Potent, selective and low-calcemic inhibitors of CYP24 Hydroxylase: 24-Sulfoximine analogues of the hormone 1α,25-dihydroxyvitamin D 3

Mehmet Kahraman; Sandra Sinishtaj; Patrick M. Dolan; Thomas W. Kensler; Sara Peleg; Uttam Saha; Samuel S. Chuang; Galina Bernstein; Bozena Korczak; Gary H. Posner

doi:10.1021/jm040129+

Potent, selective and low-calcemic inhibitors of CYP24 Hydroxylase: 24-Sulfoximine analogues of the hormone 1α,25-dihydroxyvitamin D ₃

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

Bloomberg School of Public Health

Research output: Contribution to journal › Article › peer-review

106 Scopus citations

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).

Original language	English (US)
Pages (from-to)	6854-6863
Number of pages	10
Journal	Journal of medicinal chemistry
Volume	47
Issue number	27
DOIs	https://doi.org/10.1021/jm040129+
State	Published - Dec 30 2004

ASJC Scopus subject areas

Molecular Medicine
Drug Discovery

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@article{08c98158bdbd4c22b9e88e5fdd9730eb,

title = "Potent, selective and low-calcemic inhibitors of CYP24 Hydroxylase: 24-Sulfoximine analogues of the hormone 1α,25-dihydroxyvitamin D 3",

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).",

author = "Mehmet Kahraman and Sandra Sinishtaj and Dolan, {Patrick M.} and Kensler, {Thomas W.} and Sara Peleg and Uttam Saha and Chuang, {Samuel S.} and Galina Bernstein and Bozena Korczak and Posner, {Gary H.}",

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month = dec,

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doi = "10.1021/jm040129+",

language = "English (US)",

volume = "47",

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issn = "0022-2623",

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TY - JOUR

T1 - Potent, selective and low-calcemic inhibitors of CYP24 Hydroxylase

T2 - 24-Sulfoximine analogues of the hormone 1α,25-dihydroxyvitamin D 3

AU - Kahraman, Mehmet

AU - Sinishtaj, Sandra

AU - Dolan, Patrick M.

AU - Kensler, Thomas W.

AU - Peleg, Sara

AU - Saha, Uttam

AU - Chuang, Samuel S.

AU - Bernstein, Galina

AU - Korczak, Bozena

AU - Posner, Gary H.

PY - 2004/12/30

Y1 - 2004/12/30

N2 - 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).

AB - 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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SN - 0022-2623

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JO - Journal of medicinal chemistry

JF - Journal of medicinal chemistry

IS - 27

ER -

Potent, selective and low-calcemic inhibitors of CYP24 Hydroxylase: 24-Sulfoximine analogues of the hormone 1α,25-dihydroxyvitamin D ₃

Abstract

ASJC Scopus subject areas

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