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

Yong Ling; Jing Guo; Qiuxing Yang; Peng Zhu; Jiefei Miao; Weijie Gao; Yanfu Peng; Jiaying Yang; Kun Xu; Biao Xiong; Gongqing Liu; Jinhua Tao; Lin Luo; Qing Zhu; Yanan Zhang

doi:10.1016/j.ejmech.2017.12.061

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. Epub 2017 Dec 20.

Authors

Yong Ling¹, Jing Guo¹, Qiuxing Yang², Peng Zhu², Jiefei Miao³, Weijie Gao², Yanfu Peng², Jiaying Yang², Kun Xu², Biao Xiong², Gongqing Liu², Jinhua Tao², Lin Luo³, Qing Zhu⁴, Yanan Zhang⁵

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.

MeSH terms

Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Carbolines / chemistry
Carbolines / pharmacology*
Cell Cycle Checkpoints / drug effects
Cell Proliferation / drug effects
Dose-Response Relationship, Drug
Drug Screening Assays, Antitumor
Histone Deacetylase Inhibitors / chemical synthesis
Histone Deacetylase Inhibitors / chemistry
Histone Deacetylase Inhibitors / pharmacology*
Histone Deacetylases / metabolism*
Humans
Hydroxamic Acids / chemical synthesis
Hydroxamic Acids / chemistry
Hydroxamic Acids / pharmacology*
Molecular Structure
Structure-Activity Relationship
Tumor Cells, Cultured

Substances

Antineoplastic Agents
Carbolines
Histone Deacetylase Inhibitors
Hydroxamic Acids
norharman
Histone Deacetylases