@article{shan_zheng_ballard_wang_borchardt_wang_2000, title={A facilitated cyclic ether formation and its potential application in solid-phase peptide and organic synthesis}, volume={48}, number={2}, journal={Chemical & Pharmaceutical Bulletin}, author={Shan, D. X. and Zheng, A. L. and Ballard, C. E. and Wang, W. and Borchardt, R. T. and Wang, B. H.}, year={2000}, pages={238–244} }
 @article{zheng_shan_wang_1999, title={A redox-sensitive resin linker for the solid phase synthesis of C-terminal modified peptides}, volume={64}, ISSN={["0022-3263"]}, DOI={10.1021/jo981528d}, abstractNote={With the rapid development of combinatorial chemistry using solid phase synthesis, there is a great deal of interest in developing new solid phase linkers, which are stable during the solid phase synthesis process and yet readily cleavable under mild conditions. By taking advantage of a "trimethyl lock"-facilitated lactonization reaction, we have developed a redox-sensitive resin linker for the synthesis of C-terminal-modified peptides. The cleavage only requires mild reducing agents such as sodium hydrosulfite, which is not expected to cause any problem with the commonly seen organic functional groups. Using this new linker, three short peptides were synthesized with high isolated yields (70-90%). Such a linker could potentially be used for the synthesis of modified peptide libraries, which allows for the ready cleavage of the linker under mild conditions.}, number={1}, journal={JOURNAL OF ORGANIC CHEMISTRY}, author={Zheng, A and Shan, D and Wang, B}, year={1999}, month={Jan}, pages={156–161} }
 @article{gudmundsson_pauletti_wang_shan_zhang_wang_borchardt_1999, title={Coumarinic acid-based cyclic prodrugs of opioid peptides that exhibit metabolic stability to peptidases and excellent cellular permeability}, volume={16}, ISSN={["0724-8741"]}, DOI={10.1023/A:1018828207920}, abstractNote={{"Label"=>"UNLABELLED"} To evaluate the cellular permeation characteristics and the chemical and enzymatic stability of coumarinic acid-based cyclic prodrugs 1 and 2 of the opioid peptides [Leu5]-enkephalin (H-Tyr-Gly-Gly-Phe-Leu-OH) and DADLE (H-Tyr-D-Ala-Gly-Phe-D-Leu-OH), respectively. {"Label"=>"METHODS", "NlmCategory"=>"METHODS"} The rates of conversion of the cyclic prodrugs 1 and 2 to [Leu5]-enkephalin and DADLE, respectively, in HBSS, pH 7.4 (Caco-2 cell transport buffer) and in various biological media having measurable esterase activity were determined by HPLC. The cell permeation characteristics of [Leu5]-enkephalin, DADLE and cyclic prodrugs 1 and 2 were measured using Caco-2 cell monolayers grown onto microporus membranes and monitored by HPLC. {"Label"=>"RESULTS", "NlmCategory"=>"RESULTS"} In HBSS, pH 7.4, cyclic prodrugs 1 and 2 degraded chemically to intermediates that further degraded to [Leu5]-enkephalin and DADLE, respectively, in stoichiometric amounts. In 90% human plasma and rat liver homogenate, the disappearance of cyclic prodrugs 1 and 2 was significantly faster than in HBSS, pH 7.4. The half-lives in 90% human plasma and in rat liver homogenate were substantially longer after pretreatment with paraoxon, a known inhibitor of serine-dependent esterases. When applied to the AP side of a Caco-2 cell monolayer, cyclic prodrug 1 exhibited significantly greater stability against peptidase metabolism than did [Leu5]-enkephalin. Cyclic prodrug 2 and DADLE exhibited similar stability when applied to the AP side of the Caco-2 cell monolayer. Prodrug 1 was 665-fold more able to permeate the Caco-2 cell monolayers than was [Leu5]-enkephalin, in part because of its increased enzymatic stability. Prodrug 2 was shown to be approximately 31 fold more able to permeate a Caco-2 cell monolayer than was DADLE. {"Label"=>"CONCLUSIONS", "NlmCategory"=>"CONCLUSIONS"} Cyclic prodrugs 1 and 2, prepared with the coumarinic acid promoiety, were substantially more able to permeate Caco-2 cell monolayers than were the corresponding opioid peptides. Prodrug 1 exhibited increased stability to peptidase metabolism compared to [Leu5]-enkephalin. In various biological media, the opioid peptides were released from the prodrugs by an esterase-catalyzed reaction, which is sensitive to paraoxon inhibition.}, number={1}, journal={PHARMACEUTICAL RESEARCH}, author={Gudmundsson, OS and Pauletti, GM and Wang, W and Shan, DX and Zhang, HJ and Wang, BH and Borchardt, RT}, year={1999}, month={Jan}, pages={7–15} }
 @article{wang_nimkar_wang_zhang_shan_gudmundsson_gangwar_siahaan_borchardt_1999, title={Synthesis and evaluation of the physicochemical properties of esterase-sensitive cyclic prodrugs of opioid peptides using coumarinic acid and phenylpropionic acid linkers}, volume={53}, ISSN={["1397-002X"]}, DOI={10.1034/j.1399-3011.1999.00071.x}, abstractNote={Abstract: In an attempt to improve the membrane permeabilities of opioid peptides, we have synthesized cyclic prodrugs of [Leu5]‐enkephalin and DADLE using a coumarinic acid or a phenylpropionic acid linker. The synthesis of the coumarinic acid‐ and phenylpropionic acid‐based cyclic prodrugs followed similar strategies. Key intermediates were the compounds with the C‐terminal amino acids of opioid peptides (L‐Leu, [Leu5]‐enkephalin; D‐Leu, DADLE) attached to the phenol hydroxyl group and the remaining amino acids of the peptide linked via the N‐terminal amino acid (L‐Tyr) attached to the carboxylic acid groups of the prodrug moieties (coumarinic acid or propionic acid). Cyclization of these linear precursors gave the cyclic prodrugs in 30–50% yields. These cyclic prodrugs exhibited excellent transcellular permeation characteristics across Caco‐2 cell monolayers, an in vitro model of the intestinal mucosa. To correlate the cellular permeabilities of these cyclic prodrugs with their physicochemical properties, we calculated their Stokes–Einstein molecular radii from their diffusion coefficients which were determined by NMR and we determined their membrane interaction potentials using immobilized artificial membrane (IAM) column chromatography. The cyclic prodrugs exhibited molecular radii similar to those of the parent compounds, [Leu5]‐enkephalin and DADLE. However, these cyclic prodrugs were shown to have much higher membrane interaction potentials than their corresponding opioid peptides. Therefore, the enhanced cellular permeation of the cyclic prodrugs is apparently due to the alteration of their lipophilicity and hydrogen bonding potential, but not their molecular sizes.}, number={4}, journal={JOURNAL OF PEPTIDE RESEARCH}, author={Wang, B and Nimkar, K and Wang, W and Zhang, H and Shan, D and Gudmundsson, O and Gangwar, S and Siahaan, T and Borchardt, RT}, year={1999}, month={Apr}, pages={370–382} }
 @misc{shan_nicolaou_borchardt_wang_1997, title={Prodrug strategies based on intramolecular cyclization reactions}, volume={86}, ISSN={["0022-3549"]}, DOI={10.1021/js970069d}, abstractNote={Several new prodrug systems for amines, alcohols, and peptides are reviewed. The design of these new prodrug systems takes advantage of several facile intramolecular cyclization reactions, that permit separate manipulation of the release kinetics independent of the structural features of the drug moiety. Such systems can be used for the preparation of esterase-, phosphatase-, and redox-sensitive prodrugs of amines and alcohols and esterase-sensitive cyclic prodrugs of peptides and peptide mimetics.}, number={7}, journal={JOURNAL OF PHARMACEUTICAL SCIENCES}, author={Shan, DX and Nicolaou, MG and Borchardt, RT and Wang, BH}, year={1997}, month={Jul}, pages={765–767} }