Novel β-Carboline/Hydroxamic Acid Hybrids Targeting Both Histone Deacetylase and DNA Display High Anticancer Activity via Regulation of the p53 Signaling Pathway

Yong Ling; Chenjun Xu; Lin Luo; Jingyi Cao; Jiao Feng; Yu Xue; Qing Zhu; Caoyun Ju; Fengzhi Li; Yihua Zhang; Yanan Zhang; Xiang Ling

doi:10.1021/acs.jmedchem.5b01052

Novel β-Carboline/Hydroxamic Acid Hybrids Targeting Both Histone Deacetylase and DNA Display High Anticancer Activity via Regulation of the p53 Signaling Pathway

J Med Chem. 2015 Dec 10;58(23):9214-27. doi: 10.1021/acs.jmedchem.5b01052. Epub 2015 Nov 24.

Authors

Yong Ling¹, Chenjun Xu¹, Lin Luo, Jingyi Cao, Jiao Feng, Yu Xue, Qing Zhu, Caoyun Ju, Fengzhi Li², Yihua Zhang¹, Yanan Zhang, Xiang Ling²

Affiliations

¹ State Key Laboratory of Natural Medicines, China Pharmaceutical University , Nanjing 210009, P.R. China.
² Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute , Buffalo, New York, USA.

PMID: 26555243
DOI: 10.1021/acs.jmedchem.5b01052

Abstract

A novel series of hybrids from β-carboline and hydroxamic acid were designed and synthesized. Several compounds (5m, 11b-d, and 11h) not only exerted significant antiproliferation activity against four human colorectal cancer (CRC) cell lines but also showed histone deacetylase inhibitory effects in vitro. The most potent compound, 11c, exhibited anticancer potency sevenfold higher than that of SAHA. 11c triggered more significant cancer cell apoptosis than did SAHA by cleavage of both PARP and caspase 3 in a dose-dependent manner. Furthermore, 11c simultaneously increased the acetylation of histone H3 and α-tubulin, enhanced expression of DNA damage markers histone H2AX phosphorylation and p-p53 (Ser15), and activated p53 signaling pathway in HCT116 cells. Finally, 11c showed low acute toxicity in mice and inhibited the growth of implanted human CRC in mice more potently than did SAHA. Together, 11c possessed potent antitumor activity and may be a promising candidate for the potential treatment of human CRC.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Acetylation / drug effects
Animals
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology
Antineoplastic Agents / therapeutic use*
Apoptosis / drug effects
Carbolines / chemistry
Carbolines / pharmacology
Carbolines / therapeutic use*
Cell Proliferation / drug effects
Colon / drug effects
Colon / metabolism
Colon / pathology
Colorectal Neoplasms / drug therapy*
Colorectal Neoplasms / metabolism
Colorectal Neoplasms / pathology
DNA / metabolism
Female
HCT116 Cells
Histone Deacetylase Inhibitors / chemistry
Histone Deacetylase Inhibitors / pharmacology
Histone Deacetylase Inhibitors / therapeutic use*
Histone Deacetylases / metabolism
Humans
Hydroxamic Acids / chemistry
Hydroxamic Acids / pharmacology
Hydroxamic Acids / therapeutic use*
Mice
Mice, Inbred BALB C
Mice, Nude
Rectum / drug effects
Rectum / metabolism
Rectum / pathology
Signal Transduction / drug effects
Tubulin / metabolism
Tumor Suppressor Protein p53 / metabolism*

Substances

Antineoplastic Agents
Carbolines
Histone Deacetylase Inhibitors
Hydroxamic Acids
Tubulin
Tumor Suppressor Protein p53
DNA
Histone Deacetylases