C-6 functionalized analogs of 25-hydroxyvitamin D3 and 1α,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 D-3 and its biologically important metabolites, i.e. 25-hydroxyvitamin D-3 (25-OH-D-3) and 1 alpha,25-dihydroxyvitamin D-3 [1,25(OH)(2)D-3]. We employed Mazur's cyclovitamin D method to synthesize vitamin D-3 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-D-3 15 and 16, respectively, and 6-(3-hydroxypropyl) derivative of 1,25(OH)(2)D-3 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-D-3, the strongest natural binder. but with comparable affinity with 1,25(OH)(2)D-3, the hormone. On the other hand, 6-[3-hydroxypropyl], 1 alpha,25-dihydroxyvitamin D-3 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 che parent seco-steroid [1,25(OH)(2)D-3] 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. (C) 1999 Elsevier Science Inc. All rights reserved.