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

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Both 25 R - and 25 S -25-adamantyl-23-yne-26,27-dinor-1α,25-dihydroxyvitamin D 3 ( 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 25 S isomer ( 4b ) showed high vitamin D receptor (VDR) affinity (50% of that of the natural hormone 1α,25-dihydroxyvitamin D 3, 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.