Chemical synthesis and biological evaluation of cis- and trans-12,13-cyclopropyl and 12,13-cyclobutyl epothilones and related pyridine side chain analogues

Citation
Kc. Nicolaou et al., Chemical synthesis and biological evaluation of cis- and trans-12,13-cyclopropyl and 12,13-cyclobutyl epothilones and related pyridine side chain analogues, J AM CHEM S, 123(38), 2001, pp. 9313-9323
Citations number
47
Categorie Soggetti
Chemistry & Analysis",Chemistry
Journal title
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
ISSN journal
00027863 → ACNP
Volume
123
Issue
38
Year of publication
2001
Pages
9313 - 9323
Database
ISI
SICI code
0002-7863(20010926)123:38<9313:CSABEO>2.0.ZU;2-O
Abstract
The design, chemical synthesis, and biological evaluation of series of cycl opropyl and cyclobutyl epothilone analogues (3-12, Figure 1) are described. The synthetic strategies toward these epothilones involved a Nozaki-Hiyama -Kishi coupling to form the C15-C16 carbon-carbon bond, an aldol reaction t o construct the C6-C7 carbon-carbon bond, and a Yamaguchi macrolactonizatio n to complete the required skeletal framework. Biological studies with the synthesized compounds led to the identification of epothilone analogues 3, 4, 7, 8, 9, and 11 as potent tubulin polymerization promoters and cytotoxic agents with (12R,13S,15S)-cyclopropyl 5-methylpyridine epothilone A (11) a s the most powerful compound whose potencies (e.g. IC50 = 0.6 nM against th e 1A9 ovarian carcinoma cell line) approach those of epothilone B. These in vestigations led to a number of important structure-activity relationships, including the conclusion that neither the epoxide nor the stereochemistry at C12 are essential, while the stereochemistry at both C13 and C15 are cru cial for biological activity. These studies also confirmed the importance o f both the cyclopropyl and 5-methylpyridine moieties in conferring potent a nd potentially clinically useful biological properties to the epothilone sc affold.