Synthesis and biological evaluations of C-23-modified 26,26,26,27,27,27-F6-vitamin D3 analogues.
A convenient synthetic method which could allow flexible modification at C-23 of 26,26,26,27,27,27-hexafluoro-1alpha,25-dihydroxyvitamin D3 (3) has been developed. An effective construction of hexafluoroacetone (HFA) aldol part on the side chain of 10 was achieved by aldol reaction with HFA gas. This route is also attractive as an approach to diverse 26,27-modified vitamin D3 analogues. The preliminary biological activities of 23-modifed 26,27-F6 vitamin D3 analogues are evaluated. The potency of VDR affinities of the C-23-substituted analogues (keto group (4); OH group (5a,5b); fluorine atom (6a,6b); and oxetane ring (7a,7b)) was found to vary depending upon both the nature and stereochemistry of the substituents. In contrast, the HL-60 cell differentiation property was less varied than VDR affinity, and depended upon the nature rather than the stereochemistry of the substituents.
Ikeda
M
M
Sumitomo Pharmaceuticals Co., Ltd, Osaka, Japan. ikeda@sumitomopharm.co.jp
Matsumura
H
H
Sawada
N
N
Hashimoto
K
K
Tanaka
T
T
Noguchi
T
T
Hayashi
M
M
D000096:Acetone / Q000031:analogs & derivatives* / Q000737:chemistry; D000818:Animals; D001667:Binding, Competitive; D002645:Chickens; D002762:Cholecalciferol / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000378:metabolism*; D005461:Fluorine / Q000737:chemistry; D005466:Fluorocarbons / Q000737:chemistry; D018922:HL-60 Cells / Q000737:chemistry; D006801:Humans; D007422:Intestines / Q000737:chemistry; D008968:Molecular Conformation; D015394:Molecular Structure; D011485:Protein Binding; D018167:Receptors, Calcitriol / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013816:Thermodynamics; D006845:Hydrocarbons, Fluorinated
D000096:Acetone; D002762:Cholecalciferol; D005461:Fluorine; D005466:Fluorocarbons; D018167:Receptors, Calcitriol; D018160:Receptors, Cytoplasmic and Nuclear; C017366:hexafluoroacetone; D006845:Hydrocarbons, Fluorinated