American Chemical Society
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A Series of Enthalpically Optimized Docetaxel Analogues Exhibiting Enhanced Antitumor Activity and Water Solubility

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journal contribution
posted on 2018-01-22, 22:06 authored by Yun-Tao Ma, Yanting Yang, Pei Cai, De-Yang Sun, Pedro A. Sánchez-Murcia, Xiao-Ying Zhang, Wen-Qiang Jia, Lei Lei, Mengqi Guo, Federico Gago, Hongbo Wang, Wei-Shuo Fang
A dual-purpose strategy aimed at enhancing the binding affinity for microtubules and improving the water solubility of docetaxel led to the design and synthesis of a series of C-2- and C-3′-modified analogues. Both aims were realized when the C-3′ phenyl group present in docetaxel was replaced with a propargyl alcohol. The resulting compound, 3f, was able to overcome drug resistance in cultured P-gp-overexpressing tumor cells and showed greater activity than docetaxel against drug-resistant A2780/AD ovarian cancer xenografts in mice. In addition, the considerably lower hydrophobicity of 3f relative to both docetaxel and paclitaxel led to better aqueous solubility. A molecular model of tubulin-bound 3f revealed novel hydrogen-bonding interactions between the propargyl alcohol and the polar environment provided by the side chains of Ser236, Glu27, and Arg320.