TY - JOUR
T1 - 22-Alkyl-20-epi-1α,25-dihydroxyvitamin D3 compounds of superagonistic activity
T2 - Syntheses, biological activities and interaction with the receptor
AU - Yamamoto, Keiko
AU - Inaba, Yuka
AU - Yoshimoto, Nobuko
AU - Choi, Mihwa
AU - DeLuca, Hector F.
AU - Yamada, Sachiko
PY - 2007/3/8
Y1 - 2007/3/8
N2 - We previously reported that 22R-methyl-20-epi-1,25-(OH)2D 3 (3) possesses strong binding affinity for the vitamin D receptor (VDR) and shows superagonistic biological activities. To examine the effect of the length of an alkyl substituent at C(22) and to extend our compound library, we successfully synthesized 22R-ethyl-20-epi-1,25-(OH)2D3 (4) and 22R-butyl-20-epi-1,25-(OH)2D3 (5). Surprisingly, 22-ethyl analogue 4 showed stronger VDR binding affinity and transactivation potency than the superagonist of methyl analogue 3, but its calcemic activity in vivo was weaker than that of both the methyl analogue 3 and the natural hormone (1), while 22-butyl analogue 5 showed activities comparable to those of the hormone (1). A study of the docking of these new analogues to the VDR-LBD and alanine scanning mutational analysis demonstrated that 22-methyl and 22-ethyl substituents enhance the favorable hydrophobic interactions with residues lining the ligand binding pocket of the VDR, and that 22-butyl analogue 5 binds to the VDR by an induced fit mechanism.
AB - We previously reported that 22R-methyl-20-epi-1,25-(OH)2D 3 (3) possesses strong binding affinity for the vitamin D receptor (VDR) and shows superagonistic biological activities. To examine the effect of the length of an alkyl substituent at C(22) and to extend our compound library, we successfully synthesized 22R-ethyl-20-epi-1,25-(OH)2D3 (4) and 22R-butyl-20-epi-1,25-(OH)2D3 (5). Surprisingly, 22-ethyl analogue 4 showed stronger VDR binding affinity and transactivation potency than the superagonist of methyl analogue 3, but its calcemic activity in vivo was weaker than that of both the methyl analogue 3 and the natural hormone (1), while 22-butyl analogue 5 showed activities comparable to those of the hormone (1). A study of the docking of these new analogues to the VDR-LBD and alanine scanning mutational analysis demonstrated that 22-methyl and 22-ethyl substituents enhance the favorable hydrophobic interactions with residues lining the ligand binding pocket of the VDR, and that 22-butyl analogue 5 binds to the VDR by an induced fit mechanism.
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U2 - 10.1021/jm060889f
DO - 10.1021/jm060889f
M3 - Article
C2 - 17298045
AN - SCOPUS:33847778728
SN - 0022-2623
VL - 50
SP - 932
EP - 939
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
IS - 5
ER -