Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
2028233 | Steroids | 2012 | 12 Pages |
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.
Graphical abstractFigure optionsDownload full-size imageDownload as PowerPoint slideHighlights► Potent vitamin D-like CYP24 inhibitors are efficiently prepared in convergent syntheses. ► The 25-N-cyclopropylamine side chain modified vitamin D analog 3 selectively inhibits CYP24A1. ► 3 Causes differentiation of leukemia cells nearly as well as the natural hormone. ► The calcemic activity of 3 is considerably lower than that of the native hormone. ► Docking studies provide insights to the selectivity of 3 for CYP24A1 over CYP27B1.