Trifluoromethyl ketones as inhibitors of histone deacetylase

doi:10.1016/S0960-894X(02)00754-0

Bioorganic & Medicinal Chemistry Letters

Volume 12, Issue 23, 2 December 2002, Pages 3443-3447

https://doi.org/10.1016/S0960-894X(02)00754-0 Get rights and content

Abstract

Trifluoromethyl ketones were found to be inhibitors of histone deacetylases (HDACs). Optimization of this series led to the identification of submicromolar inhibitors such as 20 that demonstrated antiproliferative effects against the HT1080 and MDA 435 cell lines.

The synthesis and evaluation of a series of non-hydroxamate histone deacetylase (HDAC) inhibitors such as 16 (HDAC IC₅₀ 380 nM) is described.

Section snippets

Acknowledgements

The authors wish to thank Kent Stewart for molecular modeling studies and Carole Goodfellow for assisting in pharmacokinetic characterization of these compounds.

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Citation Excerpt :
This bioisosteric property can be used to adjust the steric and electronic properties of a compound, or to prevent metabolic degradation [6]. A range of synthetic strategies are available for performing trifluoromethylation reactions [7], examples being the use of the Umemoto [8], Togni [9], Langlois [10], and Rupert-Prakash [11] reagents (Fig. 1). One approach to the direct trifluoromethylation of substrates involves the use of trifluoromethyl radical sources [12].
A methodology for the direct introduction of the trifluoromethyl group on to indole scaffolds is presented. The procedure involves the use of sodium trifluoromethylsulfinate (Langlois reagent) as the source of the trifluoromethyl radical, and is performed photochemically with 2-tert-butylanthraquinone as a photocatalyst. The reaction has also been probed computationally. Reaction kinetics and molecular orbital analyses from our quantum chemical computations successfully predict and rationalize the formation of the experimentally observed product and, in the case of 1-methylbenzimidazole, even reproduce the same qualitative trends in regioisomer preference.

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Trifluoromethyl ketones as inhibitors of histone deacetylase

Abstract

Section snippets

Acknowledgements

Trends Endocrinol. Metab.

J. Natl. Cancer Inst.

J. Antibiotics

Cancer Res.

Bioorg. Med. Chem. Lett.

Biochemistry

J. Med. Chem.

Bioorg. Med. Chem. Lett.

J. Am. Chem. Soc.

Cancer Res.

Science

Oncogene

Bioorg. Med. Chem. Lett.

Proc. Natl. Acad. Sci. U.S.A.

J. Natl. Cancer Inst.