlett}, author={Lemercier, B. C. and Pierce, J. G.}, year={2016}, pages={181–189} }
 @article{pierce_shymanska_edwards_2015, title={Marine natural products synthesis as a driving force for chemical and biological discovery}, volume={81}, ISSN={0032-0943 1439-0221}, url={http://dx.doi.org/10.1055/S-0035-1556104}, DOI={10.1055/S-0035-1556104}, abstractNote={Natural products bearing complex structures and potent biological activities have long been the target of chemical synthesis and have served as successful lead molecules for drug discovery. As part of our program centered on the synthesis and chemical biology of marine natural products we have achieved a rapid synthesis of synoxazolidinone A (1) and structural analogs. Through these efforts we have revealed new chemical reactions and potent lead structures for infectious disease research. The synthesis and chemical biology of the synoxazolidinones will be presented.}, number={11}, journal={Planta Medica}, publisher={Georg Thieme Verlag KG}, author={Pierce, JG and Shymanska, NV and Edwards, GA}, year={2015}, month={Jun} }
 @article{shymanska_an_guevara-zuluaga_pierce_2015, title={Rapid synthesis and antimicrobial activity of novel 4-oxazolidinone heterocycles}, volume={25}, ISSN={["1464-3405"]}, DOI={10.1016/j.bmcl.2015.06.003}, abstractNote={The synoxazolidinone family of marine natural products bear an unusual 4-oxazolidinone heterocyclic core and promising antimicrobial activity against several strains of pathogenic bacteria. As part of our research program directed at the synthesis and chemical biology of this family of natural products we have developed a one-step method for the generation of variously substituted 4-oxazolidinone scaffolds from readily available materials. These studies revealed the importance of an electron deficient aromatic ring for antimicrobial activity and serve as the basis for future SAR studies around the 4-oxazolidinone core.}, number={21}, journal={BIOORGANIC & MEDICINAL CHEMISTRY LETTERS}, author={Shymanska, Nataliia V. and An, Il Hwan and Guevara-Zuluaga, Sebastian and Pierce, Joshua G.}, year={2015}, month={Nov}, pages={4887–4889} }
 @article{moazami_gulledge_laster_pierce_2015, title={Synthesis and biological evaluation of a series of fatty acid amides from Echinacea}, volume={25}, ISSN={["1464-3405"]}, DOI={10.1016/j.bmcl.2015.06.024}, abstractNote={Alkylamides are lipophilic constituents of Echinacea and possess numerous biological activities. Although significant effort has been focused on the study of crude Echinacea extracts, very little is known regarding the activities of the individual constituents that make up these herbal treatments. Herein we explore the SAR of simple alkylamides found in Echinacea extracts with respect to their ability to decrease the production of the pro-inflammatory mediator TNF-α. Our results have revealed the key structural requirements for activity and provide lead compounds for further investigation of these poorly understood molecules.}, number={16}, journal={BIOORGANIC & MEDICINAL CHEMISTRY LETTERS}, author={Moazami, Yasamin and Gulledge, Travis V. and Laster, Scott M. and Pierce, Joshua G.}, year={2015}, month={Aug}, pages={3091–3094} }
 @article{lemercier_pierce_2015, title={Synthesis of 1,4,2-Oxathiazoles via Oxidative Cyclization of Thiohydroximic Acids}, volume={17}, ISSN={["1523-7052"]}, DOI={10.1021/acs.orglett.5b02256}, abstractNote={An oxidative formation of 1,4,2-oxathiazoles from readily available thiohydroximic acids is reported. A variety of alkyl, aryl, and heteroaryl substituents are well tolerated for both the thiohydroximic acid and activating fragments, and the reaction has been demonstrated on gram-scale. This reaction represents the only method currently available to prepare a diverse set of oxathiazoles and expands the chemistry of C–H oxidation via appended N–OH functional groups. Finally, we also demonstrate the rapid preparation of a 1,4,2-oxathiazole analog of an anticancer lead molecule.}, number={18}, journal={ORGANIC LETTERS}, author={Lemercier, Berenice C. and Pierce, Joshua G.}, year={2015}, month={Sep}, pages={4542–4545} }
 @article{pierce_moazami_2015, title={Synthesis of 2,3-Dihydro-1,3-oxazin-4-ones via a Mild Formal [4+2] Cycloaddition of Acylketenes with Aldimines}, volume={47}, ISSN={0039-7881 1437-210X}, url={http://dx.doi.org/10.1055/S-0034-1378788}, DOI={10.1055/S-0034-1378788}, abstractNote={A mild and efficient silver-mediated synthesis of 2,3-dihydro-1,3-oxazin-4-ones through a formal [4+2] cycloaddition reaction of aldimines and acylketene intermediates is described. A variety of functionalized and potentially biologically relevant heterocycles have been accessed in moderate to high yields through this process.}, number={21}, journal={Synthesis}, publisher={Georg Thieme Verlag KG}, author={Pierce, Joshua and Moazami, Yasamin}, year={2015}, month={Jul}, pages={3363–3370} }
 @article{shi_pierce_2015, title={Synthesis of the 5,6-Dihydroxymorpholin-3-one Fragment of Monanchocidin A}, volume={17}, ISSN={["1523-7052"]}, DOI={10.1021/acs.orglett.5b00069}, abstractNote={Monanchocidin A is a recently isolated pentacyclic guanidinium alkaloid that contains an unusual highly oxidized morpholinone fragment. Herein we report a rapid synthesis of this heterocyclic scaffold and confirm its structure. The key reaction involves an acid promoted hemiketalization/hemiaminalization of an α-hydroxyamide and α-ketoaldehyde that proceeds with exclusive regioselectivity and high diastereoselectivity to form the natural scaffold in moderate to high yield.}, number={4}, journal={ORGANIC LETTERS}, author={Shi, Yunlong and Pierce, Joshua G.}, year={2015}, month={Feb}, pages={968–971} }
 @article{pierce_lemercier_2015, title={Thiohydroximic Acids: Versatile Reagents for Organic Synthesis}, volume={27}, ISSN={0936-5214 1437-2096}, url={http://dx.doi.org/10.1055/S-0035-1560700}, DOI={10.1055/S-0035-1560700}, abstractNote={Thiohydroximic acids are a heteroatom-rich class of compounds that have long been used only as a means to study the biology of their glucosinolate subclass. However, due to their wide range of reactivity and surprising stability, they have recently emerged as versatile reagents for heterocycle synthesis. In this Account we highlight the current and potential uses of thiohydroximic acids as building blocks for synthesis, with a focus on recent developments from our group. Thiohydroximic acids have already proven to be useful reagents for thioimidate <i>N</i>-oxides, thiazoline, and oxathiazole synthesis, and many more applications will likely emerge as we continue to evaluate their properties. 1 Synthesis of Thiohydroximic Acids 2 Synthesis of Cyclic Thioimidate <i>N</i>-Oxides 3 Synthesis of Thiazolines 4 Synthesis of 5<i>H</i>-1,4,2-Oxathiazoles 5 Summary}, number={02}, journal={Synlett}, publisher={Georg Thieme Verlag KG}, author={Pierce, Joshua and Lemercier, Bérénice}, year={2015}, month={Oct}, pages={181–189} }
 @article{shymanska_an_pierce_2014, title={A Rapid Synthesis of 4-Oxazolidinones: Total Synthesis of Synoxazolidinones A and B**}, volume={53}, ISSN={["1521-3773"]}, DOI={10.1002/anie.201402310}, abstractNote={Abstract A five‐step total synthesis of the marine natural product synoxazolidinone A was achieved through a diastereoselective imine acylation/cyclization cascade. Synoxazolidinone B and a series of analogues were also prepared to explore the potential of these 4‐oxazolidinone natural products as antimicrobial agents. These studies confirmed the importance of the chlorine substituent for antimicrobial activity and revealed simplified dichloro derivatives that are equally potent against several bacterial strains.}, number={21}, journal={ANGEWANDTE CHEMIE-INTERNATIONAL EDITION}, author={Shymanska, Nataliia V. and An, Il Hwan and Pierce, Joshua G.}, year={2014}, month={May}, pages={5401–5404} }
 @article{lemercier_pierce_2014, title={Synthesis of Thiazolines by Copper Catalyzed Aminobromination of Thiohydroximic Acids}, volume={16}, ISSN={["1523-7052"]}, DOI={10.1021/ol500588v}, abstractNote={A copper catalyzed aminobromination of alkene tethered thiohydroximic acids is described, providing a rapid approach to unnatural thiazoline scaffolds not readily available via existing methods. Moderate to high yields of bromothiazolines are obtained with alkyl- and aryl-substituted thiohydroximic acid building blocks containing mono-, di-, and trisubstituted alkenes. The reaction provides high levels of 5-exo selectivity, and terminally monosubstituted alkenes result in predominant syn-diastereoselectivity.}, number={7}, journal={ORGANIC LETTERS}, author={Lemercier, Berenice C. and Pierce, Joshua G.}, year={2014}, month={Apr}, pages={2074–2076} }
 @article{lemercier_pierce_2014, title={Synthesis of Thiohydroxamic Acids and Thiohydroximic Acid Derivatives}, volume={79}, ISSN={["0022-3263"]}, DOI={10.1021/jo500080x}, abstractNote={An improved and expanded preparation of thiohydroxamic acids is reported along with a one-pot conversion of these compounds to novel thiohydroximic acid derivatives. A variety of aryl, heteroaryl, and alkyl substituents are well tolerated to provide a rapid approach to alkene-functionalized thiohydroximic acids that serve as potentially useful building blocks for organic synthesis.}, number={5}, journal={JOURNAL OF ORGANIC CHEMISTRY}, author={Lemercier, Berenice C. and Pierce, Joshua G.}, year={2014}, month={Mar}, pages={2321–2330} }
 @article{james_pierce_okano_xie_boger_2012, title={Redesign of Glycopeptide Antibiotics: Back to the Future}, volume={7}, ISSN={1554-8929 1554-8937}, url={http://dx.doi.org/10.1021/cb300007j}, DOI={10.1021/cb300007j}, abstractNote={The glycopeptide antibiotics are the most important class of drugs used in the treatment of resistant bacterial infections including those caused by methicillin-resistant Staphylococcus aureus (MRSA). After more than 50 years of clinical use, the emergence of glycopeptide-resistant Gram-positive pathogens such as vancomycin-resistant enterococci (VRE) and vancomycin-resistant Staphylococcus aureus (VRSA) presents a serious global challenge to public health at a time few new antibiotics are being developed. This has led to renewed interest in the search for additional effective treatments including the development of new derivatives of the glycopeptide antibiotics. General approaches have been explored for modifying glycopeptide antibiotics, typically through the derivatization of the natural products themselves or more recently through chemical total synthesis. In this Perspective, we consider recent efforts to redesign glycopeptide antibiotics for the treatment of resistant microbial infections, including VRE and VRSA, and examine their future potential for providing an even more powerful class of antibiotics that are even less prone to bacterial resistance.}, number={5}, journal={ACS Chemical Biology}, publisher={American Chemical Society (ACS)}, author={James, Robert C. and Pierce, Joshua G. and Okano, Akinori and Xie, Jian and Boger, Dale L.}, year={2012}, month={Feb}, pages={797–804} }
 @article{okano_james_pierce_xie_boger_2012, title={Silver(I)-Promoted Conversion of Thioamides to Amidines: Divergent Synthesis of a Key Series of Vancomycin Aglycon Residue 4 Amidines That Clarify Binding Behavior to Model Ligands}, volume={134}, ISSN={0002-7863 1520-5126}, url={http://dx.doi.org/10.1021/ja302808p}, DOI={10.1021/ja302808p}, abstractNote={Development of a general Ag(I)-promoted reaction for the conversion of thioamides to amidines is disclosed. This reaction was employed to prepare a key series of vancomycin aglycon residue 4 substituted amidines that were used to clarify their interaction with model ligands of peptidoglycan precursors and explore their resulting impact on antimicrobial properties.}, number={21}, journal={Journal of the American Chemical Society}, publisher={American Chemical Society (ACS)}, author={Okano, Akinori and James, Robert C. and Pierce, Joshua G. and Xie, Jian and Boger, Dale L.}, year={2012}, month={May}, pages={8790–8793} }
 @article{miller_mao_rosenker_pierce_wipf_2012, title={Synthesis of a library of tricyclic azepinoisoindolinones}, volume={8}, ISSN={1860-5397}, url={http://dx.doi.org/10.3762/bjoc.8.120}, DOI={10.3762/bjoc.8.120}, abstractNote={Hydrozirconation of 1-hexyne, the addition to in situ prepared N -acyliminium species, and ring-closing metathesis (RCM) were key steps in the preparation of a tricyclic isoindolinone scaffold. An unusual alkene isomerization process during the RCM was identified and studied in some detail. Chemical diversification for library synthesis was achieved by a subsequent alkene epoxidation and zinc-mediated aminolysis reaction. The resulting library products provided selective hits among a large number of high-throughput screens reported in PubChem, thus illustrating the utility of the novel scaffold.}, journal={Beilstein Journal of Organic Chemistry}, publisher={Beilstein Institut}, author={Miller, Bettina and Mao, Shuli and Rosenker, Kara M George and Pierce, Joshua G and Wipf, Peter}, year={2012}, month={Jul}, pages={1091–1097} }
 @article{xie_okano_pierce_james_stamm_crane_boger_2012, title={Total Synthesis of [Ψ[C(═S)NH]Tpg4]Vancomycin Aglycon, [Ψ[C(═NH)NH]Tpg4]Vancomycin Aglycon, and Related Key Compounds: Reengineering Vancomycin for Dual d-Ala-d-Ala and d-Ala-d-Lac Binding}, volume={134}, ISSN={0002-7863 1520-5126}, url={http://dx.doi.org/10.1021/ja209937s}, DOI={10.1021/ja209937s}, abstractNote={The total synthesis of [Ψ[C(═S)NH]Tpg4]vancomycin aglycon (8) and its unique AgOAc-promoted single-step conversion to [Ψ[C(═NH)NH]Tpg4]vancomycin aglycon (7), conducted on a fully deprotected substrate, are disclosed. The synthetic approach not only permits access to 7, but it also allows late-stage access to related residue 4 derivatives, alternative access to [Ψ[CH2NH]Tpg4]vancomycin aglycon (6) from a common late-stage intermediate, and provides authentic residue 4 thioamide and amidine derivatives of the vancomycin aglycon that will facilitate ongoing efforts on their semisynthetic preparation. In addition to early stage residue 4 thioamide introduction, allowing differentiation of one of seven amide bonds central to the vancomycin core structure, the approach relied on two aromatic nucleophilic substitution reactions for formation of the 16-membered diaryl ethers in the CD/DE ring systems, an effective macrolactamization for closure of the 12-membered biaryl AB ring system, and the defined order of CD, AB, and DE ring closures. This order of ring closures follows their increasing ease of thermal atropisomer equilibration, permitting the recycling of any newly generated unnatural atropisomer under progressively milder thermal conditions where the atropoisomer stereochemistry already set is not impacted. Full details of the evaluation of 7 and 8 along with several related key synthetic compounds containing the core residue 4 amidine and thioamide modifications are reported. The binding affinity of compounds containing the residue 4 amidine with the model d-Ala-d-Ala ligand 2 was found to be only 2–3 times less than the vancomycin aglycon (5), and this binding affinity is maintained with the model d-Ala-d-Lac ligand 4, representing a nearly 600-fold increase in affinity relative to the vancomycin aglycon. Importantly, the amidines display effective dual, balanced binding affinity for both ligands (Ka2/4 = 0.9–1.05), and they exhibit potent antimicrobial activity against VanA resistant bacteria (E. faecalis, VanA VRE) at a level accurately reflecting these binding characteristics (MIC = 0.3–0.6 μg/mL), charting a rational approach forward in the development of antibiotics for the treatment of vancomycin-resistant bacterial infections. In sharp contrast, 8 and related residue 4 thioamides failed to bind either 2 or 4 to any appreciable extent, do not exhibit antimicrobial activity, and serve to further underscore the remarkable behavior of the residue 4 amidines.}, number={2}, journal={Journal of the American Chemical Society}, publisher={American Chemical Society (ACS)}, author={Xie, Jian and Okano, Akinori and Pierce, Joshua G. and James, Robert C. and Stamm, Simon and Crane, Christine M. and Boger, Dale L.}, year={2012}, month={Jan}, pages={1284–1297} }
 @article{xie_pierce_james_okano_boger_2011, title={A Redesigned Vancomycin Engineered for Dual d-Ala-d-Ala and d-Ala-d-Lac Binding Exhibits Potent Antimicrobial Activity Against Vancomycin-Resistant Bacteria}, volume={133}, ISSN={0002-7863 1520-5126}, url={http://dx.doi.org/10.1021/ja207142h}, DOI={10.1021/ja207142h}, abstractNote={The emergence of bacteria resistant to vancomycin, often the antibiotic of last resort, poses a major health problem. Vancomycin-resistant bacteria sense a glycopeptide antibiotic challenge and remodel their cell wall precursor peptidoglycan terminus from d-Ala-d-Ala to d-Ala-d-Lac, reducing the binding of vancomycin to its target 1000-fold and accounting for the loss in antimicrobial activity. Here, we report [Ψ[C(═NH)NH]Tpg4]vancomycin aglycon designed to exhibit the dual binding to d-Ala-d-Ala and d-Ala-d-Lac needed to reinstate activity against vancomycin-resistant bacteria. Its binding to a model d-Ala-d-Ala ligand was found to be only 2-fold less than vancomycin aglycon and this affinity was maintained with a model d-Ala-d-Lac ligand, representing a 600-fold increase relative to vancomycin aglycon. Accurately reflecting these binding characteristics, it exhibits potent antimicrobial activity against vancomycin-resistant bacteria (MIC = 0.31 μg/mL, VanA VRE). Thus, a complementary single atom exchange in the vancomycin core structure (O → NH) to counter the single atom exchange in the cell wall precursors of resistant bacteria (NH → O) reinstates potent antimicrobial activity and charts a rational path forward for the development of antibiotics for the treatment of vancomycin-resistant bacterial infections.}, number={35}, journal={Journal of the American Chemical Society}, publisher={American Chemical Society (ACS)}, author={Xie, Jian and Pierce, Joshua G. and James, Robert C. and Okano, Akinori and Boger, Dale L.}, year={2011}, month={Sep}, pages={13946–13949} }
 @article{frantz marie-céline_pierce_pierce_kangying_qingwei_johnson_wipf_2011, title={Large-Scale Asymmetric Synthesis of the Bioprotective Agent JP4-039 and Analogs}, volume={13}, ISSN={1523-7060 1523-7052}, url={http://dx.doi.org/10.1021/ol200567p}, DOI={10.1021/ol200567p}, abstractNote={JP4-039 is a novel nitroxide conjugate capable of crossing lipid bilayer membranes and scavenging reactive oxygen species (ROS). An efficient and scalable one-pot hydrozirconation−transmetalation−imine addition methodology has been developed for its asymmetric preparation. Furthermore, this versatile methodology allows for the synthesis of cyclopropyl and fluorinated analogs of the parent lead structure.}, number={9}, journal={Organic Letters}, publisher={American Chemical Society (ACS)}, author={Frantz Marie-Céline and Pierce, Joshua G. and Pierce, Joan M. and Kangying, Li and Qingwei, Wan and Johnson, Matthew and Wipf, Peter}, year={2011}, month={May}, pages={2318–2321} }
 @article{crane_pierce_leung_tirado-rives_jorgensen_boger_2010, title={Synthesis and Evaluation of Selected Key Methyl Ether Derivatives of Vancomycin Aglycon}, volume={53}, ISSN={0022-2623 1520-4804}, url={http://dx.doi.org/10.1021/jm100946e}, DOI={10.1021/jm100946e}, abstractNote={A select series of methyl ether derivatives of vancomcyin aglycon were prepared and examined for antimicrobial activity against vancomycin-sensitive Staphylococcus aureus and vancomycin-resistant Enterococci faecalis as well as their binding affinity for D-Ala-D-Ala and D-Ala-D-Lac. The intent of the study was to elucidate the role selected key methyl groups may play in the improvement of the in vitro antimicrobial profile of the tetra methyl ether derivative of vancomycin aglycon against vancomycin-resistant Enterococci faecalis previously reported. In these studies, methodology for selective derivatization of the A-, B-, and D-ring was developed that defines the relative reactivity of the four phenols of vancomycin aglycon, providing a foundation for future efforts for site-directed modification of the vancomycin aglycon core.}, number={19}, journal={Journal of Medicinal Chemistry}, publisher={American Chemical Society (ACS)}, author={Crane, Christine M. and Pierce, Joshua G. and Leung, Siegfried S. F. and Tirado-Rives, Julian and Jorgensen, William L. and Boger, Dale L.}, year={2010}, month={Oct}, pages={7229–7235} }
 @article{rajagopalan_gupta_epperly_franicola_zhang_wang_zhao_tyurin_pierce_kagan_et al._2009, title={The Mitochondria-Targeted Nitroxide JP4-039 Augments Potentially Lethal Irradiation Damage Repair}, volume={23}, number={5}, journal={In Vivo}, author={Rajagopalan, M.S. and Gupta, K. and Epperly, M.W. and Franicola, D. and Zhang, Xichen and Wang, Hong and Zhao, Hong and Tyurin, V.A. and Pierce, J.G. and Kagan, V.E. and et al.}, year={2009}, month={Sep}, pages={717–726} }
 @article{pierce_kasi_fushimi_cuzzupe_wipf_2008, title={Synthesis of Hydroxylated Bicyclic Amino Acids from l-Tyrosine: Octahydro-1 H-indole Carboxylates}, volume={73}, ISSN={0022-3263 1520-6904}, url={http://dx.doi.org/10.1021/jo801552j}, DOI={10.1021/jo801552j}, abstractNote={A stereoselective approach to polyhydroxylated L-Choi derivatives has been developed. The oxidative cyclization of L-tyrosine was optimized to avoid partial racemization and to allow a more efficient scale-up.}, number={19}, journal={The Journal of Organic Chemistry}, publisher={American Chemical Society (ACS)}, author={Pierce, Joshua G. and Kasi, Dhanalakshmi and Fushimi, Makoto and Cuzzupe, Anthony and Wipf, Peter}, year={2008}, month={Oct}, pages={7807–7810} }
 @article{epperly_pierce_dixon_franicola_wipf_greenberger_2008, title={The Mitochondrial Targeted GS-Nitroxide JP4-039 is Radioprotective In Vitro and In Vivo}, volume={72}, ISSN={0360-3016}, url={http://dx.doi.org/10.1016/j.ijrobp.2008.06.952}, DOI={10.1016/j.ijrobp.2008.06.952}, abstractNote={Nitroxides are very efficient scavengers of free radicals and have been proposed for use as radioprotective agents. One disadvantage is the need for high concentrations for an in vivo effect. Stabilization of the mitochondria following irradiation has been demonstrated to be important to prevent ionizing irradiation-induced apoptosis. Attaching a hemi-gramicidin linker to nitroxide was evaluated as an approach to getting mitochondrial localization at lower systemic drug concentration. We report here that hemi-gramicidin linked nitroxide efficiently prevents irradiation-induced apoptosis of hematopoietic cells. Irradiation survival curves were performed by incubating 32D cl 3 murine hematopoietic progenitor cells in JP4-039 or non-mitochondrial localized tempol (1 μM) for 1 hr. The cells were then irradiated to doses ranging from 0 to 8 Gy, suspending in methylcellulose-containing media, incubating for 7 days at 37oC, and colonies of greater than 50 cells were scored. The data was analyzed using linear quadratic and single-hit, multi-target models. In vivo survival analysis was performed by injecting intraperitoneally JP4-039 or tempol (1 mg/kg) 10 min before irradiation of female C57BL/6NHsd mice to the LD 75/30 dose of 9.75 Gy. Mice were followed for survival. Those moribund from the hematopoietic syndrome were sacrificed. Incubation of 32D cl 3 cells in JP4-039 for 1 hour prior to irradiation resulted in a significant increase in Do of 2.25 ± 0.11 Gy compared to 1.19 ± 0.13 Gy for 32D cl 3 cells alone or 1.32 ± 0.09 Gy for 32D cl 3 cells incubated in tempol (p = 0.0042 or p = 0.0073, respectively). C57BL/6NHsd female mice injected with 1 mg/kg JP4-039 before irradiation had a significant increase in survival of 80% compared to 20% for control irradiated mice (p = 0.0005) or 60% for tempol treated mice (p = 0.2252). JP4-039, a mitochondrial targeted nitroxide, is an effective radioprotector. Further studies are required to optimize the schedule of drug delivery for potential translation to clinical use.}, number={1}, journal={International Journal of Radiation Oncology*Biology*Physics}, publisher={Elsevier BV}, author={Epperly, M.W. and Pierce, J.G. and Dixon, T. and Franicola, D. and Wipf, P. and Greenberger, J.S.}, year={2008}, month={Sep}, pages={S82} }
 @article{pierce_waller_wipf_2007, title={Synthesis of functionalized isoindolinones: Addition of in situ generated organoalanes to acyliminium ions}, volume={692}, ISSN={0022-328X}, url={http://dx.doi.org/10.1016/j.jorganchem.2007.05.035}, DOI={10.1016/j.jorganchem.2007.05.035}, abstractNote={Addition of in situ generated di- or trisubstituted alkenylalanes to N-acyliminium ions provides rapid access to functionalized isoindolinones. Subsequent ring closing metathesis leads to tricyclic products. These transformations proceed under mild conditions and allow for the convergent synthesis of biologically significant scaffolds from readily available starting materials.}, number={21}, journal={Journal of Organometallic Chemistry}, publisher={Elsevier BV}, author={Pierce, Joshua G. and Waller, David L. and Wipf, Peter}, year={2007}, month={Oct}, pages={4618–4629} }
 @article{wipf_pierce_2006, title={Expedient Synthesis of the α-C-Glycoside Analogue of the Immunostimulant Galactosylceramide (KRN7000)}, volume={8}, ISSN={1523-7060 1523-7052}, url={http://dx.doi.org/10.1021/ol0613057}, DOI={10.1021/ol0613057}, abstractNote={Key reactions in a concise synthesis of an α-C-galactosylceramide analogue of KRN7000 include a diastereoselective alkenylalane addition to an N-tert-butanesulfinyl imine and the use of an epoxidation/carbamate ring opening sequence to install the aminodiol stereotriad.}, number={15}, journal={Organic Letters}, publisher={American Chemical Society (ACS)}, author={Wipf, Peter and Pierce, Joshua G.}, year={2006}, month={Jul}, pages={3375–3378} }
 @article{motoyama_itonaga_ishida_takasaki_nagazhima_2005, title={Catalytic Reduction of Amides to Amines with Hydrosilanes Using a Triruthenium Carbonyl Cluster as the Catalyst​}, volume={82}, ISSN={0078-6209 2333-3553}, url={http://dx.doi.org/10.15227/orgsyn.082.0188}, DOI={10.15227/orgsyn.082.0188}, journal={Organic Syntheses}, publisher={Organic Syntheses}, author={Motoyama, Y. and Itonaga, C. and Ishida, T. and Takasaki, M. and Nagazhima, H.}, editor={Wipf, P. and Pierce, J.G.Editors}, year={2005}, pages={188} }
 @article{marshall_chobanian_2005, title={Lipase-Catalyzed Resolution of 4-Trimethylsilyl-3-Butyn-2-ol and Conversion of the (R)-Enantiomer to (R)-3-Butyn-2-yl Mesylate and (P)-1-Tributylstannyl-1,2-Butadiene}, volume={4}, ISBN={0471264229 9780471264224}, url={http://dx.doi.org/10.1002/0471264229.os082.07}, DOI={10.1002/0471264229.os082.07}, abstractNote={Abstract (R)‐4‐Trimethylsilyl‐3‐butyn‐2‐yl acetate (S)‐4‐Trimethylsilyl‐3‐butyn‐2‐yl succinate 4‐Trimethylsilyl‐3‐butyn‐2‐ol (R)‐4‐Trimethylsilyl‐3‐butyn‐2‐yl mesylate Vinyl acetate Diisobutylaluminum hydride Butyllithium Cuprous bromide‐dimethylsulfide complex ( P )‐1‐Tributylstannyl‐1, 2‐butadiene}, journal={Organic Syntheses}, publisher={John Wiley & Sons, Inc.}, author={Marshall, James A. and Chobanian, Harry}, year={2005}, month={Apr}, pages={43–55} }
 @article{wipf_pierce_zhuang_2005, title={Silver(I)-Catalyzed Addition of Zirconocenes to Glycal Epoxides. A New Synthesis of α-C-Glycosides}, volume={7}, ISSN={1523-7060 1523-7052}, url={http://dx.doi.org/10.1021/ol0475414}, DOI={10.1021/ol0475414}, abstractNote={Hydrozirconation of terminal alkynes, followed by AgClO4-catalyzed in situ addition of the resultant alkenylzirconocenes to 1,2-anhydrosugars (glycal epoxides) leads to α-C-glycosides in moderate to high yields.}, number={3}, journal={Organic Letters}, publisher={American Chemical Society (ACS)}, author={Wipf, Peter and Pierce, Joshua G. and Zhuang, Nian}, year={2005}, month={Feb}, pages={483–485} }
 @article{wipf_pierce_2005, title={Synthesis of Homoallylic Amines by Hydrozirconation−Imine Addition of Allenes}, volume={7}, ISSN={1523-7060 1523-7052}, url={http://dx.doi.org/10.1021/ol051266j}, DOI={10.1021/ol051266j}, abstractNote={Hydrozirconation of allenes followed by in situ transmetalation to dialkylzinc leads to the formation of an allylic zinc species that, upon addition of aldimines to the reaction mixture, provides homoallylic amines in 64−85% yield.}, number={16}, journal={Organic Letters}, publisher={American Chemical Society (ACS)}, author={Wipf, Peter and Pierce, Joshua G.}, year={2005}, month={Aug}, pages={3537–3540} }
 @article{wipf_pierce_wang_2003, title={Investigation of ligand loading and asymmetric amplification in CHAOx-catalyzed asymmetric diethylzinc additions}, volume={14}, ISSN={0957-4166}, url={http://dx.doi.org/10.1016/j.tetasy.2003.07.022}, DOI={10.1016/j.tetasy.2003.07.022}, abstractNote={The recently developed (cyclohexylsulfonylamino)oxazoline (CHAOx) ligand was found to provide high ee's and consistent reaction rates in the asymmetric diethylzinc addition to benzaldehyde over a remarkably large loading range of 0.05–10 mol%. Turnover numbers of 1000–2000 can be explained by the absence of a nonlinear effect and the formation of a catalytically active monomer complex. Substituents at the nitrogen donor atoms of the bidentate ligand prevent zinc-complex dimerization.}, number={22}, journal={Tetrahedron: Asymmetry}, publisher={Elsevier BV}, author={Wipf, Peter and Pierce, Joshua G. and Wang, Xiaodong}, year={2003}, month={Nov}, pages={3605–3611} }