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Open AccessArticle

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

1
College of Chemistry and Pharmacy, Northwest A&F University, No. 22 Xinong Road, Yangling 712100, China
2
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
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2018, 19(10), 3179; https://doi.org/10.3390/ijms19103179
Received: 22 August 2018 / Revised: 21 September 2018 / Accepted: 25 September 2018 / Published: 15 October 2018
(This article belongs to the Section Biochemistry)
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 C3 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. View Full-Text
Keywords: bivalent β-carbolines; antitumor; apoptosis; DNA-binding affinity; bcl-2 bivalent β-carbolines; antitumor; apoptosis; DNA-binding affinity; bcl-2
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MDPI and ACS Style

Gu, H.; Li, N.; Dai, J.; Xi, Y.; Wang, S.; Wang, J. Synthesis and In Vitro Antitumor Activity of Novel Bivalent β-Carboline-3-carboxylic Acid Derivatives with DNA as a Potential Target. Int. J. Mol. Sci. 2018, 19, 3179.

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