Journal
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
Volume 19, Issue 10, Pages -Publisher
MDPI
DOI: 10.3390/ijms19103179
Keywords
bivalent -carbolines; antitumor; apoptosis; DNA-binding affinity; bcl-2
Funding
- National Natural Science Foundation of China [81773603]
- Open Foundation of Key Laboratory of Synthetic and National Foundation Molecule Chemistry of the Ministry of Education (Northwest University, China)
- State Key Laboratory of Drug Research [SIMM1705KF-09]
- National Training Program on Undergraduate Innovation and Entrepreneurship (Northwest A&F University, China) [201803018]
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A series of novel bivalent -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 -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 C-3 position could enhance the antitumor activity of -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 -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.
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