On the Synthesis and Anticancer Testing of α,β-Unsaturated Ketones as Analogs of Combretastatin-A4

Title: On the Synthesis and Anticancer Testing of α,β-Unsaturated Ketones as Analogs of Combretastatin-A4

Volume: 6 Issue: 7

Author(s): Sameer Chavda, Ryan Davis, Amanda Ferguson, Camille Riddering, Kristin Dittenhafer, Hilary Mackay, Balaji Babu, Moses Lee, Adam Siegfried, William Pennington, Miriam Shadfan, Susan L. Mooberry, Bijay K. Mishra and Hari N. Pati

Affiliation:

Keywords: Combretastatin, Cytotoxicity, Tubulin, Microtubule, Cancer

Abstract: Twenty-one α,β-unsaturated ketone analogs of combretastatin-A4 (CA-4) that were designed for good solubility in aqueous media were synthesized. Compounds defined as Type A were derived from phenylacetone, in which subclass I contained ortho-, meta- or no substituents, sub-class II contained para-substituents, and sub-class III consisted of two substituents. Type B compounds were derived from cyclopropyl 2-fluorobenzyl ketone. The cis-configuration of the target compounds was ascertained through a single crystal X-ray crystallographic analysis of the fluorine-containing compound 8f. Five of the analogs, 8c, 8j and 8l of Type A and 9d and 9i of Type B, were shown to display modest cytotoxic potency (IC50 in the 3.8 – 21 μM range) against the growth of murine melanoma (B16) and leukemia (L1210) cells in culture. Compounds 8j, 8l and 9i were further tested against MDA-MB-435 human melanoma cells. The cyclopropanecontaining compound 9i was the most potent; with an IC50 value of 2.4 μM. Even though no appreciable effects on interphase microtubules were observed when A-10 cells were treated with 30 μM 8j or 8l, compound 9i caused extensive microtubule depolymerization at this concentration. These results suggest that compound 9i of Type B has a similar mechanism of action as CA-4 whilst compounds 8j and 8l of Type B are likely to have a different mechanism of action.

Cite this article as:

Chavda Sameer, Davis Ryan, Ferguson Amanda, Riddering Camille, Dittenhafer Kristin, Mackay Hilary, Babu Balaji, Lee Moses, Siegfried Adam, Pennington William, Shadfan Miriam, Mooberry L. Susan, Mishra K. Bijay and Pati N. Hari, On the Synthesis and Anticancer Testing of α,β-Unsaturated Ketones as Analogs of Combretastatin-A4, Letters in Drug Design & Discovery 2009; 6 (7) . https://dx.doi.org/10.2174/157018009789108277