| RRC ID |
65996
|
| Author |
Otero R, Ishizawa M, Numoto N, Ikura T, Ito N, Tokiwa H, Mouriño A, Makishima M, Yamada S.
|
| Title |
25 S-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 |
J Med Chem
|
| Abstract |
Both 25 R- and 25 S-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 25 S 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.
|
| Volume |
61(15)
|
| Pages |
6658-6673
|
| Published |
2018-8-9
|
| DOI |
10.1021/acs.jmedchem.8b00427
|
| PMID |
29989817
|
| MeSH |
Biological Transport
Chemistry Techniques, Synthetic
Crystallography, X-Ray
HEK293 Cells
Humans
Receptors, Calcitriol / chemistry*
Receptors, Calcitriol / genetics
Receptors, Calcitriol / metabolism*
Stereoisomerism
Transcription, Genetic / drug effects
Vitamin D / analogs & derivatives*
Vitamin D / chemical synthesis
Vitamin D / chemistry
Vitamin D / metabolism
Vitamin D / pharmacology
|
| IF |
6.205
|
| Resource |
| Human and Animal Cells |
U937
293(RCB1637)
MG-63(RCB1890) |
