title: Potent, selective and low-calcemic inhibitors of CYP24 hydroxylase: 24-sulfoximine analogues of the hormone 1alpha,25-dihydroxyvitamin D(3).
abstract: A dozen 24-sulfoximine analogues of the hormone 1alpha,25-dihydroxyvitamin D(3) 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 (IC(50) = 7.4 nM) having low calcemic activity. In addition, this compound shows high selectivity toward the CYP24 enzyme in comparison to CYP27A1 (IC(50) > 1000 nM) and CYP27B (IC(50) = 554 nM).
authors.affiliation: Department of Chemistry, School of Arts and Sciences, The Johns Hopkins University, Baltimore, MD 21218, USA.
authors.forename: Mehmet
authors.initials: M
authors.lastname: Kahraman
authors.forename: Sandra
authors.initials: S
authors.lastname: Sinishtaj
authors.forename: Patrick M
authors.initials: PM
authors.lastname: Dolan
authors.forename: Thomas W
authors.initials: TW
authors.lastname: Kensler
authors.forename: Sara
authors.initials: S
authors.lastname: Peleg
authors.forename: Uttam
authors.initials: U
authors.lastname: Saha
authors.forename: Samuel S
authors.initials: SS
authors.lastname: Chuang
authors.forename: Galina
authors.initials: G
authors.lastname: Bernstein
authors.forename: Bozena
authors.initials: B
authors.lastname: Korczak
authors.forename: Gary H
authors.initials: GH
authors.lastname: Posner
mesh_terms: D000818:Animals; D002117:Calcitriol / Q000031:analogs & derivatives* / Q000494:pharmacology; D002118:Calcium / Q000652:urine*; D065607:Cytochrome P-450 Enzyme Inhibitors; D008297:Male; D051381:Rats; D011916:Rats, Inbred F344; D013250:Steroid Hydroxylases / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D013450:Sulfones / Q000138:chemical synthesis* / Q000494:pharmacology; D065668:Vitamin D3 24-Hydroxylase
chemical_list: D065607:Cytochrome P-450 Enzyme Inhibitors; D013450:Sulfones; D013250:Steroid Hydroxylases; D065668:Vitamin D3 24-Hydroxylase; D002117:Calcitriol; D002118:Calcium