Cryptolepine and aromathecin based mimics as potent G-quadruplex-binding, DNA-cleavage and anticancer agents: Design, synthesis and DNA targeting-induced apoptosis

Eur J Med Chem. 2019 May 1:169:144-158. doi: 10.1016/j.ejmech.2019.02.072.

Jing-Mei Yuan ¹, Kai Wei ¹, Guo-Hai Zhang ¹, Nan-Ying Chen ¹, Xin-Wei Wei ¹, Cheng-Xue Pan ², Dong-Liang Mo ³, Gui-Fa Su ⁴

Affiliations

1 State Key Laboratory for the Chemistry and Molecular Engineering of Medicinal Resources, School of Chemistry and Pharmaceutical Sciences, Guangxi Normal University, Guilin, 541004, PR China.
2 State Key Laboratory for the Chemistry and Molecular Engineering of Medicinal Resources, School of Chemistry and Pharmaceutical Sciences, Guangxi Normal University, Guilin, 541004, PR China. Electronic address: chengxuepan@163.com.
3 State Key Laboratory for the Chemistry and Molecular Engineering of Medicinal Resources, School of Chemistry and Pharmaceutical Sciences, Guangxi Normal University, Guilin, 541004, PR China. Electronic address: moeastlight@gxnu.edu.cn.
4 State Key Laboratory for the Chemistry and Molecular Engineering of Medicinal Resources, School of Chemistry and Pharmaceutical Sciences, Guangxi Normal University, Guilin, 541004, PR China. Electronic address: gfysglgx@163.com.

PMID: 30875505 DOI: 10.1016/j.ejmech.2019.02.072

Abstract

Thirty Cryptolepine and Aromathecin based mimics were designed and synthesized. Their cytotoxicity was evaluated in four human Cancer cell lines (HepG-2, T24, NCI-H460 and MGC-803) and one normal human cell line (HL-7702). Most compounds exhibited potent Anticancer activity with IC₅₀ values from 0.31 to 11.97 μM. 8-Fluoro-10-(N-3-dimethylaminopropyl)amino-11H-indeno[1,2-b]quinoline (5b) was identified as the most promising candidate in view of its Anticancer activity. Molecular mechanism studies suggested that 5b not only could strongly bind to G-quadruplex, but intercalate into supercoil DNA and resulted in significant DNA double-strand break as well. Furthermore, 5b caused cell cycle arrest at S/G2 phase and induced Apoptosis. After treatment with 5b, pro-apoptotic proteins Bak, Bax and Bim were up-regulated, anti-apoptotic proteins Bcl-2 and Bcl-xL were down-regulated, and the effector Caspase-3/9 was activated to initiate Apoptosis. The Anticancer activity of 5b was finally validated in a MGC-803 xenograft tumor model with tumor growth inhibition (TGI) up to 53.2%, while displaying no obvious toxicity. Taken together, these results suggest that 5b may be a potential candidate of cytotoxic antineoplastic drugs for Cancer therapy.

Keywords

Aromathecins; Cryptolepine; G-quadruplex-binding and DNA-Cleavage agent; Natural products mimics; Topo I inhibitor.

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