title: Synthesis and biological activities of vitamin D-like inhibitors of CYP24 hydroxylase.
abstract: Selective inhibitors of CYP24A1 represent an important synthetic target in a search for novel vitamin D compounds of therapeutic value. In the present work, we show the synthesis and biological properties of two novel side chain modified 2-methylene-19-nor-1,25(OH)(2)D(3) analogs, the 22-imidazole-1-yl derivative 2 (VIMI) and the 25-N-cyclopropylamine compound 3 (CPA1), which were efficiently prepared in convergent syntheses utilizing the Lythgoe type Horner-Wittig olefination reaction. When tested in a cell-free assay, both compounds were found to be potent competitive inhibitors of CYP24A1, with the cyclopropylamine analog 3 exhibiting an 80-1 selective inhibition of CYP24A1 over CYP27B1. Addition of 3 to a mouse osteoblast culture sustained the level of 1,25(OH)(2)D(3), further demonstrating its effectiveness in CYP24A1 inhibition. Importantly, the in vitro effects on human promyeloid leukemia (HL-60) cell differentiation by 3 were nearly identical to those of 1,25(OH)(2)D(3) and in vivo the compound showed low calcemic activity. Finally, the results of preliminary theoretical studies provide useful insights to rationalize the ability of analog 3 to selectively inhibit the cytochrome P450 isoform CYP24A1.
authors: Department of Biochemistry, University of Wisconsin-Madison, 433 Babcock Drive, Madison, WI 53706-1544, USA.
authors: Grazia
authors: G
authors: Chiellini
authors: Simona
authors: S
authors: Rapposelli
authors: Jinge
authors: J
authors: Zhu
authors: Ilaria
authors: I
authors: Massarelli
authors: Marilena
authors: M
authors: Saraceno
authors: Anna Maria
authors: AM
authors: Bianucci
authors: Lori A
authors: LA
authors: Plum
authors: Margaret
authors: M
authors: Clagett-Dame
authors: Hector F
authors: HF
authors: DeLuca
mesh_terms: D015090:25-Hydroxyvitamin D3 1-alpha-Hydroxylase / Q000037:antagonists & inhibitors; D000595:Amino Acid Sequence; D000818:Animals; D002112:Calcifediol / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000737:chemistry; D002118:Calcium / Q000737:chemistry; D002454:Cell Differentiation; D003521:Cyclopropanes / Q000138:chemical synthesis / Q000737:chemistry; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D018922:HL-60 Cells; D006207:Half-Life; D006801:Humans; D006887:Hydroxycholecalciferols / Q000737:chemistry; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D008969:Molecular Sequence Data; D010006:Osteoblasts / Q000187:drug effects; D051381:Rats; D017386:Sequence Homology, Amino Acid; D013250:Steroid Hydroxylases / Q000037:antagonists & inhibitors*; D015533:Transcriptional Activation; D014807:Vitamin D / Q000031:analogs & derivatives* / Q000737:chemistry; D065668:Vitamin D3 24-Hydroxylase
chemical_list: D003521:Cyclopropanes; D004791:Enzyme Inhibitors; D006887:Hydroxycholecalciferols; C571969:N-cyclopropyl-2-methylene-19,25,26,27-tetranor-25-aza-1-hydroxyvitamin D; D014807:Vitamin D; C067351:cyclopropylamine; D013250:Steroid Hydroxylases; C585549:CYP24A1 protein, human; C585550:Cyp24a1 protein, mouse; C585551:Cyp24a1 protein, rat; D065668:Vitamin D3 24-Hydroxylase; D015090:25-Hydroxyvitamin D3 1-alpha-Hydroxylase; D002112:Calcifediol; D002118:Calcium