2. Academic Validation
  3. A Series of Enthalpically Optimized Docetaxel Analogues Exhibiting Enhanced Antitumor Activity and Water Solubility

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

  • J Nat Prod. 2018 Mar 23;81(3):524-533. doi: 10.1021/acs.jnatprod.7b00857.
Yun-Tao Ma 1,  Yanting Yang 2,  Pei Cai 1,  De-Yang Sun 1,  Pedro A Sánchez-Murcia 3,  Xiao-Ying Zhang 1,  Wen-Qiang Jia 1,  Lei Lei 2,  Mengqi Guo 2,  Federico Gago 3,  Hongbo Wang 2,  Wei-Shuo Fang 1
Affiliations

Affiliations

  • 1 State Key Laboratory of Bioactive Substances and Functions of Natural Medicines , Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College , Beijing 100050 , People's Republic of China.
  • 2 Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education , Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai University , Yantai 264005 , People's Republic of China.
  • 3 Área de Farmacología, Departamento de Ciencias Biomédicas , Unidad Asociada al Instituto de Química Médica del CSIC, Universidad de Alcalá , E-28805 Alcalá de Henares , Madrid , Spain.
PMID: 29359935 DOI: 10.1021/acs.jnatprod.7b00857
Abstract

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.

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