- Development of novel β-carboline-based hydroxamate derivatives as HDAC inhibitors with antiproliferative and antimetastatic activities in human cancer cells
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A series of novel β-carboline-based hydroxamate derivatives 12a-k were designed and synthesized, and their biological activities in a series of in vitro assays were evaluated. Several of these β-carboline derivatives not only showed excellent HDAC1/3/6 inhibitory effects, but also displayed significant antitumor activities against five human cancer cells. The most potent compound 12f demonstrated the highest anticancer potency against cancer cell lines with IC50 values of 0.53–1.56 μM, which was considerably more potent than harmine (IC50 = 46.7–55.3 μM) and also three-to ten-fold lower than that of SAHA (IC50 = 4.48–6.26 μM). Immunoblot analysis revealed that 12f dose-dependently inhibited histone H3 and α-tubulin acetylation, confirming its HDAC inhibitory effects. Moreover, 12f significantly arrested HepG2 cells at G2/M phase through inhibiting cell cycle related protein CDK1 and cyclin B in a concentration dependent manner. Interestingly, 12f also exerted strong anti-metastasis activity by simultaneously reducing the protein level of MMP2 and MMP9 and inhibiting MAPK signaling pathway.
- Ling, Yong,Guo, Jing,Yang, Qiuxing,Zhu, Peng,Miao, Jiefei,Gao, Weijie,Peng, Yanfu,Yang, Jiaying,Xu, Kun,Xiong, Biao,Liu, Gongqing,Tao, Jinhua,Luo, Lin,Zhu, Qing,Zhang, Yanan
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p. 398 - 409
(2018/01/01)
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- 3-Benzylamino-β-carboline derivatives induce apoptosis through G 2/M arrest in human carcinoma cells HeLa S-3
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β-Carboline derivatives are known as the lead compounds for anti-tumor agents. To examine an optimal structure for anti-tumor activity, we synthesized a variety of β-carboline derivatives, possessing a variety of substituents on the nitrogen atom of the amino group of 3-amino-β-carboline, and evaluated their anti-tumor activity for HeLa S-3 cell line. 3-(4,5- Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay showed that an optimal structure for anti-tumor activity was 3-cyclohexylmethylamino (1e) or 3-benzylamino-β-carboline (1f). An optimal counter anion of 2-methyl-3-benzylamino- β-carbolinium salts was a triflate anion 2c. In addition, the introduction of a hydroxyl group on the meta-position of the benzyl group of 3-benzylamino-β-carboline (3e) enhanced its anti-tumor activity. Hoechst 33342 staining and DNA fragmentation assay suggested that 1f, 2c and 3e induced cell death by apoptosis unlike 1e. Flow cytometry analysis showed that 1f, 2c and 3e induced cell apoptosis through arrest of the cell cycle in the G2/M phase.
- Ikeda, Reiko,Iwaki, Toshie,Iida, Tomoko,Okabayashi, Takasumi,Nishi, Eishiro,Kurosawa, Masaki,Sakai, Norio,Konakahara, Takeo
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p. 636 - 646
(2011/03/20)
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