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Potent, Selective and Low-Calcemic Inhibitors of CYP24 Hydroxylase: 24-Sulfoximine Analogues of the Hormone 1α,25-Dihydroxyvitamin D₃

Mehmet Kahraman,^† Sandra Sinishtaj,^† Patrick M. Dolan,^‡ Thomas W. Kensler,^‡ Sara Peleg,^§ Uttam Saha, Samuel S. Chuang, Galina Bernstein, Bozena Korczak, and Gary H. Posner*^†

Department of Chemistry, School of Arts and Sciences, The Johns Hopkins University, Baltimore, Maryland 21218, Division of Toxicological Sciences, Department of Environmental Health Sciences, Bloomberg School of Hygiene, The Johns Hopkins University, Baltimore, Maryland 21205, Department of Medical Specialities, The University of Texas, M. D. Anderson Cancer Center, Houston, Texas 77030, and Cytochroma, Inc., Markham, Ontario, Canada L3R 8E4

J. Med. Chem., 2004, 47 (27), pp 6854–6863

DOI: 10.1021/jm040129+

Publication Date (Web): November 24, 2004

†

Department of Chemistry, The Johns Hopkins University.

‡

Department of Environmental Health Sciences, The Johns Hopkins University.

The University of Texas.

Cytochroma, Inc.

Corresponding author: Department of Chemistry, Johns Hopkins University, 3400 N. Charles St., Baltimore, MD 21218-2685. Phone 410-516-4670; fax 410-516-8420; e-mail ghp@jhu.edu.

Abstract

A dozen 24-sulfoximine analogues of the hormone 1α,25-dihydroxyvitamin D₃ were prepared, differing not only at the stereogenic sulfoximine stereocenter but also at the A-ring. Although these sulfoximines were not active transcriptionally and were only very weakly antiproliferative, some of them are powerful hydroxylase enzyme inhibitors. Specifically, 24-(S)-NH phenyl sulfoximine 3a is an extremely potent CYP24 inhibitor (IC₅₀ = 7.4 nM) having low calcemic activity. In addition, this compound shows high selectivity toward the CYP24 enzyme in comparison to CYP27A1 (IC₅₀ > 1000 nM) and CYP27B (IC₅₀ = 554 nM).

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