Design, synthesis and biological activities of novel gemini 20s-hydroxyVitamin D3 analogs

Academic Article


  • Vitamin D3 (D3) can be metabolized by cytochrome P450scc (CYP11A1) into 20S-hydroxyVitamin D3 (20D3) 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 D3 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 20D3 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?,25-dihydroxyVitamin D3. 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.
  • Author List

  • Lin Z; Marepally SR; Kim TK; Janjetovic Z; Oak AS; Postlethwaite AE; Myers LK; Tuckey RC; Slominski AT; Miller DD
  • Start Page

  • 877
  • End Page

  • 886
  • Volume

  • 36
  • Issue

  • 3