(2-amino-phenyl)-amides of omega-substituted alkanoic acids as new histone deacetylase inhibitors.

A variety of omega-substituted alkanoic acid (2-amino-phenyl)-amides were designed and synthesized. These compounds were shown to inhibit recombinant human histone deacetylases (HDACs) with IC(50) values in the low micromolar range and induce hyperacetylation of histones in whole cells. They induced expression of p21WAF1/Cip1 and caused cell-cycle arrest in human cancer cells. Compounds in this class showed efficacy in human tumor xenograft models.

Sulfonamide anilides, a novel class of histone deacetylase inhibitors, are antiproliferative against human tumors.

Inhibition of histone deacetylases (HDACs) is emerging as a new strategy in human cancer therapy. We have designed and synthesized novel nonhydroxamate sulfonamide anilides that can inhibit human HDAC enzymes and can induce hyperacetylation of histones in human cancer cells. These compounds selectively inhibit proliferation and cause cell cycle blocks in various human cancer cells but not in normal cells. The growth inhibitory activity of sulfonamide anilides against human cancer cells in vitro is reversible and is dependent on the induction of histone acetylation. One of these compounds (Compound 2) can significantly reduce tumor growth of implanted human colon tumors in nude mice. Unlike another anilide-based HDAC inhibitor, MS-275, which decreases both red and white blood counts and reduces spleen weights in mice, Compound 2 does not exhibit noticeable toxicity. By using cDNA array analysis, we have identified downstream genes whose expression is altered by Compound 2 in human cancer cells. In correlation with its antitumor activity both in vitro and in vivo, Compound 2 induces expression of p21(WAF1/Cip1), gelsolin, and keratin 19, while down-regulating expression of cyclin A and cyclin B1 in human cancer cells in a dose-dependent manner. Our results suggest that sulfonamide anilides are novel HDAC inhibitors and may be useful as antiproliferative agents in cancer chemotherapy.

Structurally simple trichostatin A-like straight chain hydroxamates as potent histone deacetylase inhibitors.

A series of new, structurally simple trichostatin A (TSA)-like straight chain hydroxamates were prepared and evaluated for their ability to inhibit partially purified human histone deacetylase 1 (HDAC-1). Some of these compounds such as 8m, 8n, 12, and 15b exhibited potent HDAC inhibitory activity with low nanomolar IC(50) values, comparable to natural TSA. These compounds induce hyperacetylation of histones in T24 human cancer cells and significantly inhibit proliferation in various human cancer cells. They also induce expression of p21 and cause cell cycle blocks in human cancer cells. In this paper, we describe the synthesis of these new compounds as well as structure-activity relationship results from enzyme inhibition and alterations in cellular function.