Design and efficient synthesis of 2 alpha-(omega-hydroxyalkoxy)-1 alpha,25-dihydroxyvitamin D3 Analogues, including 2-epi-ED-71 and their 20-epimers with HL-60 cell differentiation activity.
A concise and efficient synthetic approach to 2 alpha-(omega-hydroxyalkoxy)-1 alpha,25-dihydroxyvitamin D(3) (4a-c), including 2-epi-ED-71, was developed starting from D-glucose as a chiral template for the construction of the 2 alpha-modified A-ring precursors (11a-c). It was found that the best ligand for the bovine thymus vitamin D receptor (VDR) in this series is 4b, which has 1.8 times greater binding affinity for the bovine thymus VDR than that of the natural hormone 1. Interestingly, potency in the induction of HL-60 cell differentiation for 4a-c was almost the same or weaker than that of 1 despite the strong binding affinity for the VDR. Next, we were interested in the "double modification"of 1 based on 4a-c with C20-epimerization, affording 2 alpha-(omega-hydroxyalkoxy)-20-epi-1 alpha,25-dihydroxyvitamin D(3) (20-epi-4a-c). All three 2 alpha-substituted 20-epi analogues of 1 (20-epi-4a-c) exhibited stronger binding affinities for the VDR, and their conformations in the ligand binding domain of VDR were analyzed by molecular modeling. Double-modified analogues of 20-epi-4a-c showed marked HL-60 cell differentiation activity, and 20-epi-4a possesses an activity 58-fold higher than that of the natural hormone 1.
Saito
Nozomi
N
Department of Pharmaceutical Chemistry, Faculty of Pharmaceutical Sciences, Teikyo University, Sagamiko, Kanagawa 199-0195, Japan.
Suhara
Yoshitomo
Y
Kurihara
Masaaki
M
Fujishima
Toshie
T
Honzawa
Shinobu
S
Takayanagi
Hitoshi
H
Kozono
Toshiro
T
Matsumoto
Masahiko
M
Ohmori
Masayuki
M
Miyata
Naoki
N
Takayama
Hiroaki
H
Kittaka
Atsushi
A
D000818:Animals; D002117:Calcitriol / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000494:pharmacology; D002417:Cattle; D002454:Cell Differentiation; D018360:Crystallography, X-Ray; D018922:HL-60 Cells; D006801:Humans; D008958:Models, Molecular; D008968:Molecular Conformation; D015394:Molecular Structure; D013237:Stereoisomerism; D013950:Thymus Gland / Q000378:metabolism
D002117:Calcitriol