Synthesis and biological evaluation of 5-aminoethyl benzophenanthridone derivatives as DNA topoisomerase IB inhibitors

Eur J Med Chem. 2019 Sep 15:178:81-92. doi: 10.1016/j.ejmech.2019.05.074.

Wen-Lin Tang ¹, Yu Zhang ², De-Xuan Hu ², Hui Yang ², Qian Yu ², Jian-Wen Chen ², Keli Agama ³, Yves Pommier ³, Lin-Kun An ⁴

Affiliations

1 School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, 510006, China; Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, Guangzhou, 510006, China.
2 School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, 510006, China.
3 Developmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA.
4 School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, 510006, China; Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, Guangzhou, 510006, China. Electronic address: lssalk@mail.sysu.edu.cn.

PMID: 31176097 DOI: 10.1016/j.ejmech.2019.05.074

Abstract

DNA Topoisomerase IB (TOP1) regulates DNA topological structure in many cellular metabolic processes and is a validated target for development of antitumor agents. Our previous study revealed that the benzophenanthridone scaffold is a novel chemotype for the discovery of TOP1 inhibitors. In this work, a series of novel 5-aminoethyl substituted benzophenanthridone derivatives have been synthesized and evaluated for TOP1 inhibition and cytotoxicity. Compound 12 exhibits the most potent TOP1 inhibition (+++) and cytotoxicity in human Cancer cell lines with GI₅₀ values at nanomolar concentration range. 12 induces the cellular TOP1cc formation and DNA damage, resulting in HCT116 cell Apoptosis. The pharmacokinetics, acute toxicity and antitumor efficiency in vivo of 12 were also studied.

Keywords

Antitumor; Benzophenanthridone; Cytotoxicity; DNA damage; Inhibitor; Topoisomerase.

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