2. Academic Validation
  3. Synthesis, biological evaluation and modeling studies of terphenyl topoisomerase IIα inhibitors as anticancer agents

Synthesis, biological evaluation and modeling studies of terphenyl topoisomerase IIα inhibitors as anticancer agents

  • Eur J Med Chem. 2015 Apr 13:94:427-35. doi: 10.1016/j.ejmech.2015.03.010.
Jin Qiu 1,  Baobing Zhao 2,  Wanxia Zhong 3,  Yuemao Shen 4,  Houwen Lin 5
Affiliations

Affiliations

  • 1 Key Laboratory for Marine Drugs, Department of Pharmacy, State Key Laboratory of Oncogenes and Related Genes, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Pujian Road 160, Shanghai 200127, People's Republic of China.
  • 2 Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, No. 44 West Wenhua Road, Jinan, Shandong 250012, People's Republic of China.
  • 3 Shanghai Key Laboratory for Assisted Reproduction and Reproductive Genetics, Center for Reproductive Medicine, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, People's Republic of China.
  • 4 Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, No. 44 West Wenhua Road, Jinan, Shandong 250012, People's Republic of China. Electronic address: yshen@sdu.edu.cn.
  • 5 Key Laboratory for Marine Drugs, Department of Pharmacy, State Key Laboratory of Oncogenes and Related Genes, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Pujian Road 160, Shanghai 200127, People's Republic of China. Electronic address: franklin67@126.com.
PMID: 25800514 DOI: 10.1016/j.ejmech.2015.03.010
Abstract

We report the synthesis and evaluation of a series of novel terphenyls. Compound 17 had the most potent Anticancer activity, indicating that the phenolic hydroxyl was a key group. A DNA relaxation test showed that compound 17 had a strong inhibitory effect on TOP2α, but not on TOP1, which was consistent with the docking analysis results. We performed a 3D-QSAR study using CoMFA and CoMSIA to determine, for the first time, the chemical-biological relationship in the inhibition of TOP by terphenyls. The CoMFA and CoMSIA model had good modeling statistics: leave-one-out q(2) of 0.605 and 0.622, r(2) of 0.998 and 0.994, and r(2)pred (test set) of 0.742 and 0.660. These results suggest that the ortho-phenolic hydroxyl on ring A is important for producing terphenyls with more efficacious activity.

Keywords

3D-QSAR; Terphenyls; Topoisomerase.

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