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Synthesis and antitumor activity of benzils related to combretastatin A-4.

Bioorganic & medicinal chemistry letters (2008-05-15)
Céline Mousset, Anne Giraud, Olivier Provot, Abdallah Hamze, Jérôme Bignon, Jian-Miao Liu, Sylviane Thoret, Joëlle Dubois, Jean-Daniel Brion, Mouâd Alami
ABSTRACT

A series of benzil derivatives related to combretastatin A-4 (CA-4) have been synthesized by oxidation of diarylalkynes promoted by PdI(2) in DMSO. Using this new protocol, 14 benzils were prepared in good to excellent yields and their biological activity has been delineated. Several benzils exhibited excellent antiproliferative activity: for example, 4j and 4k bearing the greatest resemblance to CA-4 and AVE-8062, respectively, were found to inhibit cell growth at the nanomolar level (20-50nM) on four human tumor cell lines. Flow cytometric analysis indicates that these compounds act as antimitotics and arrest the cell cycle in G(2)/M phase. A cell-based assay indicated that compounds 4j and 4k displayed a similar inhibition of tubulin assembly with an IC(50) value similar to CA-4. These results clearly demonstrated that the Z-double bond of CA-4 can be replaced by a 1,2-diketone unit without significant loss of cytotoxicity and inhibition of tubulin assembly potency.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Benzil, 98%

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