Novel Syntheses of Cis and Trans Isomers of Combretastatin A-4

Abstract

A high-yielding, two-step stereoselective synthesis of the anticancer drug (Z)-combretastatin A-4 (1) has been devised. The method uses the Perkin condensation of 3,4,5-trimethoxyphenylacetic acid and 3-hydroxy-4-methoxybenzaldehyde followed by decarboxylation of the cinnamic acid intermediate using copper and quinoline. The iodine-catalyzed isomerization of the Z isomer 1 results in complete conversion to the E isomer. The Suzuki cross-coupling of an aryl boronic acid and vinyl bromide has also been successfully employed to produce both Z and E isomers of combretastatin A-4 stereoselectively. Both methods are far superior to the current five-step Wittig synthesis in which both isomers are produced nonstereoselectively.

In Vitro Metabolism Study of Combretastatin A-4 in Rat and Human Liver Microsomes

“…Compound 17 was easily obtained by deprotection of 16 (see Scheme 3 in Supplemental Data). The E isomer 19 was prepared starting from 16 by using I 2 -induced isomerization (Gaukroger et al, 2001) and deprotection with TBAF. The synthesis of the putative metabolites 23 required the preparation of aldehyde intermediate 21, which was subsequently reacted with phosphonium salt 6 to give 22 as a Z/E mixture, which could not be separated by column chromatography (see Scheme 4 in Supplemental Data).…”

“…Melting points were determined in an open glass capillary with an SMP3 apparatus (Stuart Scientific, Stone, Staffordshire, UK), and values are uncorrected. The following compounds were prepared according to literature procedures: CA-4 1 and (E)-combretastatin A-4 (Gaukroger et al, 2001); 3,4,5-trimethoxybenzyltriphenylphosphonium bromide 6 (Kong et al, 2005); 2,3-dihydroxy-4-methoxy-benzaldehyde 20 (Kaisalo et al, 1986); and 3,5-dihydroxy-4-methoxy-benzoic acid methyl ester 12 (Cardona et al, 1986).…”

Synthesis of combretastatin A-4 O-alkyl derivatives and evaluation of their cytotoxic, antiangiogenic and antitelomerase activity

“…27 Conversion into O-alkyl derivatives 2a-2n was performed as depicted in Scheme 1 using bromides 3a-3n (Scheme 2) as the alkylating reagents. Yields are given in the experimental part.…”

Design and synthesis of pironetin analogue/combretastatin A-4 hybrids containing a 1,2,3-triazole ring and evaluation of their cytotoxic activity

“…Combretastatin A-4 (13) was prepared according to a literature procedure [24]. Its O-alkyl derivatives 9e12 were prepared as depicted in Scheme 1 by means of alkylation with u-haloalkynes 16e19 (for experimental details, see the Supporting Information).…”