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

Autor: Yuan JM; 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., Wei K; 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., Zhang GH; 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., Chen NY; 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., Wei XW; 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., Pan CX; 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., Mo DL; 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., Su GF; 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.
Jazyk: angličtina
Zdroj: European journal of medicinal chemistry [Eur J Med Chem] 2019 May 01; Vol. 169, pp. 144-158. Date of Electronic Publication: 2019 Mar 04.
DOI: 10.1016/j.ejmech.2019.02.072
Abstrakt: 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 IC 50 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.
(Copyright © 2019 Elsevier Masson SAS. All rights reserved.)
Databáze: MEDLINE
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