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Total Synthesis and Biological Evaluation of a Series of Macrocyclic Hybrids and Analogues of the Antimitotic Natural Products Dictyostatin, Discodermolide, and Taxol
Author(s) -
Paterson Ian,
Naylor Guy J.,
Gardner Nicola M.,
Guzmán Esther,
Wright Amy E.
Publication year - 2011
Publication title -
chemistry – an asian journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.18
H-Index - 106
eISSN - 1861-471X
pISSN - 1861-4728
DOI - 10.1002/asia.201000541
Subject(s) - polyketide , chemistry , antimitotic agent , stereochemistry , epothilone , hybrid , biological activity , total synthesis , cancer cell lines , combinatorial chemistry , computational biology , tubulin , biochemistry , cancer cell , biology , cancer , microtubule , in vitro , biosynthesis , botany , gene , genetics , microbiology and biotechnology
The design, synthesis, and biological evaluation of a series of hybrids and analogues of the microtubule‐stabilizing 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 endeavors 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. Biological assays of the anti‐proliferative activity of these compounds in a series of human cancer cell lines, including the taxol‐resistant NCI/ADR‐Res cell line, 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 with a similar biological profile to dictyostatin.