New Benzothiazole/thiazole-Containing Hydroxamic Acids as Potent Histone Deacetylase Inhibitors and Antitumor Agents

Truong   Thanh   Tung; Dao   Thi   Kim Oanh; Phan   Thi   Phuong Dung; Van   Thi   My Hue; Sang   Ho   Park; Byung   Woo   Han; Youngsoo      Kim; Jin-Tae      Hong; Sang-Bae      Han; Nguyen-Hai      Nam

Abstract

Results from clinical studies have demonstrated that inhibitors of histone deacetylase (HDAC) enzymes possess promise for the treatment of several types of cancer. Zolinza^® (widely known as SAHA) has been approved by the FDA for the treatment of T-cell lymphoma. As a continuity of our ongoing research to find novel small molecules to target these important enzymes, we synthesized a series of benzothiazole-containing analogues of SAHA and found several compounds with very potent anticancer cytotoxicity. In this study, three more compounds of this type, including N¹-(6- chlorobenzo[d]thiazol-2-yl)-N⁸-hydroxyoctanediamide (3a), N¹-[6-(trifluoromethyl)benzo[d]thiazol-2-yl]-N⁸-hydroxyoctanediamide (3b) and N¹-(thiazol-2-yl)-N⁸-hydroxyoctanediamide (6) were synthesized and evaluated for HDAC inhibition and cytotoxic activities. All three compounds showed very potent HDAC inhibitory effects. Docking revealed that both two compounds 3a, 3b showed higher affinities towards HDAC⁸ compared to SAHA. In vitro, compound 3a exhibited cytotoxicity equipotent to SAHA against five human cancer cell lines. In term of in vivo activity, compound 3a demonstrated equivalent efficacy to SAHA in mouse xenograft model.

Keywords: Histone deacetylase inhibitors, benzothiazole, heterocycle.

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