TY - JOUR
T1 - Ligands with a 3,3-diphenylpentane skeleton for nuclear vitamin D and androgen receptors
T2 - Dual activities and metabolic activation
AU - Hosoda, Shinnosuke
AU - Tanatani, Aya
AU - Wakabayashi, Ken ichi
AU - Makishima, Makoto
AU - Imai, Keisuke
AU - Miyachi, Hiroyuki
AU - Nagasawa, Kazuo
AU - Hashimoto, Yuichi
N1 - Funding Information:
The work described in this paper was partially supported by Grants-in-Aid for Scientific Research from The Ministry of Education, Culture, Sports, Science and Technology, Japan, and the Japan Society for the Promotion of Science.
PY - 2006/8/15
Y1 - 2006/8/15
N2 - Ligands possessing dual vitamin D3 (VD3)-agonistic and androgen-antagonistic activities with various activity spectra were prepared based on a substituted 3,3-diphenylpentane (DPP) skeleton. Among the compounds, (R,S)-DPP-1023 [(R,S)-7b] and (S,S)-DPP-0123 [(S,S)-7c] showed the most potent vitamin D3-agonistic activity [with potency comparable to that of 1α,25-dihydroxyvitamin D3 (1,25-VD3)] and nuclear androgen receptor (AR)-binding activity (with higher affinity than that of hydroxyflutamide), respectively. Metabolic activation (reduction of the carbonyl group) of pivaloyl analogs [DPP-1113 (3a), DPP-1013 (3b), DPP-0113 (3c), and DPP-0013 (3d)] in HL-60 cells was found to be necessary for binding to nuclear vitamin D3 receptor (VDR).
AB - Ligands possessing dual vitamin D3 (VD3)-agonistic and androgen-antagonistic activities with various activity spectra were prepared based on a substituted 3,3-diphenylpentane (DPP) skeleton. Among the compounds, (R,S)-DPP-1023 [(R,S)-7b] and (S,S)-DPP-0123 [(S,S)-7c] showed the most potent vitamin D3-agonistic activity [with potency comparable to that of 1α,25-dihydroxyvitamin D3 (1,25-VD3)] and nuclear androgen receptor (AR)-binding activity (with higher affinity than that of hydroxyflutamide), respectively. Metabolic activation (reduction of the carbonyl group) of pivaloyl analogs [DPP-1113 (3a), DPP-1013 (3b), DPP-0113 (3c), and DPP-0013 (3d)] in HL-60 cells was found to be necessary for binding to nuclear vitamin D3 receptor (VDR).
KW - Agonist
KW - Androgen
KW - Antagonist
KW - Diphenylpentane
KW - Metabolism
KW - Vitamin D
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U2 - 10.1016/j.bmc.2006.04.039
DO - 10.1016/j.bmc.2006.04.039
M3 - Article
C2 - 16698269
AN - SCOPUS:33745604630
VL - 14
SP - 5489
EP - 5502
JO - Bioorganic and Medicinal Chemistry
JF - Bioorganic and Medicinal Chemistry
SN - 0968-0896
IS - 16
ER -