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

Z. Lin, S. R. Marepally, T. Kim, Z. Janjetovic, A. S. W Oak, A. E. Postlethwaite, L. K. Myers, Robert C. Tuckey, A. T. Slominski, D. D. Miller, W. Li

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

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.
Original languageEnglish
Pages (from-to)877-886
Number of pages10
JournalAnticancer Research
Volume36
Issue number3
Publication statusPublished - 2016

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Calcitriol Receptors
Hydroxycholecalciferols
Cholesterol Side-Chain Cleavage Enzyme
Anti-Inflammatory Agents
Transient Receptor Potential Channels
Cholecalciferol
Hydroxyl Radical
Interferons
Melanoma
Cell Proliferation
Ligands
Messenger RNA
Genes

Cite this

Lin, Z., Marepally, S. R., Kim, T., Janjetovic, Z., Oak, A. S. W., Postlethwaite, A. E., ... Li, W. (2016). Design, Synthesis and Biological Activities of Novel Gemini 20S-Hydroxyvitamin D-3 Analogs. Anticancer Research, 36(3), 877-886.
Lin, Z. ; Marepally, S. R. ; Kim, T. ; Janjetovic, Z. ; Oak, A. S. W ; Postlethwaite, A. E. ; Myers, L. K. ; Tuckey, Robert C. ; Slominski, A. T. ; Miller, D. D. ; Li, W. / Design, Synthesis and Biological Activities of Novel Gemini 20S-Hydroxyvitamin D-3 Analogs. In: Anticancer Research. 2016 ; Vol. 36, No. 3. pp. 877-886.
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abstract = "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.",
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Lin, Z, Marepally, SR, Kim, T, Janjetovic, Z, Oak, ASW, Postlethwaite, AE, Myers, LK, Tuckey, RC, Slominski, AT, Miller, DD & Li, W 2016, 'Design, Synthesis and Biological Activities of Novel Gemini 20S-Hydroxyvitamin D-3 Analogs' Anticancer Research, vol. 36, no. 3, pp. 877-886.

Design, Synthesis and Biological Activities of Novel Gemini 20S-Hydroxyvitamin D-3 Analogs. / Lin, Z.; Marepally, S. R. ; Kim, T.; Janjetovic, Z.; Oak, A. S. W; Postlethwaite, A. E. ; Myers, L. K. ; Tuckey, Robert C.; Slominski, A. T. ; Miller, D. D. ; Li, W.

In: Anticancer Research, Vol. 36, No. 3, 2016, p. 877-886.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Design, Synthesis and Biological Activities of Novel Gemini 20S-Hydroxyvitamin D-3 Analogs

AU - Lin, Z.

AU - Marepally, S. R.

AU - Kim, T.

AU - Janjetovic, Z.

AU - Oak, A. S. W

AU - Postlethwaite, A. E.

AU - Myers, L. K.

AU - Tuckey, Robert C.

AU - Slominski, A. T.

AU - Miller, D. D.

AU - Li, W.

PY - 2016

Y1 - 2016

N2 - 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.

AB - 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.

M3 - Article

VL - 36

SP - 877

EP - 886

JO - Anticancer Research

JF - Anticancer Research

SN - 0250-7005

IS - 3

ER -

Lin Z, Marepally SR, Kim T, Janjetovic Z, Oak ASW, Postlethwaite AE et al. Design, Synthesis and Biological Activities of Novel Gemini 20S-Hydroxyvitamin D-3 Analogs. Anticancer Research. 2016;36(3):877-886.