Dimer and Superstructure of the Active Form of a Vitamin D3. 1.ALPHA.,24(R)Dihydroxy-vitamin D3 Monohydrate, C27O3H44 H2O.

Abstract

The structure of vitamin D was first analyzed on calciferol by heavy atom method in 1948.2) In 1977, 25-hydroxy-vitamin D 3 (25(OH)-VD 3 ) was solved by direct method precisely.3) Until the analysis of calcipotriol mono-hydrate in 1993, 4) the active form of vitamin D 3 in which the hydroxyl group is replaced at the 1a position by metabolism was not analyzed. Calcipotriol is a 1,24(R)(OH) 2 -type VD 3 , and has a rigid chain with a double bond and a terminal three-membered ring. In 1996, 1,25(OH) 2 -VD 3 was analyzed 5) as a trihydrate, of which two water molecules are disordered. The conformation of the A ring of both calcipotriol and 1,25(OH) 2 -VD 3 is b -form, that is, 3-OH is axial. 1a,24(R) (1,24(OH)2-VD 3 ; Fig. 1) has a linear chain like 25(OH)-VD 3 and 1,25(OH) 2 -VD 3 . It has the same activity as 1,25(OH)-VD 3 , and is especially applied to treat skin disease like psoriasis. It takes the crystal form of a superstructure, that is, its asymmetric unit consists of two subunits which are slightly different. The superstructure is difficult to solve, and only a few reports have been published on the subjects. In a centro-symmetrical crystal, it was solved using only reflections for the layers with subunits ("pseudo cell" in author's words) by direct method, but the accuracy is not good.6) In this case of an optically active molecule and a non centro-symmetrical crystal, reflections other than the layers of the subunits are not weak, nor absent. No direct method strategies were effective, 7,8) though they only suggested the existence of pseudo translation and pointed out the incompatibility of symmetry. Another method of integrated Patterson and direct methods 9,10) has been attempted here. ExperimentalCrystals of pharmaceutical from a methanol-water solution are too small for data collection; they were recrystallized from a dioxane-water (1 : 1) solution. Prismatic clear crystals 0.10ϫ0.10ϫ0.20 mm in size were obtained by slow evaporation. Crystal data from the different solutions are the same. , space group P2 1 2 1 2 1 . The asymmetric unit contains 4 molecules. Data were collected by Rigaku automated four-circle diffractometer RASA-5R, with w-2q scan mode, CuKa radiation and diffraction angle 2Ͻ2qϽ105°. Intensities decrease rapidly at higher diffraction angle. As the crystal is degradative, it was changed at every 5% decrease of monitoring 3 reflections. Three crystals were used, and three data sets were processed by TEXAN.11) Of the 6659 independent reflections, 4506F 2 O Ͼ0 were observed. For (0, k, 0) reflections, features other than systematic absence are, kϭ4n strong, kϭ2nϪ1 absent, kϭ4nϪ2 weak, indicative of a superstructure.Structure Determination and Refinement. Preparation As the search fragment model, the more rigid ring part of the A ring to the condensed C,D ring through a conjugated diene was selected from 25(OH)-VD 3 . The 1a oxygen atom was added and minimized by MMϩforce field.12) Super-sharpened Patterson function with coefficient (E 3 *F) 1/2 and the largest 200 E-values were calculat...

Synthesis and Biological Activity of Two C-7 Methyl Analogues of Vitamin D

“…30 This fact could, in turn, decrease the ability of the synthesized analogue to bind VDR and affect its biological activity. Literature data prove that the natural hormone 31 and the vast majority of other 1α-hydroxylated vitamin D compounds adopt in the crystalline state exclusively the β-form of their A rings (with an exception of tacalcitol monohydrate 32 and calcipotriol anhydrate 33 ) characterized by equatorial and axial disposition of 1α-and 3β-hydroxyls, respectively, whereas the 5,7-diene fragment of their B-seco rings is almost planar. Crystallographic data from the growing number of solved crystalline complexes of the vitamin D receptor (VDR) and vitamin D analogues 34 indicate the s-trans conformation of the ligand's intercyclic C(5)C(6)−C( 7)C(8) diene moiety, exhibiting a torsion angle of ca.…”

“…The residue was purified by flash chromatography (SiO 2 , 0.5% Et 2 O/hexanes) to afford nitrile 29 (490 mg, 95%, colorless oil, contaminated with ca. 20% of its 4′Z-isomer): 1 H NMR (200 MHz, CDCl 3 ) δ 2.99 (1H, dm, J ∼ 13.0 Hz), 1.98 (3H, br s), 1.19 (6H, s), 0.94 (9H, t, J = 8.0 Hz), 0.94 (3H, d, J ∼ 6 Hz), 0.67 (3H, s), 0.56 (6H, q, J = 8.0 Hz); minor 4′Z-isomer: δ (selected signals) 2.64 (m); 13 2-[(1′R,3a′R,7a′R)-1′-[(R)-1″,5″-Dimethyl-5″-[(triethylsilyl)oxy]hexyl]-7a′-methyloctahydro-inden-(4′E)-ylidene]-propionaldehyde (32). A solution of diisobutylaluminum hydride in toluene (2.25 mL, 1 M, 2.25 mmol) was added to a stirred solution of nitrile 29 (487 mg, 1.13 mmol) in dry toluene/CH 2 Cl 2 (2:1, 15 mL) at −78 °C under argon.…”

Synthesis and Crystal Structure of Anhydrous Analog of 1,25-Dihydroxyvitamin D3

“…Contrary to the plain vitamin D 3 and its circulating metabolite (25‐OH‐D 3 ,, both lacking 1α‐hydroxyl, 1,25‐(OH) 2 D 3 trihydrate exists in the solid state exclusively in the β‐form . Surprisingly, the natural precursor of the final metabolite of vitamin D 3 (tacalcitol, 1,24‐dihydroxyvitamin D 3 ) was found to exist as a monohydrate in the solid state in the α‐form, as the only analog of 1,25‐(OH) 2 D 3 that exists in the solid state in this conformation. The latest finding is not in favor with the early considerations in this field and posterior hypothesis that vitamins D adopt the β‐form of A‐ring during the interaction with their receptor.…”

Effect of Vitamin D Conformation on Interactions and Packing in the Crystal Lattice

“…Analysis of the results showed that the chair β-conformation was required for binding . Until now, the only known examples of the chair α-conformation in the crystal lattice were the monohydrate of (24 R )-1,24-dihydroxyvitamin D 3 (tacalcitol) and 7-methyl-1α,25-(OH) 2 -19- nor -D 3 . Moreover, several examples of vitamin D 3 adopting a chair α-conformation − have been described along with an example of the anhydrous form of calcipotriol also adopting both α- and β-conformations.…”