Fluorinated Vitamin D Analogs to Probe the Conformation of Vitamin D in Its Receptor Complex: 19F-NMR Studies and Biological Activity.

Abstract

The active vitamin D 3 , 1a,25-dihydroxyvitamin D 3 [1,25-(OH) 2 D 3 , 1] (Fig. 1) is a multi-functional hormone. In addition to its central action in regulating calcium and phosphorus homeostasis, 1 plays a role in controlling growth and differentiation of cells and in immuno-modulation.1) 1,25-(OH) 2 D 3 has been widely used as a potential therapeutic agent in the treatment of bone metabolic diseases and the skin disorder psoriasis. However, the use of 1 is limited because a high dose causes critical hypercalcemia. Vitamin D analogs which have a selective activity profile, such as a high cell differentiating potential with little calcemic activity, have been developed by structural modification of the parent 1,25-(OH) 2 D 3 .2) 1,25-(OH) 2 D 3 exerts most of its effects via the vitamin D receptor (VDR), which is a member of the nuclear receptor superfamily.3) Binding of 1 to VDR induces a conformational change in the ligand-binding domain (LBD). VDR binds as a heterodimer with the retinoid X receptor (RXR) 4) to vitamin D response elements (VDREs), which are located in the promoter regions of 1,25-(OH) 2 D 3 target genes. It is now clear that binding of a coactivator to this heterodimer is critical for the transactivation of target genes.To understand, on a molecular basis, the mode of action of the native hormone at the transcription level, it is essential to determine in detail the three-dimensional structure of liganded VDR and its dynamic properties in solution. 1,25-(OH) 2 D 3 can be conveniently divided into four parts with unique structural characteristics, the A-ring, the seco-B-ring, the C/D-ring, and the side chain. By our initial study on the conformation-function relationship of vitamin D employing conformationally restricted side chain analogs as tools, we have proposed a concept of the active space region of the side chain. [5][6][7][8] Our interest is now extended to the A-ring and the seco-B-ring triene parts: the geometry of the A-ring is important for vitamin D to bind to the VDR, and the conjugated triene has unique structural and electronic features compared with other steroid hormones. The A-ring is known to exist as a roughly equal population of two conformations in solution, which correspond to the two chair forms of the a-(1a-OH in axial and 3b-OH in equatorial orientation) and April 2002 Chem. Pharm. Bull. 50(4) 475-483 (2002) 475 * To whom correspondence should be addressed. D derivatives to be used for the study, 4,4-difluoro-1a a,25-dihydroxyvitamin D 3 [4,4-F 2 -1,25-(OH) 2 D 3 , 2a], and (10Z)-and (10E )-19-fluoro-1a a,25-dihydroxyvitamin D 3 [19-F-1,25-(OH) 2 D 3 , 3a, 4a]. In this paper, we examined the H-NMR studies of fluorovitamin D compounds, we determined the free energy of activation for the interconversion between the two conformations of 2a (9.9 kcal/mol) and 4a (10.8, 11.5 kcal/mol). Introduction of the 1a a-hydroxyl group raised the activation energy about 1 kcal/mol. The affinity for VDR was evaluated, and the relative potency of 2a, 3a and 4a was found to be 1%...

Preparation of 9α‐Fluorinated Sesquiterpenic Drimanes and Evaluation of Their Antifeedant Activities

“…The tertiary hydroxy group 37 was dehydrated regioselectively to the C8-C12 position by treatment with thionyl chloride in pyridine to give in nearly quantitative yield compound 38, a 9α-fluorodrimane closely related to several naturally occurring olepupuane-type drimanes. [55] On the other hand, hydroxylation of 9α-fluoroalbicanol acetate (14) under the same conditions as described above for 13 gave the corresponding diol 39. Initial attempts to oxidize the hydroxymethyl group (using, for example, NaOClO, Me 2 CH=CHMe 2 , tBuOH) to the corresponding carboxylic acid group failed.…”

“…As substituent it is rarely boring, always good for a surprise, but often completely unpredictable". [5] Over the last few years there has been a growing interest in the synthesis of fluorine-containing analogues of natural products and a large number of fluorinated natural products with biological significance such as amino acids, [6] peptides, [7] glycosides, [8] nucleosides, [9] lipids, [10] oligosaccharides, [11] steroids, [12] prostaglandins, [13] vitamins, [14] antibiotics, [15] pheromones [16] alkaloids [17] and others [18] have been synthesized and some have subsequently been developed as pharmaceuticals and are marketed, registered or at the clinical development stage. [19] Also, a relatively significant number of fluoro derivatives of bioactive terpene-type compounds have bee reported and in many cases these show an increase in activity with respect to the corresponding hydrogen analogue.…”

Synthesis and Biological Evaluation of 4-Substituted Vitamin D and 14-Epi-Previtamin D Analogs

“…Among the huge library of vitamin D 3 derivatives, few compounds possess substituents at the 4-position, and their biological effects remain unclear, except 4-fluorovitamin D analogs. 11,12) We expected that 4-oxy-substitution of the previtamin D form, especially, could construct a new hydrogen bond in vitamin D receptor (VDR), and also 4-substitution would help us to understand the genomic activity of the pre-form compounds. 10) At the beginning of the study of 4-substitution in vitamin D 3 , we report the synthesis and biological evaluation of 4-hydroxy and 4-methoxy analogs of 14-epi-1a,25-dihydroxyprevitamin D 3 (14-epi-1a,25(OH) 2 preD 3 , 14-epi-pre1) and also of 1a,25(OH) 2 D 3 (1), that is, compounds 3 and 2, respectively (Fig.…”

Recent advances (1995–2005) in fluorinated pharmaceuticals based on natural products

“…Fluorinated analogues of the Vitamin D 3 metabolites have also been used as probes using 19 F NMR, to perform studies on the conformation of the complex between Vitamin D and its receptor [60].…”