2-Benzazolyl-4-Piperazin-1-Ylsulfonylbenzenecarbohydroxamic Acids as Novel Selective Histone Deacetylase-6 Inhibitors with Antiproliferative Activity

Abstract

We have screened our compound collection in an established cell based assay that measures the derepression of an epigenetically silenced transgene, the locus derepression assay. The screen led to the identification of 4-[4-(1-methylbenzimidazol-2-yl)piperazin-1-yl]sulfonylbenzenecarbohydroxamic acid (9b) as an active which was found to inhibit HDAC1. In initial structure activity relationships study, the 1-methylbenzimidazole ring was replaced by the isosteric heterocycles benzimidazole, benzoxazole, and benzothiazole and the position of the hydroxamic acid substituent on the phenyl ring was varied. Whereas compounds bearing a para substituted hydroxamic acid (9a-d) were active HDAC inhibitors, the meta substituted analogues (8a-d) were appreciably inactive. Compounds 9a-d selectively inhibited HDAC6 (IC50 = 0.1–1.0μM) over HDAC1 (IC50 = 0.9–6μM) and moreover, also selectively inhibited the growth of lung cancer cells vs. patient matched normal cells. The compounds induce a cell cycle arrest in the S-phase while induction of apoptosis is neglible as compared to controls. Molecular modeling studies uncovered that the MM-GBSA energy for interaction of 9a-d with HDAC6 was higher than for HDAC1 providing structural rationale for the HDAC6 selectivity.

Structure-Based Design and Synthesis of Novel Inhibitors Targeting HDAC8 from Schistosoma mansoni for the Treatment of Schistosomiasis

“…The docking results and structure–activity relationship studies suggest that meta substitution of benzohydroxamates is important to gain HDAC8 selectivity. This is also supported by previous publications showing that meta-substituted benzohydroxamic acids are more active on human HDAC8 and -6 in comparison with HDAC1 and other class I HDACs. ,,− …”

Structure-Based Design and Biological Characterization of Selective Histone Deacetylase 8 (HDAC8) Inhibitors with Anti-Neuroblastoma Activity

“…The selectivity of the compounds over HDAC1 could be easily explained by the docking results (see Supporting Information Figure S1) which clearly show that the compounds are not able to properly chelate the catalytic zinc ion. HDAC1 is characterized by its narrow pocket as compared to HDAC8 and -6, and hence, meta-substituted benzhydroxamic acids generally show a HDAC6/8 over HDAC1 selectivity as has been frequently demonstrated in previous studies. ,,− …”

Chemoselective Reactions of Functionalized Sulfonyl Halides

“…Indeed, over 90 % of selective transformations of functionalized sulfonyl chlorides at the SO 2 Cl moiety include their reactions with N-nucleophiles (Figure 2). These reactions are highly chemoselective and were shown to tolerate the presence of alkyl halogenide, [330] carboxylic acid [331][332][333][334][335][336][337] ester, [338] aldehyde, [339,340] or ketone, [341,342] nitrile, [338,343] SO 2 Me [344] groups, as well as both conjugated and isolated double [345][346][347] or triple [338] bonds (Scheme 50).…”