Computational simulations of HIV-1 proteases--multi-drug resistance due to nonactive site mutation L90M

Human immunodeficiency virus type 1 protease (HIV-1 PR) is one of the proteins that currently available anti-HIV-1 drugs target. Inhibitors of HIV-1 PR have become available, and they have lowered the rate of mortality from acquired immune deficiency syndrome (AIDS) in advanced countries. However, the rate of emergence of drug-resistant HIV-1 variants is quite high because of their short retroviral life cycle and their high mutation rate. Serious drug-resistant mutations against HIV-1 PR inhibitors (PIs) frequently appear at the active site of PR. Exceptionally, some other mutations such as L90M cause drug resistance, although these appear at nonactive sites. The mechanism of resistance due to nonactive site mutations is difficult to explain. In this study, we carried out computational simulations of L90M PR in complex with each of three kinds of inhibitors and one typical substrate, and we clarified the mechanism of resistance. The L90M mutation causes changes in interaction between the side chain atoms of the 90th residue and the main chain atoms of the 25th residue, and a slight dislocation of the 25th residue causes rotation of the side chain at the 84th residue. The rotation of the 84th residue leads to displacement of the inhibitor from the appropriate binding location, resulting in a collision with the flap or loop region. The difference in levels of resistance to the three inhibitors has been explained from energetic and structural viewpoints, which provides the suggestion for promising drugs keeping its efficacy even for the L90M mutant.     

Bisanthraquinone metabolites produced by the endophytic fungus Diaporthe sp

Two bisanthraquinones named (+)-epicytoskyrin (1) and (+)-1,1'-bislunatin (2) were produced by the endophytic fungus from a tea plant, which is a species closely related to Diaporthe phaseolorum strain sw-93-13. The chemical structures of the metabolites were elucidated on the basis of the physicochemical properties including the circular dichroism (CD) spectrum.     

Imaging findings of solitary fibrous tumor of the prostate: a case report

The imaging findings of a solitary fibrous tumor of the prostate are presented. A 35-year-old male presented with urinary retention and was found on transrectal ultrasonography to have a hypoechoic tumor of the prostate, measuring 5.5 cm in size. Magnetic resonance imaging on, the tumor showed low signal intensity on T1-weighted images and heterogeneous mixed signal intensity on T2-weighted images. Gadolinium-enhanced dynamic study showed gradual enhancement from the periphery to the center, and the enhancement is sustained. On immunohistochemistry, the spindle cells of the tumor showed positive staining for CD34 and bcl-2. Although the tumor was labeled as a low-grade malignancy on account of a low mitotic index (MIB-1 index) of about 5%, the patient developed local recurrence of the tumor with bladder wall invasion 12 months later.     

Loop coproducts in string topology and triviality of higher genus TQFT operations

Cohen and Godin constructed a positive boundary topological quantum field theory (TQFT) structure on the homology of free loop spaces of oriented closed smooth manifolds by associating certain operations called string operations to orientable surfaces with parametrized boundaries. We show that all TQFT string operations associated to surfaces of genus at least one vanish identically. This is a simple consequence of properties of the loop coproduct which will be discussed in detail. One interesting property is that the loop coproduct is nontrivial only on the degree d homology group of the connected component of LM consisting of contractible loops, where d=dimM, with values in the degree 0 homology group of constant loops. Thus the loop coproduct behaves in a dramatically simpler way than the loop product.     

Dihydropyrene annelated with dihydrothieno[3.4-b]pyrazine: synthesis and photoswitching property

In this study, 9,10-diacetoxyl-2,7-di-tert-butyl-trans-10b,10c-dimethyl-10b,10c-dihydropyrene annelated with a dihydrothieno[3.4-b]pyrazine unit (1a) was prepared, for the first time, from 5,13-di-tert-butyl-8,16-dimethyl-1,2,9,10-tetrahydroxy[2.2]metacyclophane and 3,4-diaminothiophene in two steps. The photoisomerization property of 1 was investigated by UV and ¹H NMR spectroscopies, and the quantitative isomerization between the more stable dihydropyrene (DHP) form and the less stable metacyclophane-diene (MCPD) form was observed. A thermally induced return reaction from the MCPD to the DHP form was examined at various temperatures, and the reaction rate was 0.0049 min⁻¹ at 45 °C, which is slower than that of the parent MCPD.     

New strategy for drastic enhancement of selectivity via chemical modification of counter anions in ionic liquid polymer phase

A new strategy for the design of a new chromatographic stationary phase via simple modifications of the counter anions in poly(ionic liquid)-grafted silica phase based on ionic self-assembly technology is proposed. The phase with methyl orange dye as counter anions exhibits ultra-high selectivity towards shape-constrained isomers.     

A new imidazolium-embedded C18 stationary phase with enhanced performance in reversed-phase liquid chromatography

In this paper, a new imidazolium-embedded C₁₈ stationary phase (SiImC₁₈) for reversed-phase high-performance liquid chromatography is described. 1-Allyl-3-octadecylimidazolium bromide ionic liquid compound having a long alkyl chain and reactive groups was newly prepared and grafted onto 3-mercaptopropyltrimethoxysilane-modified silica via a surface-initiated radical-chain transfer addition reaction. The SiImC₁₈ obtained was characterized by elemental analysis, infrared spectroscopy, thermogravimetric analysis, diffuse reflectance infrared Fourier transform, and solid-state ¹³C and ²⁹Si cross-polarization/magic angle spinning nuclear magnetic resonance spectroscopy. The selectivity toward polycyclic aromatic hydrocarbons relative to that toward alkylbenzenes exhibited by SiImC₁₈ was higher than the corresponding selectivity exhibited by a conventional octadecyl silica (ODS) column, which could be explained by electrostatic π–π interaction cationic imidazolium and electron-rich aromatic rings. On the other hand, SiImC₁₈ also showed high selectivity for polar compounds, which was based on the multiple interaction and retention mechanisms of this phase with different analytes. 1,6-Dinitropyrene and 1,8-dinitropyrene, which form a positional isomer pair of dipolar compounds, were separated successfully with the SiImC₁₈ phase. Seven nucleosides and bases (i.e. cytidine, uracil, uridine, thymine, guanosine, xanthosine, and adenosine) were separated using only water as the mobile phase within 8 min, which is difficult to achieve when using conventional hydrophobic columns such as ODS. The combination of electrostatic and hydrophobic interactions is important for the effective separation of such basic compounds without the use of any organic additive as the eluent in the octadecylimidazolium column.     

Syntheses of 4-(benzo[b]furan-2 or 3-yl)- and 4-(benzo[b]-thiophen-3-yl)piperidines with 5-HT2 antagonist activity

The syntheses of 4-(benzo[b]furan-3-yl)piperidines, 4-(benzo[b]furan-2-yl)piperidines and 4-(benzo[b]thiophen-3-yl)piperidines with 5-HT₂ antagonist activity are described. Reaction of 1-acetyl-4-(2,4-difluorobenzo-yl)piperidine 2 with methyl glycolate gave methyl 6-fluoro-3-(1-acetylpiperidin-4-yl)benzo[b]furan-2-carboxylate 3 , which was converted to 2-[2-[4-(benzo[b]furan-3-yi)piperidin-1-yl]ethyl-5,6,7,8-tetrahydro-1,2,4-triazolo-[4,3-a]pyridin-3(2H)-one hydrochloride 9 . Analogous benzo[b]furans 17a-d and benzo[b]thiophenes 10a,b and 18a were prepared by a similar method. Cyclization of 4-fluoro-2-(4-pyridinylmethoxy)acetophenones 20a,b afforded 4-(benzo[b]furan-2-yl)pyridines 21a,b , which were converted to 2-[2-[4-(benzo[b]furan-2-yl)-piperidin-1-yl]ethyl-5,6,7,8-tetrahydro-1,2,4-triazolo[4,3-a]pyridin-3(2H)-one hydrochlorides 24a,b. Among them, benzo[b]furans 9 and 17a,d and benzo[b]thiophenes 10 and 18a showed potent 5-HT₂ antagonist activity in vitro.