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

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 N(1)-(6-chlorobenzo[d]thiazol-2-yl)-N(8)-hydroxyoctanediamide (3a), N(1)-[6-(trifluoromethyl)benzo[d]thiazol-2-yl]-N(8)-hydroxyoctanediamide (3b) and N(1)-(thiazol-2-yl)-N(8)-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 HDAC(8) 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.

The Development Process: from SAHA to Hydroxamate HDAC Inhibitors with Branched CAP Region and Linear Linker

“…However, the most efficient compound 5a observed in vitro was less active in vivo due to hepatic oxidation of the methyl group. To solve this issue, new compounds 5d was developed . Compound 5d was more efficient than SAHA in all the cell lines examined except MCF‐7.…”

Synthesis and bioevaluation of new 5-benzylidenethiazolidine-2,4-diones bearing benzenesulfonamide moiety

“…To gain possible mode of binding of this type of compounds with histone deacetylase, we performed docking study with one compound 4b using HDAC2 and HDAC8. We executed control docking experiments with SAHA to the crystal structures of HDAC2 and HDAC8 using AutoDock Vina program (Trott and Olson, 2010) after SAHA was removed from the complex structures, as described previously Tung et al, 2013;Oanh et al, 2011). It was found from docking experiments that compound 4b was predicted to sit at the top and block the SAHA binding pocket (Fig.…”

Novel hydroxamic acids incorporating 1-((1H-1,2,3-Triazol-4-yl)methyl)-3-hydroxyimino-indolin-2-ones: synthesis, biological evaluation, and SAR analysis

“…[17][18][19][20] Several representative compounds from these series also demonstrated very potent antitumor activity in PC-3 prostate cancer cells xenografted mice model. 18 Encouraged by these results, we expanded our design to the new series of 17 hydroxamic acids. In these hydroxamic acids the 2-oxoindoline system is employed as a cap group and linkers of different lengths incorporating a triazole moiety are probed.…”