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Int J Mol Sci. 2018 Oct 15;19(10). pii: E3179. doi: 10.3390/ijms19103179.

Synthesis and In Vitro Antitumor Activity of Novel Bivalent β-Carboline-3-carboxylic Acid Derivatives with DNA as a Potential Target.

Author information

1
College of Chemistry and Pharmacy, Northwest A&F University, No. 22 Xinong Road, Yangling 712100, China. honglingguw@163.com.
2
College of Chemistry and Pharmacy, Northwest A&F University, No. 22 Xinong Road, Yangling 712100, China. lnuk@nwsuaf.edu.cn.
3
College of Chemistry and Pharmacy, Northwest A&F University, No. 22 Xinong Road, Yangling 712100, China. daijkun@hotmail.com.
4
College of Chemistry and Pharmacy, Northwest A&F University, No. 22 Xinong Road, Yangling 712100, China. mysteryxi@163.com.
5
College of Chemistry and Pharmacy, Northwest A&F University, No. 22 Xinong Road, Yangling 712100, China. 444795415@nwafu.edu.cn.
6
College of Chemistry and Pharmacy, Northwest A&F University, No. 22 Xinong Road, Yangling 712100, China. wangjunru@nwafu.edu.cn.
7
State key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Zhangjiang Hi-Tech Park, Shanghai 201203, China. wangjunru@nwafu.edu.cn.

Abstract

A series of novel bivalent β-carboline derivatives were designed and synthesized, and in vitro cytotoxicity, cell apoptosis, and DNA-binding affinity were evaluated. The cytotoxic results demonstrated that most bivalent β-carboline derivatives exhibited stronger cytotoxicity than the corresponding monomer against the five selected tumor cell lines (A549, SGC-7901, Hela, SMMC-7721, and MCF-7), indicating that the dimerization at the position could enhance the antitumor activity of β-carbolines. Among the derivatives tested, 4B, 6i, 4D, and 6u displayed considerable cytotoxicity against A549 cell line. Furthermore, 4B, 6i, 4D, and 6u induced cell apoptosis in a dose-dependent manner, and caused cell cycle arrest at the S and G2/M phases. Moreover, the levels of cytochrome C in mitochondria, and the expressions of bcl-2 protein, decreased after treatment with β-carbolines, which indicated that 6i and 6u could induce mitochondria-mediated apoptosis. In addition, the results of UV-visible spectral, thermal denaturation, and molecular docking studies revealed that 4B, 6i, 4D, and 6u could bind to DNA mainly by intercalation.

KEYWORDS:

DNA-binding affinity; antitumor; apoptosis; bcl-2; bivalent β-carbolines

PMID:
30326662
DOI:
10.3390/ijms19103179
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