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

被引：40
|
作者：
Ma, Yun-Tao [1 ,2 ]
Yang, Yanting [3 ]
Cai, Pei [1 ,2 ]
Sun, De-Yang [1 ,2 ]
Sanchez-Murcia, Pedro A. [4 ]
Zhang, Xiao-Ying [1 ,2 ]
Jia, Wen-Qiang [1 ,2 ]
Lei, Lei [3 ]
Guo, Mengqi [3 ]
Gago, Federico [4 ]
Wang, Hongbo [3 ]
Fang, Wei-Shuo [1 ,2 ]
机构：
[1] Chinese Acad Med Sci, Inst Mat Med, State Key Lab Bioact Subst & Funct Nat Med, Beijing 100050, Peoples R China
[2] Peking Union Med Coll, Beijing 100050, Peoples R China
[3] Yantai Univ, Key Lab Mol Pharmacol & Drug Evaluat, Minist Educ, Collaborat Innovat Ctr Adv Drug Delivery Syst & B, Yantai 264005, Peoples R China
[4] Univ Alcala De Henares, CSIC, Area Farmacol, Unidad Asociada,Inst Quim Med,Dept Ciencias Biome, E-28805 Madrid, Spain
来源：
JOURNAL OF NATURAL PRODUCTS | 2018年 / 81卷 / 03期
关键词：
TUMOR DRUG-RESISTANCE; ALPHA-BETA-TUBULIN; BINDING-AFFINITY; MOLECULAR-DYNAMICS; P-GLYCOPROTEIN; BREAST-CANCER; III-TUBULIN; IN-VITRO; PACLITAXEL; TAXANE;
D O I：
10.1021/acs.jnatprod.7b00857
中图分类号：
Q94 [植物学];
学科分类号：
071001 ;
摘要：
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.
引用
收藏
页码：524 / 533
页数：10
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