jm8b00427_si_002.pdf (9.24 MB)
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
journal contribution
posted on 2018-07-10, 00:00 authored by Rocio Otero, Michiyasu Ishizawa, Nobutaka Numoto, Teikichi Ikura, Nobutoshi Ito, Hiroaki Tokiwa, Antonio Mouriño, Makoto Makishima, Sachiko YamadaBoth
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.