Low-calcemic, efficacious, 1alpha,25-dihydroxyvitamin D3 analog QW-1624F2-2: calcemic dose-response determination, preclinical genotoxicity testing, and revision of A-ring stereochemistry.
Based on an X-ray crystal structure determination, the A-ring stereochemistry of hybrid analog QW-1624F2-2 (1alpha-hydroxymethyl-16-ene-24,24-difluoro-25-hydroxy-26,27-bis-homovitamin D3) is revised to be 1alpha-CH2OH-3beta-OH. This analog is shown to be approximately 80-100 times less calciuric than the natural hormone 1alpha,25-dihydoxyvitamin D3. This analog is shown also to be non-genotoxic in three different standard assays.
Posner
Gary H
GH
Department of Chemistry, The Johns Hopkins University, 3400 North Charles Street, Baltimore, MD 21218, USA. ghp@jhu.edu
Jeon
Heung Bae
HB
Sarjeant
Amy
A
Riccio
Edward S
ES
Doppalapudi
Rupa S
RS
Kapetanovic
Izet M
IM
Saha
Uttam
U
Dolan
Patrick
P
Kensler
Thomas W
TW
D000818:Animals; D001854:Bone Marrow Cells / Q000378:metabolism; D016466:CHO Cells; D002117:Calcitriol / Q000031:analogs & derivatives* / Q000737:chemistry*; D002118:Calcium / Q000378:metabolism*; D006224:Cricetinae; D018360:Crystallography, X-Ray; D004305:Dose-Response Relationship, Drug; D004926:Escherichia coli / Q000378:metabolism; D051379:Mice; D015162:Micronucleus Tests; D008956:Models, Chemical; D008958:Models, Molecular; D009154:Mutation; D018167:Receptors, Calcitriol / Q000378:metabolism; D012475:Salmonella / Q000378:metabolism; D013237:Stereoisomerism
C113641:QW 1624F2-1; D018167:Receptors, Calcitriol; D002117:Calcitriol; D002118:Calcium