Synthesis and Biological Activity of Fluorinated Combretastatin Analogues

Abstract

With the aim of understanding the influence of fluorine on the double bond of the cis-stilbene moiety of combretastatin derivatives and encouraged by a preliminary molecular modeling study showing a different biological environment on the interaction site with tubulin, we prepared, through various synthetic approaches, a small library of compounds in which one or both of the olefinic hydrogens were replaced with fluorine. X-ray analysis on the difluoro-CA-4 analogue demonstrated that the spatial arrangement of the molecule was not modified, compared to its nonfluorinated counterpart. SAR analysis confirmed the importance of the cis-stereochemistry of the stilbene scaffold. Nevertheless, some unpredicted results were observed on a few trans-fluorinated derivatives. The position of a fluorine atom on the double bond may affect the inhibition of tubulin polymerization and cytotoxic activity of these compounds.

The Vascular Targeting Agent Combretastatin-A4 and a Novelcis-Restricted β-Lactam Analogue, CA-432, Induce Apoptosis in Human Chronic Myeloid Leukemia Cells and Ex Vivo Patient Samples Including Those Displaying Multidrug Resistance

“…A review by Hsieh et al, (2005) collates this vast array of chemistry focusing on the stabilization of the two aryl rings of CA-4 using one to three atom bridgeheads. CA-4 analogs identified to date include: fluorinated (Alloatti et al, 2008), macrocyclic (Mateo et al, 2007), naphthalene , and imidazolebased (Bellina et al, 2006) analogs. Our group recently designed a novel series of synthetic analogs of CA-4 based on the ␤-lactam scaffold structure.…”

Synthesis and biological evaluation of 3′,4′,5′-trimethoxychalcone analogues as inhibitors of nitric oxide production and tumor cell proliferation

“…1), a natural cis-stilbene product has received major attention owing to its strong inhibition of tubulin polymerization and selective targeting of tumor vascular systems (cancer vascular disrupting), which cuts off the tumor blood flow, leading to hemorrhagic necrosis as well as cancer antiangiogenesis. 12 A reported critical structural requirement for the activity of these compounds is the cis-configuration of the double bond and the 3,4,5-trimethoxyphenyl ring (ring A). 13 Taking into account of these reports, and an attempt to discover a potent compound that suppresses both the inflammation and cancer was an attractive idea.…”

Synthesis and biological activity of pyrrole analogues of combretastatin A-4

“…[1][2][3][4][5][6][7][8][9][10][11][12][13] Combretastatin A-4 binds to the colchicine (1) domain of tubulin and inhibits microtubule polymerisation, resulting in destabilisation of the microtubule cytoskeleton and inhibition of mitosis. The structural simplicity and potent cytotoxicity of CA-4 has led to the development of analogues of CA-4 as new anticancer agents (Fig.…”

“…The 3,4,5-trimethoxy group on ring A affects cytotoxic activity and 3-hydroxy-4-methoxy groups on ring B affects binding to tubulin. 1,4,5,8,13 In terms of the spatial relationship, the cis-orientation of the two rings of CA-4 is required for binding in the colchicine-binding site of tubulin. Nevertheless, it is notable that the cis-olefin in CA-4 can convert into the thermodynamically more stable, and inactive, trans-olefin due to its metabolic instability.…”

“…This cis-trans isomerisation results in a loss of antimitotic activity and cytotoxicity. 1,2,5,7,9,14 The low water-solubility of CA-4 results in its low efficacy in vivo and therefore the water-soluble sodium phosphate prodrug of CA-4, fosbretabulin (CA-4P), was designed and is currently in phase II/III clinical trials. [5][6][7][8][9][10][11] Efforts to remove the possibility of cis-trans isomerisation have been attempted by replacing the cis-olefin with a five-membered heterocycle which result in a cis-like constrained configuration.…”