Revisiting the 7,8-cis-vitamin D3 derivatives: synthesis, evaluating the biological activity, and study of the binding configuration
2016
Sawada, Daisuke | Kakuda, Shinji | Kamimura-Takimoto, Midori | Takeuchi, Akiko | Matsumoto, Yotaro | Kittaka, Atsushi
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.
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