학술논문
Novel Cryptophycin Antitumor Agents: Synthesis and Cytotoxicity of Fragment B Analogues
Document Type
Article
Source
Journal of Medicinal Chemistry; July 15, 1999, Vol. 42 Issue: 14 p2588-2603, 16p
Subject
Language
ISSN
00222623; 15204804
Abstract
A general synthetic approach to novel cryptophycin analogues 6 is described. N-Hydroxysuccinimide active ester 15 , a key common intermediate, was converted to β-epoxide 6 in three steps, via initial coupling with unprotected amino acid 9 , followed by deprotection/macrolactamization of acyclic precursor 16 , and final oxidation of styrene 7 to install the C7−C8 β-epoxide. Cryptophycin styrenes 7 and β-epoxides 6 , bearing diverse side chains in fragment B, were evaluated for cytotoxic activity. β-Epoxides 6 , in general, were significantly more potent than the corresponding α-epoxides 17 and styrenes 7 . A benzyl side chain was required for potent activity, with β-epoxide 6u , possessing a 3-Cl,4-(dimethylamino)benzyl moiety, as the most potent cytotoxic agent prepared, with an IC50 = 54 pM, only 2-fold less than that of Cryptophycin-52 (3 ).