10.1021/acs.jmedchem.8b00427.s001
Rocio Otero
Rocio
Otero
Michiyasu Ishizawa
Michiyasu
Ishizawa
Nobutaka Numoto
Nobutaka
Numoto
Teikichi Ikura
Teikichi
Ikura
Nobutoshi Ito
Nobutoshi
Ito
Hiroaki Tokiwa
Hiroaki
Tokiwa
Antonio Mouriño
Antonio
Mouriño
Makoto Makishima
Makoto
Makishima
Sachiko Yamada
Sachiko
Yamada
25<i>S</i>‑Adamantyl-23-yne-26,27-dinor-1α,25-dihydroxyvitamin
D<sub>3</sub>: Synthesis, Tissue Selective Biological Activities,
and X‑ray Crystal Structural Analysis of Its Vitamin D Receptor
Complex
American Chemical Society
2018
1 VDR-LBD complexes
Vitamin D Receptor Complex
alkenyl-boronic ester 8
4 b
24A
25 S isomer
vitamin D receptor
MG
25 S -25- adamantyl -23-yne D 3
rat VDR-ligand binding domain
HEK
SW
helix 11. Helix 11
CYP
2018-07-10 00:00:00
Dataset
https://acs.figshare.com/articles/dataset/25_i_S_i_Adamantyl-23-yne-26_27-dinor-1_25-dihydroxyvitamin_D_sub_3_sub_Synthesis_Tissue_Selective_Biological_Activities_and_X_ray_Crystal_Structural_Analysis_of_Its_Vitamin_D_Receptor_Complex/6848429
Both
25<i>R</i>- and 25<i>S</i>-25-adamantyl-23-yne-26,27-dinor-1α,25-dihydroxyvitamin
D<sub>3</sub> (<b>4a</b> and <b>4b</b>) were stereoselectively
synthesized by a Pd(0)-catalyzed ring closure and Suzuki–Miyaura
coupling between enol-triflate <b>7</b> and alkenyl-boronic
ester <b>8</b>. The 25<i>S</i> isomer (<b>4b</b>) showed high vitamin D receptor (VDR) affinity (50% of that of the
natural hormone 1α,25-dihydroxyvitamin D<sub>3</sub>, <b>1</b>) and transactivation potency (kidney HEK293, 90%). In endogenous
gene expression, it showed high cell-type selectivity for kidney cells
(HEK293, CYP24A1 160% of <b>1</b>), bone cells (MG63, osteocalcin
64%), and monocytes (U937, CAMP 96%) over intestine (SW480, CYP24A1
8%) and skin (HaCaT, CYP24A1 7%) cells. The X-ray crystal structural
analysis of <b>4b</b> in complex with rat VDR-ligand binding
domain (LBD) showed the highest Cα positional shift from the <b>1/</b>VDR-LBD complex at helix 11. Helix 11 of the <b>4b</b> and <b>1</b> VDR-LBD complexes also showed significant differences
in surface properties. These results suggest that <b>4b</b> should
be examined further as another candidate for a mild preventive osteoporosis
agent.