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 OteroRocio IshizawaMichiyasu NumotoNobutaka IkuraTeikichi ItoNobutoshi TokiwaHiroaki MouriñoAntonio MakishimaMakoto YamadaSachiko 2018 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.