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.

Yong Ling ¹, Chenjun Xu ¹, Lin Luo, Jingyi Cao, Jiao Feng, Yu Xue, Qing Zhu, Caoyun Ju, Fengzhi Li ², Yihua Zhang ¹, Yanan Zhang, Xiang Ling ²

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.

Name
Email *

	Sorry, but the email address you supplied was invalid.