Rational design, synthesis, and biological activity of novel conformationally restricted vitamin D analogues, (22R)- and (22S)-22-ethyl-1,25-dihydroxy-23,24-didehydro-24a,24b-dihomo-20-epivitamin D(3).
Two new vitamin D analogues, (22R)- and (22S)-22-ethyl-1,25-dihydroxy-23,24-didehydro-24a,24b-dihomo-20-epivitamin D(3) (3 and 4), were rationally designed on the basis of the active space group concept previously proposed by us. The 22R ethyl group of 3 restricts the mobility of the side chain to active space regions, whereas the 22S ethyl group of 4 confines the side chain to an inactive region. The double bond at C(23) further restricts the side chain flexibility. These compounds (3 and 4) were synthesized using ortho ester Claisen rearrangement as the key step. As expected, the 22R isomer 3 has nearly 100 times higher efficacy than 1,25-dihydroxyvitamin D(3) (1) in cell differentiation, although its affinity for the vitamin D receptor (VDR) was one-seventh of that of 1. The 22S isomer 4 has significantly lower efficacy than 3. A docking study in combination with site-directed mutation analysis revealed that two carbon elongated side chain analogue 3 could be fitted in the ligand binding pocket of the VDR by adopting a stable conformation.
Masuno
Hiroyuki
H
Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University, 2-3-10, Kanda-Surugadai, Chiyoda-ku, Tokyo 101-0062, Japan.
Yamamoto
Keiko
K
Wang
Xinxiang
X
Choi
Mihwa
M
Ooizumi
Hiroshi
H
Shinki
Toshimasa
T
Yamada
Sachiko
S
D000818:Animals; D019556:COS Cells; D002118:Calcium / Q000172:deficiency; D002454:Cell Differentiation / Q000187:drug effects; D018360:Crystallography, X-Ray; D018922:HL-60 Cells; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D008968:Molecular Conformation; D016297:Mutagenesis, Site-Directed; D051381:Rats; D018167:Receptors, Calcitriol / Q000378:metabolism; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D014807:Vitamin D / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D014808:Vitamin D Deficiency / Q000378:metabolism
C453981:22-ethyl-1,25-dihydroxy-23,24-didehydro-24a,24b-dihomo-20-epivitamin D(3); D008024:Ligands; D018167:Receptors, Calcitriol; D014807:Vitamin D; D002118:Calcium