Synthesis, Conformational Analysis, and Evaluation of the Multidrug Resistance-Reversing Activity of the Triamide and Proline Analogs of Hapalosin

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.

Marine Natural Products as Models to Circumvent Multidrug Resistance

“…Substitution at C-12 in 80 furnished analogs 84-88, which exhibited higher vincristine accumulation than verapamil and 80 in MDR 2780AD cells at 10 μM [183]. It was postulated that the cis-peptide might be essential to express the MDR-reversing activity, and the bioactive function of 80 and analogs depends on the S-cis or S-trans configuration [182,184]. Also, a free hydroxyl and aromatic groups may be important for the anti-MDR activity of hapalosin (80) At 20 µM concentration, compound 80 significantly enhanced the accumulation of [ 3 H]-paclitaxel in SKVLB1 cells, and exhibited a similar activity to verapamil in breast cancer cell MCF-7/ADR in the range of 1.5-10 µM [180,181].…”

Marine Metabolites Overcoming or Circumventing Multidrug Resistance Mediated by ATP-Dependent Transporters: A New Hope for Patient with Tumors Resistant to Conventional Chemotherapy

“…Accordingly, several syntheses of the natural product and its analogues have been proposed, leading to interesting SAR informations. Since replacing the N-Me-L-phenylalanine by proline favors the synthesis of the s-cis rotamer, several proline analogues and one triamide analogue of hapalosin have been synthesized [80][81][82]. This important point has further been confirmed by new studies done on the synthetic analogues 34-36 which possess the cis-conformation [80].…”

Enantioselective Hydroazidation of Trisubstituted Non‐Activated Alkenes

“…Running the azidation process at lower temperatures hardly improved the diastereoselectivity . However, 1‐phenyl‐1‐cyclohexene ( 1 e ) as well as a series of cyclopentene derivatives ( 1 f – 1 m ) provided satisfactory to high trans selectivities (Scheme ; 3 e – 3 m ) . The acyclic alkene 1 n afforded azide 3 n in 89:11 e.r.…”