C-6 functionalized analogs of 25-hydroxyvitamin D3 and 1alpha,25-dihydroxyvitamin D3: synthesis and binding analysis with vitamin D-binding protein and vitamin D receptor.
In this article, we describe the development of a general synthetic strategy to functionalize the C-6 position of vitamin D3 and its biologically important metabolites, i.e. 25-hydroxyvitamin D3 (25-OH-D3) and 1alpha,25-dihydroxyvitamin D3 [1,25(OH)2D3]. We employed Mazur's cyclovitamin D method to synthesize vitamin D3 analogs with several functionalities at the C-6 position. In addition, we synthesized 6-(3-hydroxypropyl) and 6-[(2-bromoacetoxy)propyl] derivatives of 25-OH-D3 15 and 16, respectively, and 6-(3-hydroxypropyl) derivative of 1,25(OH)2D3 17. Competitive binding assays of 15-17 with human serum vitamin D-binding protein showed that all these analogs specifically bound to this protein, although with significantly lower affinity than the 25-OH-D3, the strongest natural binder, but with comparable affinity with 1,25(OH)2D3, the hormone. On the other hand, 6-[3-hydroxypropyl], 1alpha,25-dihydroxyvitamin D3 17 did not show any specific binding for recombinant nuclear vitamin D receptor. These results indicated that the region containing the C-6 position of the parent seco-steroid [1,25(OH)2D3] may be an important recognition marker towards vitamin D receptor binding. Information, delineated in this article, will be important for evaluating structure-activity relationship in synthetic analogs of vitamin D and its metabolites.
Department of Medicine, Boston University School of Medicine, Massachusetts 02118, USA.
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D001665:Binding Sites; D001667:Binding, Competitive; D002112:Calcifediol / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism; D002117:Calcitriol / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism; D002762:Cholecalciferol / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000378:metabolism; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D018167:Receptors, Calcitriol / Q000378:metabolism*; D013237:Stereoisomerism; D014809:Vitamin D-Binding Protein / Q000378:metabolism*
D018167:Receptors, Calcitriol; D014809:Vitamin D-Binding Protein; D002762:Cholecalciferol; D002117:Calcitriol; D002112:Calcifediol