Improved antiproliferative activity of 1,3,4-thiadiazole-containing histone deacetylase (HDAC) inhibitors by introduction of the heteroaromatic surface recognition motif

Bioorg Med Chem. 2014 Nov 1;22(21):5766-75. doi: 10.1016/j.bmc.2014.09.039.

Peng Guan ¹, Lei Wang ¹, Xuben Hou ¹, Yichao Wan ¹, Wenfang Xu ¹, Weiping Tang ², Hao Fang ³

Affiliations

1 Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmacy, Shandong University, Jinan, Shandong 250012, PR China.
2 Division of Pharmaceutical Sciences, School of Pharmacy, University of Wisconsin, Madison 53705, USA.
3 Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmacy, Shandong University, Jinan, Shandong 250012, PR China. Electronic address: haofangcn@sdu.edu.cn.

PMID: 25311567 DOI: 10.1016/j.bmc.2014.09.039

Abstract

A series of 1,3,4-thiadiazole-containing hydroxamic acids, in accord with the common pharmacophore of histone deacetylase (HDAC) inhibitors (a Zn(2+) binding moiety-a linker-a surface recognition motif), was identified as submicromolar HDAC inhibitors by our group. In this study, we continued our efforts to develop 1,3,4-thiadiazole bearing hydroxamate analogues by modifying the surface recognition motif. We found that 1,3,4-thiadiazoles having a heteroaromatic substituent showed better HDAC inhibitory activity in enzymatic assay and higher antiproliferative potency in cellular assay compared to SAHA.

Keywords

1,3,4-Thiadiazole; Antiproliferation; Histone deacetylase inhibitor; Hydroxamic acid; Surface recognition motif.

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