Synthesis and biological activities of vitamin D-like inhibitors of CYP24 hydroxylase

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• 作者：Grazia Chiellini^a ; ^b ; Simona Rapposelli^c ; Jinge Zhu^a ; Ilaria Massarelli^d ; Marilena Saraceno^c ; Anna Maria Bianucci^c ; ^e ; Lori A. Plum^a ; Margaret Clagett-Dame^a ; Hector F. DeLuca^a ; ^{deluca@bioChem.wisc.edu}
• 关键词：1 ; 25-Dihydroxyvitamin D3 ; Cytochrome P450 inhibitors ; CYP24A1 ; Cyclopropylamines ; Cancer therapy ; Molecular docking
• 刊名：Steroids
• 出版年：2012
• 出版时间：February 2012
• 年：2012
• 卷：77
• 期：3
• 页码：212-223
• 全文大小：1390 K

文摘

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)₂D₃ 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)₂D₃, 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)₂D₃ 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.