Total synthesis of dendroamide A, a novel cyclic peptide that reverses multiple drug resistance.
Dendroamide A (1) was isolated from a blue-green alga on the basis of its ability to reverse drug resistance in tumor cells that overexpress either of the transport proteins, P-glycoprotein or MRP1. Because of this activity, methods for the synthesis of analogues of this oxazole- and thiazole-containing cyclic peptide have been developed, and the total synthesis of 1 has been completed. Highlights of the synthetic strategy are as follows: (1) a dicyclohexylcarbodiimide coupling of D-Ala and L-Thr, followed by reaction with Burgess reagent and DBU-assisted oxidation to form D-Ala-oxazole; (2) formation of D-Val-thiazole and D-Ala-thiazole via modified Hantzsch reactions; and (3) use of molecular modeling to select the preferred precursor for the final cyclization of the peptide analogue. Synthetic 1 demonstrated spectral properties identical to those of the natural product and reversed P-glycoprotein-mediated drug resistance more effectively than MRP1-mediated resistance. Certain of the synthetic precursors had biological activity, indicating that cell permeability and peptide cyclization are necessary for optimal activity. Thus, the structure and the biological activities of the natural product are confirmed, and methods for the synthesis of analogues for further structure-activity explorations are defined.
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Department of Pharmacology, Pennsylvania State University, Hershey, PA 17033, USA.
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D000970:Antineoplastic Agents / Q000138:chemical synthesis*; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D018432:Drug Resistance, Multiple; D006801:Humans; D019906:Nuclear Magnetic Resonance, Biomolecular; D010456:Peptides, Cyclic / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011355:Prodrugs; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured / Q000187:drug effects
D000970:Antineoplastic Agents; D010456:Peptides, Cyclic; D011355:Prodrugs; C100903:dendroamide A