Zp. Xia et Cd. Smith, Total synthesis of dendroamide A, a novel cyclic peptide that reverses multiple drug resistance, J ORG CHEM, 66(10), 2001, pp. 3459-3466
Dendroamide A (1) was isolated from a blue-green alga on the basis of its a
bility 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-contain
ing cyclic peptide have been developed, and the total synthesis of I has be
en completed. Highlights of the synthetic strategy are as follows: (1) a di
cyclohexylcarbodiimide coupling of D-Ala and L-Thr, followed by reaction wi
th Burgess reagent and DBU;assisted oxidation to form D-Ala-oxazole; (2) fo
rmation of D-Val-thiazole and D-Ala-thiazole via modified Hantzsch reaction
s; and (3) use of molecular modeling to select the preferred precursor for
the final cyclization of the peptide analogue. Synthetic 1 demonstrated spe
ctral properties identical to those of the natural product and reversed P-g
lycoprotein-mediated drug resistance more effectively than MRP1-mediated re
sistance. Certain. of the synthetic precursors had biological activity, ind
icating that cell permeability and peptide cyclization are necessary for op
timal activity. Thus; the-structure and the biological activities of the na
tural product are confirmed, and methods for the synthesis of analogues for
further structure-activity explorations are defined.