Synthesis and biological evaluation of novel larotaxel analogues

Eur J Med Chem. 2018 Aug 5:156:692-710. doi: 10.1016/j.ejmech.2018.07.029.

Sumei Ren ¹, Yujie Wang ¹, Junfei Wang ¹, Dingding Gao ¹, Minmin Zhang ², Ning Ding ³, Yingxia Li ⁴

Affiliations

1 Department of Medicinal Chemistry, School of Pharmacy, Fudan University, Shanghai, 201203, China.
2 Division of Anti-tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
3 Department of Medicinal Chemistry, School of Pharmacy, Fudan University, Shanghai, 201203, China; Zhangjiang Technology Institute, Fudan University, 825 Zhangheng Road, Shanghai, 201203, China. Electronic address: dingning@fudan.edu.cn.
4 Department of Medicinal Chemistry, School of Pharmacy, Fudan University, Shanghai, 201203, China; Laboratory of Marine Drugs and Biological Products, Pilot National Laboratory for Marine Science and Technology, Qingdao, 266237, China. Electronic address: liyx417@fudan.edu.cn.

PMID: 30036834 DOI: 10.1016/j.ejmech.2018.07.029

Abstract

Taxoids are a class of successful drugs and have been successfully used in chemotherapy for a variety of Cancer types. However, despite the hope and promises that these taxoids have engendered, their utility is hampered by some clinic limitations. Extensive structure-activity relationship (SAR) studies of toxoids have been performed in many different laboratories. Whereas, SAR studies that based on the new-generation toxoid, larotaxel, have not been reported yet. In view of the advantages in preclinical and clinical data of larotaxel over former toxoids, new taxoids that strategicly modified at the C3'/C3'-N and C2 positions of larotaxel were designed, semi-synthesized, and examined for their potency and efficacy in vitro. As a result, it has been shown that the majority of these larotaxel analogues are exceptionally potent against both drug-sensitive tumor cells and tumor cells with drug resistance arising from P-glycoprotein over expression. Further in vivo antitumor efficacies investigations revealed A2 might be a potent antitumor drug candidate for further preclinical evaluation.

Keywords

Cytotoxicity; Drug-resistant; Larotaxel; Semi-synthesis; Structure-activity relationship; Toxoids.

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