LAUSR

A dual 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 novel C-2 and C-39 modified analogs. Among the latter, a compound demonstrated a higher affinity constant for microtubules that resulted in the ability to overcome resistance in cultured P-gp overexpressing tumor cells and a superior activity to docetaxel in drug-resistant A2780/AD ovarian cancer cells xenografted in mice. In addition, the considerably lower hydrophobicity of this compound relative to both docetaxel and paclitaxel led to a 3-fold better aqueous solubility. A molecular modelling was performed to explain its potent activity at structural level. Citation Format: Weishuo Fang, Hongbo Wang, Federico Gago. Potent and water-soluble C-3’ modified docetaxel analogs by enthalpic driven optimization [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr A076.