Design, Synthesis and Biological Activities of Novel Gemini 20S-Hydroxyvitamin D-3 Analogs

Vitamin D-3 (D-3) can be metabolized by cytochrome P450scc (CYP11A1) into 20S-hydroxyvitamin D-3 (20D(3)) as a major metabolite. This bioactive metabolite has shown strong antiproliferative, antifibrotic, pro-differentiation and antiinflammatory effects while being non-toxic (non-calcemic) at high concentrations. Since D-3 analogs with two symmetric side chains (Gemini analogs) result in potent activation of the vitamin D receptor (VDR), we hypothesized that the chain length and composition of these types of analogs also containing a 20-hydroxyl group would affect their biological activities. In this study, we designed and synthesized a series of Gemini 20D(3) analogs. Biological tests showed that some of these analogs are partial VDR activators and can significantly stimulate the expression of mRNA for VDR and VDR-regulated genes including CYP24A1 and transient receptor potential cation channel V6 (TRPV6). These analogs inhibited the proliferation of melanoma cells with potency comparable to that of 1 alpha, 25-dihydroxyvitamin D-3. Moreover, these analogs reduced the level of interferon. and up-regulated the expression of leukocyte associated immunoglobulin-like receptor 1 in splenocytes, indicating that they have potent anti-inflammatory activities. There are no clear correlations between the Gemini chain length and their VDR activation or biological activities, consistent with the high flexibility of the ligand-binding pocket of the VDR.