Design, Synthesis and Biological Testing of Cyclohexenone Derivatives of Combretastatin-A4

Title: Design, Synthesis and Biological Testing of Cyclohexenone Derivatives of Combretastatin-A4

Volume: 4 Issue: 2

Author(s): Jennifer Ruprich, Andrew Prout, John Dickson, Brent Younglove, Lawrence Nolan, Khyati Baxi, Regan LeBlanc, Lori Forrest, Patrice Hills, Herman Holt Jr, Hilary Mackay, Toni Brown, Susan L. Mooberry and Moses Lee

Affiliation:

Keywords: Combretastatin-A4, Tubulin, Anticancer, Cyclohexenone, Cytotoxicity, Synthesis

Abstract: Sixteen 2-cyclohexenone and 6-(ethoxycarbonyl)-2-cyclohexenone analogs of combretastatin-A4 (CA-4, 1) were synthesized, and their ability to inhibit the growth of two murine cancer cell lines (B16 melanoma and L1210 leukemia) was determined using an MTT assay. One of the cyclohexenone analogs, 8, which contains the same substituents as CA-4 (1) is the most potent (IC50 = 0.91 μM, L1210). Exposure of A- 10 aortic cells to cyclohexenone 8 and its ester congener 7 produced significant reduction in cellular microtubules, with EC50 values of 27 and 37 μM, respectively. Molecular modeling studies indicate that analog 8 adopts a twisted conformation, similar to CA-4, suggesting that conformation and structure are crucial for activity. These compounds are worthy of further investigation as potential tubulin inhibitors in the quest for novel anti-cancer agents.

Cite this article as:

Ruprich Jennifer, Prout Andrew, Dickson John, Younglove Brent, Nolan Lawrence, Baxi Khyati, LeBlanc Regan, Forrest Lori, Hills Patrice, Holt Jr Herman, Mackay Hilary, Brown Toni, Mooberry L. Susan and Lee Moses, Design, Synthesis and Biological Testing of Cyclohexenone Derivatives of Combretastatin-A4, Letters in Drug Design & Discovery 2007; 4 (2) . https://dx.doi.org/10.2174/157018007779422442