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 I 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.