SYNTHESIS, CONFORMATIONAL-ANALYSIS, AND EVALUATION OF THE MULTIDRUG RESISTANCE-REVERSING ACTIVITY OF THE TRIAMIDE AND PROLINE ANALOGS OF HAPALOSIN

Four analogs were synthesized which have trans-4-hydroxyl-L-proline re placing the N-Me-L-phenylalanine moiety in hapalosin. The triamide ana log of hapalosin containing two secondary amide bonds in lieu of the t wo ester bonds in hapalosin was also synthesized. Conformations of hap alosin, the triamide analog, and two of the four proline analogs in ch loroform were calculated utilizing distance constraints between NOESY- correlated protons. The lowest-energy, distance-constrained conformati on of hapalosin is similar to that of the triamide analog and does not differ substantially from that of the two proline analogs. All confor mations have an s-cis tertiary amide bond. The analogs' ability to rev erse P-glycoprotein-mediated multidrug resistance was evaluated in cyt otoxicity and drug accumulation assays using MCF-7/ADR cells which ove rexpress P-glycoprotein. Two of the proline analogs are more potent th an hapalosin (which has a similar activity as verapamil) whereas the o ther two proline analogs and the triamide analog are less active than hapalosin.