Theoretical studies on the structural rearrangement of ligand binding pocket in human vitamin D receptor

The structural rearrangement of the ligand binding domain (LBD) of human Vitamin D receptor (hVDR) complexed with 1α, 25‐dihydroxyvitamin D₃ (natural ligand) and its analogues (denoted as b and c ) was studied by molecular dynamics (MD) simulations. MD simulations revealed that these ligands could induce different structural changes of LBD, in which 1α, 25‐dihydroxyvitamin D₃ only led to a minute change, suggesting that LBD adopted its canonical active conformation upon binding the natural ligand, while b and c could provoke a clear structural rearrangement of the LBD. In complex of hVDR‐LBD/ b , it is found that helix 6 (H6) and subsequent loop 6‐7 shift outward and the last turn of H11 shifts away from H12, which generate a new cavity at the bottom of binding pocket to accommodate the extra butyl group on the side chain of ligand b . As for hVDR‐LBD/ c , the steric exclusion of the second side chain of ligand c makes the N‐terminal of H7 move outsides and C‐terminal of H11 close to H12, expanding the bottom of the pocket. These calculation results agree well the experimental observations. © 2010 Wiley Periodicals, Inc. Int J Quantum Chem, 2011     

Design,Synthesis, Evaluation and Structure of Allenic 1α,25-Dihydroxyvitamin D3 Analogs with Locked Mobility at C-17

Vitamin D receptor ligands have potential for the treatment of hyperproliferative diseases and disorders related to the immune system. However, hypercalcemic effects limit their therapeutical uses and call for the development of tissue-selective new analogs. We have designed and synthesized the first examples of 1α,25-dihydroxyvitamin D₃ analogs bearing an allenic unit attached to the D ring to restrict the side-chain conformational mobility. The triene system was constructed by a Pd⁰-mediated cyclization/Suzuki-Miyaura cross-coupling process in the presence of an allenic side chain. The allenic moiety was built through an orthoester-Claisen rearrangement of a propargylic alcohol. The biological activity and structure of (22S)-1α,25-dihydroxy-17,20-dien-24-homo-21-nor-vitamin D₃ bound to binding domain of the vitamin D receptor, provide information concerning side-chain conformational requirements for biological activity.     

Synthesis of Bioactive Side‐Chain Analogues of TAN‐2483B

The fungal metabolite TAN‐2483B has a 2,6‐trans‐relationship across the pyran ring of its furo[3,4‐b]pyran‐5‐one core, which has thwarted previous attempts at its synthesis. We have now developed a chiral pool approach to this core and prepared side‐chain analogues of TAN‐2483B. The synthesis relies on ring expansion of a reactive furan ring‐fused dibromocyclopropane and alkynylation of the resulting pyran. The furan ring is constructed by palladium‐catalysed carbonylative lactonisation. Various side‐chains are appended through Wittig‐type chemistry. The prepared analogues showed micromolar activity towards cancer cell lines HL‐60, 1A9 and MCF‐7 and certain human disease‐relevant kinases, including Bruton's tyrosine kinase (Btk).     

New C15-substituted active vitamin D3

C15-Substituted 1α,25-dihydroxyvitamin D(3) analogs were synthesized for the first time to investigate the effects of the modified CD-ring on biological activity concerning the agonistic positioning of helix-3 and helix-12 of the vitamin D receptor (VDR). X-ray cocrystallographic analysis proved that 0.6 ? shifts of the CD-ring and shrinking of the side chain were necessary to maintain the position of the 25-hydroxy group for proper interaction with helix-12. The 15-hydroxy-16-ene derivative showed higher binding affinity for hVDR than the natural hormone.     

Vitamin D and click chemistry. Part 1: A stereoselective route to vitamin D analogues with triazole rings in their side chains

Efficient preparation of vitamin D CD ring system synthons with triazole rings in their side chains is based on the formation of the triazole ring from a [3+2]-cycloaddition of a vitamin D side chain terminal azide with a terminal acetylene.     

A molecular mechanics force field for the cobalt corrinoids

A force field for the cobalt (III) corrinoids (derivatives of vitamin B₁₂) for use with a modified version of the molecular mechanics program 2(87) has been developed empirically around 19 cobalt corrinoid crystal structures. Bond lengths, bond angles and torsional angles are reproduced with r.m.s. differences of 0.01 Å, 2.4 °, and 4.2 °, respectively, within the standard deviation of the mean of these parameters found in the solid state. The axial ligand occupying the lower coordination site in the cobalamins, 5,6-dimethylbenzimidazole, is shown to have very limited rotational freedom and is constrained by the downward-pointing b and d propionamide side chains of the corrin ring. Strain-energy profiles for rotation of the side chains of the corrin ring show the existence of several local energy minima and this explains the observed variability in the orientations of these side chains in the solid state. The known change in conformation which occurs in the C ring when the e side chain is epimerized from the lower to the upper face of the corrin ring in cyano-13-epicobalamin is correctly predicted, provided the starting conformation of the C ring is unbiased. A study of cyano-8-epicobalamin indicates that an analogous conformational change does not occur in the B ring and the epimerized d side chain assumes an equatorial orientation relative to the corrin ring. Parameters for the Co---C bond in alkylcobalamins were developed and the structure of methyl- and adenosylcobalamin are accurately reproduced. An examination of the strain energy consequences of rotation of the adenosyl ligand about the Co---C bond identifies a number of low-energy conformations at least two of which, in which adenosyl lies over the “southern” and “eastern” portions of the corrin ring, respectively, have been previously deduced from NMR observations. Coordinated neopentyl in neopentylcobalamin is much more hindered to rotation about the Co---C bond and the lowest conformation finds two γ(C) atoms straddling the upwardly projecting C46 methyl group of the corrin.     

Substituent control of hydrogen bonding in palladium(II)-pyrazole complexes

Inter- and intramolecular hydrogen bonding of an N-H group in pyrazole complexes was studied using ligands with two different groups at pyrazole C-3 and C-5. At C-5, groups such as methyl, i-propyl, phenyl, or tert-butyl were present. At C-3, side chains L-CH(2)- and L-CH(2)CH(2)- (L = thioether or phosphine) ensured formation of chelates to a cis-dichloropalladium(II) fragment through side-chain atom L and the pyrazole nitrogen closest to the side chain. The significance of the ligands is that by placing a ligating side chain on a ring carbon (C-3), rather than on a ring nitrogen, the ring nitrogen not bound to the metal and its attached proton are available for hydrogen bonding. As desired, seven chelate complexes examined by X-ray diffraction all showed intramolecular hydrogen bonding between the pyrazole N-H and a chloride ligand in the cis position. In addition, however, intermolecular hydrogen bonding could be controlled by the substituent at C-5: complexes with either a methyl at C-5 or no substituent there showed significant intermolecular hydrogen bonding interactions, which were completely avoided by placing a tert-butyl group at C-5. The acidity of two complexes in acetonitrile solutions was estimated to be closer to that of pyridinium ion than those of imidazolium or triethylammonium ions.     

A concise and efficient route to 2alpha-(omega-hydroxyalkoxy)-1alpha,25-dihydroxyvi tam in D3: remarkably high affinity to vitamin D receptor

[reaction: see text]A convenient and potentially valuable synthetic approach to the novel 2alpha-functionalized 1alpha,25-dihydroxyvitamin D3 [1alpha,25(OH)2D3] derivatives (1a-c), which are the C2-epimer of ED-71 and its analogues, has been developed. The C2alpha-modified ring A precursors (1,7-enynes 16, n = 0, 1, and 2) were constructed stereoselectively starting from D-glucose in high yield. In the synthesized 2alpha-(omega-hydroxyalkoxy)-1alpha,25(OH)2D3 derivatives, 1a and 1b showed a greater binding affinity to vitamin D receptor (VDR), up to 1.8 times that of the native hormone.     

Design and concise synthesis of novel vitamin D analogues bearing a functionalized aromatic ring on the side chain

Five novel vitamin D analogues (2a, 2b, 3a, 3b and 4) bearing an aromatic side chain have been designed and synthesized in a convergent manner. The requisite CD-ring synthons (10a–c) were prepared from C22 aldehyde (5) using four- or five-step procedures. Using turbo-Grignard reagents allowed aromatic side chains with a polar functional moiety to be installed in a single step with excellent yields. A preliminary biological evaluation using bovine thymus vitamin D receptor (VDR) suggested that incorporating a carboxylic acid instead of the C25-hydroxy group had a positive effect on the VDR affinity compared with the corresponding esters.     

Synthesis and conformational analysis of 17alpha,21-cyclo-22-unsaturated analogues of calcitriol

Six new calcitriol analogues, conformationally restricted at their side chain by the introduction of both a cyclopropane ring at C17-C20 and a double or triple bond at C22, were synthesized using the Wittig-Horner approach to construct the triene system. The six CD-ring and side-chain bearing fragments were prepared from ketone 14 by a divergent route to generate both series of epimers at C20, followed by stereoselective cyclopropanation. The (E)-alkenyl side chain was synthesized by means of a Wittig reaction. The alkynyl side chain was prepared by Corey-Fuchs homologation, followed by alkylation. The (Z)-alkenyl side chain was prepared from the previous alkyne by partial hydrogenation. The 20-epi analogues bind more strongly to VDR than the corresponding analogues with the C20 natural stereochemistry. These results can be reasoned by conformational analysis and hydrophobic interactions with the VDR ligand-binding domain.     

Synthesis of novel analogues of 1alpha,25-dihydroxyvitamin D(3) with side chains at C-18

Novel analogues of the hormone 1alpha,25-(OH)(2)-D(3) with side chains attached to C-18 were synthesized by a versatile route in which key steps were the remote radical-induced functionalization of the 18-methyl by the C-8beta-hydroxyl group and the introduction of the side chains by Wittig reactions on a C-18-aldehyde. The triene system of the novel analogues was constructed by the convergent Lythgoe-Hoffmann la Roche approach, which involves reaction of a phosphine oxide (the ring A fragment) with a ketone (the upper fragment).     

Total synthesis of ent-cholesterol via a steroid C,D-ring side-chain synthon

For the first time, one of the two enantiomers of cholesterol (ent-cholesterol) has been synthesized by a synthetic route that starts from a precursor containing the D-ring and entire side chain of cholesterol. As part of the reported synthetic route, a method of general utility for the large scale (>10 g) preparation of each enantiomer of [1 alpha(R*),7a alpha]-1-(1,5-dimethylhexyl)-1,2,3,6,7,7a-hexahydro-7a-methyl-5H-inden-5-one, C,D ring-side chain synthons that can be used for the synthesis of enantiomers of vitamin D(3), cholesterol, and their analogues was also developed. Using the enantiomer of the C,D-ring side-chain synthon that leads to ent-cholesterol, the A- and B-rings were elaborated from a linear fragment that is sequentially cyclized to form the steroid B- and A-rings. Using this route, ent-cholesterol was prepared in 23 steps from the methyl ester of (1 alpha,5 alpha,6 alpha)-(+/-)-6-methyl-2-oxo-bicyclo[3.1.0]hexane-1-carboxylic acid in a total yield of 2.6%.     

Conformation of cyclo-(L-Leu-L-Tyr-delta-Avaler-delta-Avaler), a synthetic inhibitor of chymotrypsin, by x-ray analysis.

The synthetic cyclic tetrapeptide (L-Leu-L-Tyr-delta-Avaler-delta-Avaler) is an effective inhibitor of chymotrypsin, competitive with linear peptides like Ac-L-Leu-L-Tyr-OMe. An x-ray diffraction analysis of the crystal structure of the cyclic peptide shows that the conformation of the 18-membered ring is very similar to that of one of the four conformers of cyclic hexaglycyl. There is no internal hydrogen bonding. Side chains are located on two "corners" of the approximately rectangular ring. The chii1 angles for Leu and Tyr are -74 and -48 degrees, respectively. The Leu side chain is extended away from the polypeptide ring while the Tyr side chain is folded under an adjacent carbonyl bond. The cell parameters for the space group P2U are: a = 9.361 (3 A, b = 19.039 (10) A, c = 9.603 (3), A, and beta = 116.54 (3) degrees. A molecule of (CH3)2SO (disordered) and a molecule of H2O cocrystallized with the cyclic peptide.     

Carbon-13 NMR spectra of DDT,its analogues and related compounds

Carbon-13 NMR spectra of mono- and disubstituted aromatic compounds including DDT, its analogues, homologues, derivatives and certain model compounds have been studied. The Savitsky scheme of carbon chemical shifts in disubstituted benzenes is applicable to these compounds. The data obtained show that in mono- and disubstituted aromatic compounds containing two different substituents in the α- and β-positions of the side chain, the substituted ring carbon atom shifts follow the additivity rule and can be calculated from substituent increments. Mutual effects of substituents in the ring and in the side chains are analysed. The chlorine atoms in α-position to the phenyl ring give rise to an additive α-effect of about 25 ppm, as in perchloroalkanes. The influence of a β-chlorine atom in the side chain on the substituted carbon atom in the ring is, however, only 3 ppm as against the usual value of about 10 ppm for the β-effect in alkyl chains. Moreover, the first β-chlorine substituent has no noticeable influence on the substituted ring carbon chemical shift: the effect of 3 ppm is transferred to the para-carbon atom almost without attenuation. The ring substituted carbon atom signal shifts caused by the γ-effect of chlorine in the side chain are similar to those observed in aliphatic chains. The ortho-chlorine substituents shift the side chain α-carbon atom signal by 3.6-5.2 ppm to high field compared to para-chlorophenyl compounds. This is similar to the chlorine γ-effect in aliphatic chains.     

Parallel synthesis of a vitamin D(3) library in the solid-phase.

A highly efficient synthesis of the vitamin D(3) system on solid support is described. Two synthetic strategies for the solid-phase synthesis of vitamin D(3) were developed. One is for 11-hydroxy analogues, and the other is for most other synthetic analogues. In the latter strategy, the sulfonate-linked CD-ring 58 was initially immobilized on PS-DES resin to give solid-supported CD-ring 63 (Scheme 10). Similarly, solid-supported CD-ring 63 was prepared by attachment of the CD-ring 10 to the chlorosulfonate resin 64. The vitamin D(3) system was synthesized by Horner-Wadsworth-Emmons reaction of the A-ring phosphine oxide to a solid-supported CD-ring, followed by simultaneous introduction of the side chain and cleavage from resin with a Cu(I)-catalyzed Grignard reagent. Parallel synthesis of the vitamin D(3) analogues was accomplished by a split and pool methodology utilizing radio frequency encoded combinatorial chemistry, and a manual parallel synthesizer for side chain diversification and deprotection. Additionally, we demonstrated the synthesis of various A-rings in a similar protocol for efficient preparation of building blocks.     

Synthesis of Tetracyclic Analogues of Calcitriol (1α,25‐Dihydroxyvitamin D3) with Side‐Chain‐Locked Spatial Orientations at C(20)

We present our first results on the synthesis of a new class of conformationally restricted vitamin D analogues bearing an extra five‐membered ring formed by linking C(18) and C(21). Two analogues of calcitriol ( 1 ) with unsaturations at the extra ring and the lateral chain were prepared. The triene system was introduced by the convergent Wittig Horner approach developed by Lythgoe [8] and F. Hoffmann‐La Roche [9]. The key steps in the preparation of the requisite fragments were: i) the long‐distance functionalization of ketal 11 at C(18), ii) the ring closure on 15 through an intramolecular aldol condensation to give the α,β‐unsaturated ketone 10 , and iii) the Pd‐catalyzed installation of the side chains.     

以二亚乙基三胺为模板的链状结构硫酸钬配合物的合成、晶体结构及性质

通过溶剂热技术合成了一种以二亚乙基三胺(dien)为模板的链状结构硫酸钬(H₃dien)[Ho(SO₄)₃(H₂O)₂] (1),并通过X射线分析、红外光谱、元素分析和粉末衍射进行了表征。X射线晶体结构分析,化合物1结晶于单斜晶系,P2₁/c空间群,a=0.660 20(13) nm,b=1.476 7(3) nm,c=1.655 6(3)nm,β=93.313(2)°,V=1.611 4(5) nm³,Z=4。化合物1是由HoO₈多面体和SO₄四面体为建筑单元构建成新颖的单一链状结构。在a轴方向上,配位水分子通过氢键连接相邻的链形成三维超分子结构。有机胺分子镶嵌于链间,在合成化合物1合成过程中,pH值(pH=1.5)起了关键作用。     

Theory of volume phase transitions of side-chain liquid crystalline gels

We present a mean field theory to describe volume phase transitions of side-chain liquid crystalline gels. Three different uniaxial nematic phases (N(1), N(2), and N(3)) are defined by using orientational order parameter S(m) of side-chain liquid crystals (mesogens) and S(b) of backbone chains. We derive the free energy for the three nematic phases of side-chain liquid crystalline gels dissolved in isotropic solvents and calculate the swelling curve of the gel, the order parameters of a backbone chain and of side-chain liquid crystals, and the deformation of the gel as a function of temperature and an electric field. We find isotropic-nematic (N(1), N(2), and N(3)) and N(1)N(2) phase transitions of the gels, depending on the interaction between a backbone chain and a side-chain liquid crystal.