TY - JOUR
T1 - Synthesis of 2α- and 2β-(3-hydroxypropyl)- 7,8-cis-14-epi-1α,25-dihydroxy-19-norvitamin D3 and their biological activity
AU - Sawada, Daisuke
AU - Ochiai, Eiji
AU - Takeuchi, Akiko
AU - Kakuda, Shinji
AU - Kamimura-Takimoto, Midori
AU - Kawagoe, Fumihiro
AU - Kittaka, Atsushi
N1 - Funding Information:
The authors are grateful for Grants-in-Aid from the Japan Society for the Promotion of Science (No. 23590015 to D.S., No. 24590021 and No. 15K07869 to A.K.), and AMED-CREST, AMED for partial support in the preparation of this manuscript.
Publisher Copyright:
© 2016 Elsevier Ltd
PY - 2017/10
Y1 - 2017/10
N2 - According to the binding mode of 14-epi-1α,25-dihydroxy-19-nortachysterol in the ligand binding domain of human vitamin D receptor (hVDR), i.e., 5,6- and 7,8-s-trans configuration that was shown by X-ray co-crystallographic analysis, 7,8-cis-locked 1α,25(OH)2D3 analogs were synthesized. In this paper, the synthesis and biological activity of 2α- and 2β-(3-hydroxypropyl)-7,8-cis-14-epi-1α,25-dihydroxy-19-norvitamin D3 are reported. The A-ring and CD-ring precursors for the Julia-Kociensky coupling reaction to create a diene system of the target molecules were prepared using our original methods. hVDR binding affinity and osteocalcin promoter transactivation activity of the new 7,8-cis-14-epi-vitamin D3 analogs were evaluated. Interestingly, the 2β-substituted 7,8-cis-analog was a better binder for hVDR than the 2α-isomeric counterpart.
AB - According to the binding mode of 14-epi-1α,25-dihydroxy-19-nortachysterol in the ligand binding domain of human vitamin D receptor (hVDR), i.e., 5,6- and 7,8-s-trans configuration that was shown by X-ray co-crystallographic analysis, 7,8-cis-locked 1α,25(OH)2D3 analogs were synthesized. In this paper, the synthesis and biological activity of 2α- and 2β-(3-hydroxypropyl)-7,8-cis-14-epi-1α,25-dihydroxy-19-norvitamin D3 are reported. The A-ring and CD-ring precursors for the Julia-Kociensky coupling reaction to create a diene system of the target molecules were prepared using our original methods. hVDR binding affinity and osteocalcin promoter transactivation activity of the new 7,8-cis-14-epi-vitamin D3 analogs were evaluated. Interestingly, the 2β-substituted 7,8-cis-analog was a better binder for hVDR than the 2α-isomeric counterpart.
KW - 7,8-cis-19-norvitamin D analog
KW - Synthesis
KW - Transactivation
KW - VDR binding affinity
KW - Vitamin D receptor
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U2 - 10.1016/j.jsbmb.2016.09.007
DO - 10.1016/j.jsbmb.2016.09.007
M3 - Article
C2 - 27629592
AN - SCOPUS:85011028506
VL - 173
SP - 79
EP - 82
JO - Journal of Steroid Biochemistry
JF - Journal of Steroid Biochemistry
SN - 0960-0760
ER -
