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Novel Hydroxamate and Anilide Derivatives as Potent Histone Deacetylase Inhibitors: Synthesis and Antiproliferative Evaluation

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There is a currently growing interest in the development of histone deacetylase inhibitors (HDACs) as anticancer agents. Histone deacetylases are critically important in the functional regulation of gene transcription as well as in chromatin structure remodeling. A number of small molecule inhibitors of HDAC, such as the naturally occurring trichostatin A (TSA), as well as synthetic compounds, such as suberoylanilide hydroxamic acid (SAHA), scriptaid, oxamflatin or MS-275, have been reported to induce differentiation of several cancer cell lines and suppress cell proliferation. This article will review the recent progress being made in our laboratories in the development of two new families of potent HDAC inhibitors: sulfonamide hydroxamic acids and anilides, as well as TSA-like straight chain derivatives. Some of these compounds inhibit partially purified recombinant human HDAC enzymes with IC50's in the micromolar to low nanomolar range and can induce hyperacetylation of histones in human cancer cells. These compounds significantly inhibit proliferation, induce expression of p21WAF1 / Cip1, and cause cell cycle arrest in various human cancer cells. The lead candidates were screened in a panel of human tumor and normal cell lines. The inhibition of HDAC activity represents a novel approach for intervening in cell cycle regulation and may be used in future cancer therapies. The structure-activity relationships, the antiproliferative activity and the in vivo efficacy are discussed.
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Keywords: anilide derivatives; anticancer agents; hdac enzymes; hdacs; histone deacetylase inhibitors; hydroxamate; structure-activity relationships; suberoylanilide hydroxamic acid; trichostatin a; tsa

Document Type: Review Article

Affiliations: Department of Medicinal Chemistry, MethylGene Inc., 7220 Frederick-Banting, Montreal, Quebec H4S 2A1, Canada.

Publication date: 2003-11-01

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  • Current Medicinal Chemistry covers all the latest and outstanding developments in medicinal chemistry and rational drug design. Each issue contains a series of timely in-depth reviews written by leaders in the field covering a range of the current topics in medicinal chemistry. Current Medicinal Chemistry is an essential journal for every medicinal chemist who wishes to be kept informed and up-to-date with the latest and most important developments.
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