TY - JOUR
T1 - Revisiting the 7,8-cis-Vitamin D3 derivatives
T2 - Synthesis, evaluating the biological activity, and study of the binding configuration
AU - Sawada, Daisuke
AU - Kakuda, Shinji
AU - Kamimura-Takimoto, Midori
AU - Takeuchi, Akiko
AU - Matsumoto, Yotaro
AU - Kittaka, Atsushi
N1 - Funding Information:
This work was supported in part by 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.), The Uehara Memorial Foundation , and Takeda Science Foundation (to D.S.). The authors are grateful for AMED-CREST, AMED for partial support in the preparation of this manuscript.
Publisher Copyright:
© 2016 Elsevier Ltd. All rights reserved.
PY - 2016/6/2
Y1 - 2016/6/2
N2 - Four 7,8-cis-1α,25-dihydroxyVitamin D3 derivatives, 7,8-cis- and 7,8-cis-14-epi-1α,25-dihydroxy-19-norVitamin D3 as well as 7,8-cis- and 7,8-cis-14-epi-1α,25-dihydroxyVitamin D3 were synthesized, and their chemical stability was characterized. In our previous work, we disclosed that 14-epi-19-nortachysterol showed the unprecedented binding configuration in human Vitamin D receptor (hVDR), that is, 5,6- and 7,8-s-trans configuration. However, this configuration is variable because of the rotation at the single bond between C7 and C8. For the precise discussion of the 7,8-s-trans configuration, we designed and synthesized the 7,8-cis-locked skeleton of Vitamin D3 derivatives. Among four analogs, the 19-nor derivatives were stable at ambient temperature, and their hVDR binding affinity and co-crystallographic analysis of their hVDR complexes were studied. The other derivatives with the triene system were isomerized to corresponding preVitamin D3 and Vitamin D3.
AB - Four 7,8-cis-1α,25-dihydroxyVitamin D3 derivatives, 7,8-cis- and 7,8-cis-14-epi-1α,25-dihydroxy-19-norVitamin D3 as well as 7,8-cis- and 7,8-cis-14-epi-1α,25-dihydroxyVitamin D3 were synthesized, and their chemical stability was characterized. In our previous work, we disclosed that 14-epi-19-nortachysterol showed the unprecedented binding configuration in human Vitamin D receptor (hVDR), that is, 5,6- and 7,8-s-trans configuration. However, this configuration is variable because of the rotation at the single bond between C7 and C8. For the precise discussion of the 7,8-s-trans configuration, we designed and synthesized the 7,8-cis-locked skeleton of Vitamin D3 derivatives. Among four analogs, the 19-nor derivatives were stable at ambient temperature, and their hVDR binding affinity and co-crystallographic analysis of their hVDR complexes were studied. The other derivatives with the triene system were isomerized to corresponding preVitamin D3 and Vitamin D3.
KW - 7,8-cis-Vitamin D
KW - Vitamin D receptor
KW - Vitamin D
KW - X-ray cocrystallography
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U2 - 10.1016/j.tet.2016.03.081
DO - 10.1016/j.tet.2016.03.081
M3 - Article
AN - SCOPUS:84963974357
SN - 0040-4020
VL - 72
SP - 2838
EP - 2848
JO - Tetrahedron
JF - Tetrahedron
IS - 22
ER -