On the synthesis and anticancer testing of α,β-unsaturated ketones as analogs of combretastatin-A4

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, Hari N. Pati

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4 Scopus citations

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 sub-class 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 cyclopropane-containing 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.

Original languageEnglish (US)
Pages (from-to)531-537
Number of pages7
JournalLetters in Drug Design and Discovery
Volume6
Issue number7
DOIs
Publication statusPublished - Oct 1 2009

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Keywords

  • Cancer
  • Combretastatin
  • Cytotoxicity
  • Microtubule
  • Tubulin

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmaceutical Science
  • Drug Discovery

Cite this

Chavda, S., Davis, R., Ferguson, A., Riddering, C., Dittenhafer, K., Mackay, H., ... Pati, H. N. (2009). On the synthesis and anticancer testing of α,β-unsaturated ketones as analogs of combretastatin-A4. Letters in Drug Design and Discovery, 6(7), 531-537. https://doi.org/10.2174/157018009789108277