2. Academic Validation
  3. Development of novel β-carboline-based hydroxamate derivatives as HDAC inhibitors with antiproliferative and antimetastatic activities in human cancer cells

Development of novel β-carboline-based hydroxamate derivatives as HDAC inhibitors with antiproliferative and antimetastatic activities in human cancer cells

  • Eur J Med Chem. 2018 Jan 20:144:398-409. doi: 10.1016/j.ejmech.2017.12.061.
Yong Ling 1,  Jing Guo 1,  Qiuxing Yang 2,  Peng Zhu 2,  Jiefei Miao 3,  Weijie Gao 2,  Yanfu Peng 2,  Jiaying Yang 2,  Kun Xu 2,  Biao Xiong 2,  Gongqing Liu 2,  Jinhua Tao 2,  Lin Luo 3,  Qing Zhu 4,  Yanan Zhang 5
Affiliations

Affiliations

  • 1 School of Pharmacy and Jiangsu Province Key Laboratory for Inflammation and Molecular Drug Target, Nantong University, Nantong 226001, PR China; State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, 210009, PR China.
  • 2 School of Pharmacy and Jiangsu Province Key Laboratory for Inflammation and Molecular Drug Target, Nantong University, Nantong 226001, PR China.
  • 3 School of Pharmacy and Jiangsu Province Key Laboratory for Inflammation and Molecular Drug Target, Nantong University, Nantong 226001, PR China; The Affiliated Hospital of Nantong University, Nantong University, Nantong 226001, PR China.
  • 4 School of Pharmacy and Jiangsu Province Key Laboratory for Inflammation and Molecular Drug Target, Nantong University, Nantong 226001, PR China. Electronic address: zhuqing7883@163.com.
  • 5 School of Pharmacy and Jiangsu Province Key Laboratory for Inflammation and Molecular Drug Target, Nantong University, Nantong 226001, PR China. Electronic address: zhangyanan@gmail.com.
PMID: 29288941 DOI: 10.1016/j.ejmech.2017.12.061
Abstract

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.

Keywords

Antimetastasis; Antiproliferative activity; Histone deacetylase inhibitors; Synthesis; β-Carbolines.

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