Total Synthesis and Biological Evaluation of a Series of Macrocyclic Hybrids and Analogues of the Antimitotic Natural Products Dictyostatin Discodermolide and Taxol

摘要

The design, synthesis and biological evaluation of a series of hybrids and analogues of the microtubule-stabilising anticancer agents dictyostatin, discodermolide and taxol is described. A 22-membered macrolide scaffold was prepared by adapting earlier synthetic routes directed towards dictyostatin and discodermolide, taking advantage of the distinctive structural and stereochemical similarities between these two polyketide-derived marine natural products. Initial endeavours towards accessing novel discodermolide/dictyostatin hybrids led to the adoption of a late-stage diversification strategy and the construction of a small library of methyl ether derivatives, along with the first triple hybrids bearing the side chain of taxol or taxotere attached through an ester linkage. Following biological assays of the antiproliferative activity of these compounds in a series of human cancer cell lines, including the taxol-resistant NCI/ADR-Res cell line, the results allowed the proposal of various structure-activity relationships. This led to the identification of a potent macrocyclic discodermolide/dictyostatin hybrid >12 and its C9 methoxy derivative >38, accessible by an efficient total synthesis and having a similar biological profile to dictyostatin.