| Autor: |
Lin Z; Department of Pharmaceutical Sciences, University of Tennessee Health Science Center, 881 Madison Avenue, Room 561, Memphis, TN, 38163, United States., Chen H; Department of Pharmaceutical Sciences, University of Tennessee Health Science Center, 881 Madison Avenue, Room 561, Memphis, TN, 38163, United States., Belorusova AY; Department of Integrative Structure Biology, IGBMC - CNRS UMR7104 - Inserm U964, 1, rue Laurent Fries, Illkirch, 67400, France.; Department of Medicinal Chemistry, RIA iMed, AstraZeneca R&D, Pepparedsleden 1, S-431 83, Mölndal, Sweden., Bollinger JC; Department of Structural Biology, St. Jude Children's Research Hospital, Memphis, TN, 38105, United States., Tang EKY; School of Chemistry and Biochemistry, University of Western Australia, Crawley, WA, 6009, Australia., Janjetovic Z; Department of Dermatology, University of Alabama at Birmingham, Birmingham, AL, 35294, United States., Kim TK; Department of Dermatology, University of Alabama at Birmingham, Birmingham, AL, 35294, United States., Wu Z; Department of Pharmaceutical Sciences, University of Tennessee Health Science Center, 881 Madison Avenue, Room 561, Memphis, TN, 38163, United States., Miller DD; Department of Pharmaceutical Sciences, University of Tennessee Health Science Center, 881 Madison Avenue, Room 561, Memphis, TN, 38163, United States., Slominski AT; Department of Dermatology, University of Alabama at Birmingham, Birmingham, AL, 35294, United States.; VA Medical Center, Birmingham, AL, 35294, United States., Postlethwaite AE; Department of Medicine, University of Tennessee Health Science Center, Memphis, TN, 38163, United States.; VA Medical Center, Memphis, TN, 38104, United States., Tuckey RC; School of Chemistry and Biochemistry, University of Western Australia, Crawley, WA, 6009, Australia., Rochel N; Department of Integrative Structure Biology, IGBMC - CNRS UMR7104 - Inserm U964, 1, rue Laurent Fries, Illkirch, 67400, France., Li W; Department of Pharmaceutical Sciences, University of Tennessee Health Science Center, 881 Madison Avenue, Room 561, Memphis, TN, 38163, United States. wli@uthsc.edu. |
| Abstrakt: |
1α,20S-Dihydroxyvitamin D3 [1,20S(OH) 2 D 3 ], a natural and bioactive vitamin D3 metabolite, was chemically synthesized for the first time. X-ray crystallography analysis of intermediate 15 confirmed its 1α-OH configuration. 1,20S(OH) 2 D 3 interacts with the vitamin D receptor (VDR), with similar potency to its native ligand, 1α,25-dihydroxyvitamin D 3 [1,25(OH) 2 D 3 ] as illustrated by its ability to stimulate translocation of the VDR to the nucleus, stimulate VDRE-reporter activity, regulate VDR downstream genes (VDR, CYP24A1, TRPV6 and CYP27B1), and inhibit the production of inflammatory markers (IFNγ and IL1β). However, their co-crystal structures revealed differential molecular interactions of the 20S-OH moiety and the 25-OH moiety to the VDR, which may explain some differences in their biological activities. Furthermore, this study provides a synthetic route for the synthesis of 1,20S(OH) 2 D 3 using the intermediate 1α,3β-diacetoxypregn-5-en-20-one (3), and provides a molecular and biological basis for the development of 1,20S(OH) 2 D 3 and its analogs as potential therapeutic agents. |
