Pseudoequatorial Conformation Research Articles

The potential of natural product vs neurodegenerative disorders: In silico study of artoflavanocoumarin as BACE-1 inhibitor

Increasing evidence suggests the beneficial impact of flavonoid-rich nutrition on normal cognitive function. It has been revealed that flavonoids can slow neurodegenerative processes in situations such as Alzheimer’s disease (AD). The β-secretase (BACE-1) is one of the most studied targets in AD therapy owing to its role in producing Aβ plaques. In fact the unique role of BACE-1 in pathogenesis of neurodegenerative diseases has made it a druggable target to develop anti-AD agents. Taking into account the anti-amyloidogenic and anti-oxidative properties, flavonoids have received considerable attention as lead candidates for anti-AD drug discovery projects. In continuation to our interest toward rational exploration of potential anti-AD agents, it was attempted to conduct a combined structure based in silico study and explore pharmacophore of a flavanocoumarin derivative as BACE-1 Inhibitor. Ab initio studies showed that both pseudo-axial and pseudo-equatorial conformers could convert to each other freely at room temperature. Within this study it was revealed that artoflavanocoumarin possess essential pharmacophoric groups to inhibit BACE-1. Considering four different protonation states of BACE-1 as di-deprotonated, diprotonated, protonated Asp32 and protonated Asp228, it was also found that affinity of artoflavanocoumarin toward different protonation states of BACE-1could be ranked as Asp32p-Asp228i > di-deprotonated ∼ Asp32i-Asp228p >> diprotonated. PMF study on artoflavanocoumarin showed that it could pass 1.8 kcal/mol free energy barrier from water to DPPC lipid bilayer. Moreover the pros and cons of artoflavanocoumarin as a lead compound were elucidated.

3-Trimethylsilylcycloalkylidenes. γ-Silyl vs γ-Hydrogen Migration to Carbene Centers.

A series of γ-trimethylsilyl-substituted carbenes have been studied experimentally and by computational methods. In an acyclic system, 1,3-trimethylsilyl migration successfully competes with 1,3-hydrogen migration to the carbene center. The behavior of cyclic 3-trimethylsilyl-substituted carbenes contrasts with that of the acyclic system. Only 1,2-hydrogen migration processes are observed in the five-membered ring due to the high barrier to 1,3-hydrogen migration. In the cyclohexyl system, a small amount of a cyclopropane derived from 1,3-hydrogen migration occurs, as shown by a labeling study. In the cycloheptyl carbene system, a labeling study again showed that 1,3-hydrogen migration to the carbene center leads to the major product. Computational studies suggest that the cyclic carbenes all have lower energy conformations where the trimethylsilyl group is in a pseudo equatorial conformation where it cannot migrate to the carbene center. Computational studies also suggest that cyclohexyl and cycloheptyl carbene systems are slightly stabilized by a rear lobe interaction of the Si-C bond with the carbene center.

NMR spectroscopy and theoretical calculations in the conformational analysis of 1-methylpyrrolidin-2-one 3-halo-derivatives.

This study reports the results of ab initio and density functional theory (DFT) electronic structure calculations as well as (3)J(HH) experimental and calculated coupling constant data obtained in the investigation of the conformational equilibrium of 3-halo-derivatives of 1-methylpyrrolidin-2-one. The five-membered ring assumes an envelope conformation owing to the plane of formation of the O═C-N-R bond, with C4 forming the "envelope lid". When the conformation changes, the "lid" alternates between positions above and below the amide plane. The α-carbonyl halogen assumes two positions: a pseudo-axial and a pseudo-equatorial. In the gaseous phase, the calculations indicate that the pseudo-axial conformer is more stable and preferable going down the halogen family. Natural bond orbital analysis showed that electronic delocalization is significant only for the iodo derivative. In the other derivatives, the electrostatic repulsion between oxygen and the halogen determines the conformational equilibrium. When the solvated molecule was taken into account, the pseudo-equatorial conformer population increased with the relative permittivity of the solvent. This variation was strong in the fluoro derivative, and the preference was inverted. In the chlorine derivative, the two populations became closer in methanol and acetonitrile. In the bromine and iodine derivatives, the percentage of pseudo-equatorial conformer increased only slightly owing to the dipole moment of the conformation: the pseudo-equatorial conformation has a greater dipole moment and thus is stable in media with high relative permittivity.

Synthesis and antitubercular activity of 7-(R)- and 7-(S)-methyl-2-nitro-6-(S)-(4-(trifluoromethoxy)benzyloxy)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazines, analogues of PA-824

Nitroimidazoles such as PA-824 and OPC-67683 are currently in clinical development as members of a promising new class of therapeutics for tuberculosis. While the antitubercular activity of these compounds is high, they both suffer from poor water solubility thus complicating development. We determined the single crystal X-ray structure of PA-824 and found a close packing of the nitroimidazoles facilitated by a pseudoaxial conformation of the p-trifluoromethoxybenzyl ether. To attempt to disrupt this tight packing by destabilizing the axial preference of this side chain, we prepared the two diastereomers of the 7-methyl-nitroimidazo-oxazine. Determination of the crystal structure of the 7-(S)-methyl derivative (5, cis) revealed that the benzylic side chain remained pseudoaxial while the 7-(R)-methyl derivative (6, trans) adopted the desired pseudoequatorial conformation. Both derivatives displayed similar activities against Mycobacterium tuberculosis, but neither showed improved aqueous solubility, suggesting that inherent lattice stability is not likely to be a major factor in limiting solubility. Conformational analysis revealed that all three compounds have similar energetically accessible conformations in solution. Additionally, these results suggest that the nitroreductase that initially recognizes PA-824 is somewhat insensitive to substitutions at the 7-position.

Characterization of DNA adducts and tetraols derived from anti-benzo[ghi]fluoranthane-3,4-dihydrodiol-5,5a-epoxide.

A total of seven DNA adducts and two racemic tetraols derived from anti-benzo[ghi]fluoranthene-3,4-dihydrodiol-5,5a-epoxide (anti-B[ghi]FDE, 2) were characterized by analyses of UV, (1)H NMR, CD, and MALDI mass spectra. The structure of 2 is the first example of a diolepoxide in which a fully fused cyclopentane ring is covalently linked to the saturated ring bearing the epoxide function. Compound 2 is also a conformationally rigid structure analogue of the extensively studied anti-benzo[c]phenanthrene-3,4-dihydrodiol-1,2-epoxide (anti-BcPDE), thus serving as a model for probing the diolepoxide-DNA interaction [Chang et al. (2002) Chem. Res. Toxicol. 15, 198-208 (following paper in this issue)]. The most abundant adducts are formed from trans- or cis-openings of the epoxide by the amino groups of either deoxyguanosine or deoxyadenosine. Adducts of minor abundance formed by the attachment of the diolepoxide to the amino group of deoxycytidine N(4) and guanine N(7) were also isolated. Post-source decay MALDI spectra of the (M + H)(+) molecule ions are consistent with the assigned adduct structures. The lack of a typical benzylic proton at the site of deoxynucleoside attachment necessitated a new NMR assignment strategy. Despite the steric constraint, the epoxide ring opening of 2 occurred exclusively at the dibenzylic C5a, not at C5. The assignments on the trans- and cis-epoxide opening were made based on the molecular modeling structures, i.e., the pseudoaxial H5 in cis-adducts is placed directly under the strong influence of a shielding cone of the aromatic ring system, while the same proton in trans-adducts adopts a pseudoequatorial conformation, thereby protruding away from the aromatic ring system. The absolute configuration at the site of deoxynucleoside attachment (C5a) was tentatively assigned on the basis of the empirical rules that have been established for deoxynucleoside-adducts derived from traditional alternant PAH diolepoxides.

Modeling the conformation of polyphenols and their complexation with polypeptides: self-association of catechin and its complexation with L-proline glycine oligomers.

Over the past 10 years, several scientific thrusts have come together in the study of flavanoids that make it possible to move forward into the study of complexation between polyphenols and polypeptides. Enhanced understanding of the conformational properties of flavanoid monomers and polyflavanoids through molecular modeling, combined with the detailed NMR experimental data now in the literature, provide the foundation.1–13 Recent work using conformational searching techniques with the GMMX6–8 protocol has shown additional detail about the distribution of pseudo equatorial and pseudo low-energy axial conformers in the ensemble, as shown in figure 1. This leads to information about the relationship between the conformer ensemble and the Boltzmann averaged NMR proton coupling constants that one would expect to observe in a solution. Figure 1 also illustrates the pseudo equatorial to axial transformation that takes place in all catechin or (+)-catechin-(4α→8)-(+)-catechin (B3) dimer complexes during the conformer searches and which would also be expected to occur in solution. Interest continues to further understand the details about this conformer distribution as well as in the prediction of complexation of tannins with metal ions and proteins. Although the GMMX software has given many interesting results, it is limited in handling cases that require systematic conformational searching of molecules combined in a complex. In addition, there are no solvent model options.KeywordsLower Energy StructureAmber Force FieldPyran RingMMFF Force FieldAxial ConformerThese keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

(1R*,3R*,4S*)-4-(tert-Butyldiphenylsilyloxy)-6,7-dimethoxy-1-methyl-3-phenyl-1,2,3,4-tetrahydroisoquinoline

Ambiguous information obtained from 1H-NMR spectroscopy has prompted an investigation of the correct stereochemistry of the title compound, C34H39NO3Si, by X-ray diffraction analysis. An uncommon pseudoaxial–axial trans conformation was observed for the substituents linked to the C-4 and C-3 atioms (IUPAC numbering). The pseudo-equatorial conformation of the methyl group joined to the C-1 atom was also confirmed.

Conformational studies of substituted dibenzo-14-crown-4 ethers: a 1-D and 2-D 1H and 13C NMR investigation

The solution structures of substituted dibenzo-14-crown-4 ethers have been investigated by one- and two-dimensional NMR methods (proton vicinal coupling constants, 13C chemical shifts and ROESY). The preferred conformations in solution for substituents on sym-dibenzo-14-crown-4 ethers have been shown to depend on the atom (carbon or oxygen) linking the substituent to the crown ring. Substituents attached by a carbon linkage, including methyl, 2-hydroxyethyl and carboxymethyl, prefer a pseudo-equatorial conformation, i.e. with the substitutent oriented anti to the ring C–O bond. Substituents attached by an oxygen linkage, including hydroxy, methoxy, and carboxymethoxy, prefer the pseudo-axial (gauche) conformation.

1H and13C NMR spectra, stereoisomerism, and conformational states of 3-phenyl-5-isopropoxytetrahydro-2-furanones

The1H and13C NMR spectra of the diastereomers of 3-phenyl-5-isopropoxytetrahydro-2-furanone were obtained. The stereoisomerism and preferred conformational states of these diastereomers were established by means of the spectroscopic criteria found for 3,4-disubstituted sulfolanes and 1,1,3,4-tetrasubstituted silacyclopentanes. It is shown that for the cis isomer the equilibrium is shifted to favor pseudoequatorial conformers, whereas for the trans isomer it shifted to favor ae conformers with a preferred pseudoequatorial orientation of phenyl substituent.

Role of diaxial versus diequatorial hydroxyl groups in the tumorigenic activity of a benzo[a]pyrene bay-region diol epoxide.

Tumorigenic activities of the (7R,8S,9S,10R)-7,8-dihydroxy-9,10-epoxy-7,8,9,10-tetrahydro derivatives of benzo[a]pyrene [(+)-B[a]P diol epoxide-2] and 6-fluorobenzo[a]pyrene (6-FB[a]P diol epoxide-2) were evaluated in newborn CD-1 mice. A total dose of 14 nmol of either diol epoxide was administered to preweanling mice, and tumorigenic activity was determined when the mice were 32 to 36 weeks old. At the termination of the study, 13% of solvent-treated control mice had developed lung tumors with an average of 0.19 tumor per mouse. No other tumors were observed in control animals. (+)-B[a]P diol epoxide-2 induced pulmonary tumors in 60% of the mice with an average of 1.9 tumors per mouse, and 14% of the male mice developed hepatic tumors with an average of 0.18 tumor per mouse. In contrast, 6-FB[a]P diol epoxide-2 had no significant tumorigenic activity at the 14-nmol dose. Although both bay-region diol epoxides have the same absolute configuration, (7R,8S,9S,10R), the hydroxyl groups of (+)-B[a]P diol epoxide-2 prefer the pseudoequatorial conformation whereas the hydroxyl groups of 6-FB[a]P diol epoxide-2 prefer the pseudoaxial conformation. The tumorigenicity results reported here are the first direct demonstration that conformation of the hydroxyl groups in a bay-region diol epoxide, in addition to the documented effect of absolute configuration, is an important determinant in the tumorigenic activity of these ultimate carcinogens.

Temperature dependence of the low-frequency vibrational optical activity of α-phellandrene

Dramatic change with temperature in the Raman optical activity of two low-frequency vibrational bands of (–)α-phellandrene, which could be associated with the interconversion of the pseudoaxial and pseudo-equatorial conformers, are reported.

Radical-anions of the isomeric 9-substituted thioxanthen S-oxides

Radical-anions of 9-substituted thioxanthen S-oxides have been prepared and their e.s.r. spectra measured. For the two 9-methyl isomers the S–O group has the pseudoaxial conformation, in contrast to its pseudoequatorial conformation in the neutral compounds. The spectra of decomposition products are also observed.

The stereochemistry of organometallic compounds. Part IV. Dipole moments of cis- and trans-tricarbonyl-(2-cyanoindane)chromiums and of 2-cyano-4,5-dibromoindane

The dipole moments of cis- and trans-tricarbonyl-(2-cyanoindane)chromium have been measured. The results indicate that in both isomers the cyano-group prefers a pseudo-equatorial conformation. 2-Cyano-5,6-dibromo-indane has been synthesised but its measured moment gives no clear indication of a preference for either the pseudo-equatorial of pseudo-axial conformation by the cyano-group.