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

Zongtao Lin, Srinivasa R. Marepally, Tae Kang Kim, Zorica Janjetovic, Allen Sw Oak, Arnold Postlethwaite, Linda Myers, Robert C. Tuckey, Andrzej T. Slominski, Duane Miller, Wei Li

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)877-886
Number of pages10
JournalAnticancer research
Volume36
Issue number3
StatePublished - Mar 1 2016

Fingerprint

Calcitriol Receptors
Cholesterol Side-Chain Cleavage Enzyme
Anti-Inflammatory Agents
Transient Receptor Potential Channels
Cholecalciferol
Hydroxyl Radical
Interferons
20-hydroxyvitamin D3
Melanoma
Cell Proliferation
Ligands
Messenger RNA
Genes

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

Lin, Z., Marepally, S. R., Kim, T. K., Janjetovic, Z., Oak, A. S., Postlethwaite, A., ... Li, W. (2016). Design, synthesis and biological activities of novel gemini 20s-hydroxyVitamin D3 analogs. Anticancer research, 36(3), 877-886.

Design, synthesis and biological activities of novel gemini 20s-hydroxyVitamin D3 analogs. / Lin, Zongtao; Marepally, Srinivasa R.; Kim, Tae Kang; Janjetovic, Zorica; Oak, Allen Sw; Postlethwaite, Arnold; Myers, Linda; Tuckey, Robert C.; Slominski, Andrzej T.; Miller, Duane; Li, Wei.

In: Anticancer research, Vol. 36, No. 3, 01.03.2016, p. 877-886.

Research output: Contribution to journalArticle

Lin, Z, Marepally, SR, Kim, TK, Janjetovic, Z, Oak, AS, Postlethwaite, A, Myers, L, Tuckey, RC, Slominski, AT, Miller, D & Li, W 2016, 'Design, synthesis and biological activities of novel gemini 20s-hydroxyVitamin D3 analogs', Anticancer research, vol. 36, no. 3, pp. 877-886.
Lin Z, Marepally SR, Kim TK, Janjetovic Z, Oak AS, Postlethwaite A et al. Design, synthesis and biological activities of novel gemini 20s-hydroxyVitamin D3 analogs. Anticancer research. 2016 Mar 1;36(3):877-886.
Lin, Zongtao ; Marepally, Srinivasa R. ; Kim, Tae Kang ; Janjetovic, Zorica ; Oak, Allen Sw ; Postlethwaite, Arnold ; Myers, Linda ; Tuckey, Robert C. ; Slominski, Andrzej T. ; Miller, Duane ; Li, Wei. / Design, synthesis and biological activities of novel gemini 20s-hydroxyVitamin D3 analogs. In: Anticancer research. 2016 ; Vol. 36, No. 3. pp. 877-886.
@article{d7bf1203904541748a9038c889fee07d,
title = "Design, synthesis and biological activities of novel gemini 20s-hydroxyVitamin D3 analogs",
abstract = "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 = "Zongtao Lin and Marepally, {Srinivasa R.} and Kim, {Tae Kang} and Zorica Janjetovic and Oak, {Allen Sw} and Arnold Postlethwaite and Linda Myers and Tuckey, {Robert C.} and Slominski, {Andrzej T.} and Duane Miller and Wei Li",
year = "2016",
month = "3",
day = "1",
language = "English (US)",
volume = "36",
pages = "877--886",
journal = "Anticancer Research",
issn = "0250-7005",
publisher = "International Institute of Anticancer Research",
number = "3",

}

TY - JOUR

T1 - Design, synthesis and biological activities of novel gemini 20s-hydroxyVitamin D3 analogs

AU - Lin, Zongtao

AU - Marepally, Srinivasa R.

AU - Kim, Tae Kang

AU - Janjetovic, Zorica

AU - Oak, Allen Sw

AU - Postlethwaite, Arnold

AU - Myers, Linda

AU - Tuckey, Robert C.

AU - Slominski, Andrzej T.

AU - Miller, Duane

AU - Li, Wei

PY - 2016/3/1

Y1 - 2016/3/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84991671517&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84991671517&partnerID=8YFLogxK

M3 - Article

VL - 36

SP - 877

EP - 886

JO - Anticancer Research

JF - Anticancer Research

SN - 0250-7005

IS - 3

ER -