Divergent synthesis and antitumour activity of novel conformationally constrained (−)-muricatacin analogues

Abstract

Four novel conformationally restricted (?)-muricatacin analogues bearing a methoxy group at the C-5 position, with an alkoxymethyl group ?s the C-7 side chain, have been synthesised and their in vitro antiproliferative activity was evaluated against a panel of seven human tumour cell lines, as well as a single normal cell line. All analogues (9-12) showed diverse antiproliferative effects against all tested human malignant cell lines, but were devoid of any significant cytotoxicity towards the normal foetal lung fibroblasts (MRC-5). A SAR study reveals that the introduction of THF ring, exchange of C-8 methylene group in the side chain of muricatacin analogues with the O-8 ether functionality, as well as the length of side chain may be beneficial for the antiproliferative effects of these lactones. All novel analogues were more potent than lead compound, (?)-muricatacin, against HL-60 cell line.