%0 Generic %A Otero, Rocio %A Ishizawa, Michiyasu %A Numoto, Nobutaka %A Ikura, Teikichi %A Ito, Nobutoshi %A Tokiwa, Hiroaki %A Mouriño, Antonio %A Makishima, Makoto %A Yamada, Sachiko %D 2018 %T 25S‑Adamantyl-23-yne-26,27-dinor-1α,25-dihydroxyvitamin D3: Synthesis, Tissue Selective Biological Activities, and X‑ray Crystal Structural Analysis of Its Vitamin D Receptor Complex %U 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 %R 10.1021/acs.jmedchem.8b00427.s001 %2 https://acs.figshare.com/ndownloader/files/12467993 %K 1 VDR-LBD complexes %K Vitamin D Receptor Complex %K alkenyl-boronic ester 8 %K 4 b %K 24A %K 25 S isomer %K vitamin D receptor %K MG %K 25 S -25- adamantyl -23-yne D 3 %K rat VDR-ligand binding domain %K HEK %K SW %K helix 11. Helix 11 %K CYP %X Both 25R- and 25S-25-adamantyl-23-yne-26,27-dinor-1α,25-dihydroxy­vitamin D3 (4a and 4b) were stereoselectively synthesized by a Pd(0)-catalyzed ring closure and Suzuki–Miyaura coupling between enol-triflate 7 and alkenyl-boronic ester 8. The 25S isomer (4b) showed high vitamin D receptor (VDR) affinity (50% of that of the natural hormone 1α,25-dihydroxy­vitamin D3, 1) and transactivation potency (kidney HEK293, 90%). In endogenous gene expression, it showed high cell-type selectivity for kidney cells (HEK293, CYP24A1 160% of 1), 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 4b in complex with rat VDR-ligand binding domain (LBD) showed the highest Cα positional shift from the 1/VDR-LBD complex at helix 11. Helix 11 of the 4b and 1 VDR-LBD complexes also showed significant differences in surface properties. These results suggest that 4b should be examined further as another candidate for a mild preventive osteoporosis agent. %I ACS Publications