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 anti-inflammatory 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 1α,25-dihydroxyvitamin D3. Moreover, these analogs reduced the level of interferon γ 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.
authors.affiliation: Department of Pharmaceutical Sciences, University of Tennessee Health Science Center, Memphis, TN, U.S.A.
authors.forename: Zongtao
authors.initials: Z
authors.lastname: Lin
authors.affiliation: Department of Pharmaceutical Sciences, University of Tennessee Health Science Center, Memphis, TN, U.S.A.
authors.forename: Srinivasa R
authors.initials: SR
authors.lastname: Marepally
authors.affiliation: Department of Dermatology, University of Alabama at Birmingham, Birmingham, AL, U.S.A.
authors.forename: Tae-Kang
authors.initials: TK
authors.lastname: Kim
authors.affiliation: Department of Dermatology, University of Alabama at Birmingham, Birmingham, AL, U.S.A.
authors.forename: Zorica
authors.initials: Z
authors.lastname: Janjetovic
authors.affiliation: Department of Dermatology, University of Alabama at Birmingham, Birmingham, AL, U.S.A.
authors.forename: Allen Sw
authors.initials: AS
authors.lastname: Oak
authors.affiliation: Department of Medicine, University of Tennessee Health Science Center, Memphis, TN, U.S.A. Veterans Affairs Medical Center at Memphis, Memphis, TN, U.S.A.
authors.forename: Arnold E
authors.initials: AE
authors.lastname: Postlethwaite
authors.affiliation: Department of Medicine, University of Tennessee Health Science Center, Memphis, TN, U.S.A.
authors.forename: Linda K
authors.initials: LK
authors.lastname: Myers
authors.affiliation: School of Chemistry and Biochemistry, University of Western Australia, Crawley, WA, Australia.
authors.forename: Robert C
authors.initials: RC
authors.lastname: Tuckey
authors.affiliation: Department of Dermatology, University of Alabama at Birmingham, Birmingham, AL, U.S.A. Veterans Affairs Medical Center at Birmingham, Birmingham, AL, U.S.A.
authors.forename: Andrzej T
authors.initials: AT
authors.lastname: Slominski
authors.affiliation: Department of Pharmaceutical Sciences, University of Tennessee Health Science Center, Memphis, TN, U.S.A.
authors.forename: Duane D
authors.initials: DD
authors.lastname: Miller
authors.affiliation: Department of Pharmaceutical Sciences, University of Tennessee Health Science Center, Memphis, TN, U.S.A. wli@uthsc.edu.
authors.forename: Wei
authors.initials: W
authors.lastname: Li
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D002112:Calcifediol / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D054697:Cytostatic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D015195:Drug Design; D006801:Humans; D019169:Jurkat Cells; D015603:Keratinocytes / Q000187:drug effects / Q000276:immunology; D051379:Mice; D018167:Receptors, Calcitriol / Q000378:metabolism; D013154:Spleen / Q000166:cytology / Q000187:drug effects / Q000276:immunology
chemical_list: C480634:20-hydroxyvitamin D3; D000893:Anti-Inflammatory Agents; D054697:Cytostatic Agents; D018167:Receptors, Calcitriol; D002112:Calcifediol
keywords: 20-Hydroxyvitamin D3; CYP24A1; Gemini analogs; anti-inflammation; anti-proliferation; vitamin D receptor