Synthesis, conformational analysis, and evaluation of the multidrug resistance-reversing activity of the triamide and proline analogs of hapalosin

Tam Q. Dinh, Xiaohui Du, Charles D. Smith, Robert W. Armstrong

Research output: Contribution to journalArticle

42 Scopus citations

Abstract

Four analogs were synthesized which have trans-4-hydroxyl-L-proline replacing the N-Me-L-phenylalanine moiety in hapalosin. The triamide analog of hapalosin containing two secondary amide bonds in lieu of the two ester bonds in hapalosin was also synthesized. Conformations of hapalosin, the triamide analog, and two of the four proline analogs in chloroform were calculated utilizing distance constraints between NOESY-correlated protons. The lowest-energy, distance-constrained conformation of hapalosin is similar to that of the triamide analog and does not differ substantially from that of the two proline analogs. All conformations have an s-cis tertiary amide bond. The analogs ability to reverse P-glycoprotein-mediated multidrug resistance was evaluated in cytotoxicity and drug accumulation assays using MCF-7/ADR cells which overexpress P-glycoprotein. Two of the proline analogs are more potent than hapalosin (which has a similar activity as verapamil) whereas the other two proline analogs and the triamide analog are less active than hapalosin.

Original languageEnglish (US)
Pages (from-to)6773-6783
Number of pages11
JournalJournal of Organic Chemistry
Volume62
Issue number20
DOIs
StatePublished - Jan 1 1997

All Science Journal Classification (ASJC) codes

  • Organic Chemistry

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