Molecular Umbrella as a Nanocarrier for Antifungals

A molecular umbrella composed of two O-sulfated cholic acid residues was applied for the construction of conjugates with cispentacin, containing a “trimethyl lock” (TML) or o-dithiobenzylcarbamoyl moiety as a cleavable linker. Three out of five conjugates demonstrated antifungal in vitro activity against C. albicans and C. glabrata but not against C. krusei, with MIC90 values in the 0.22–0.99 mM range and were not hemolytic. Antifungal activity of the most active conjugate 24c, containing the TML–pimelate linker, was comparable to that of intact cispentacin. A structural analogue of 24c, containing the Nap-NH2 fluorescent probe, was accumulated in Candida cells, and TML-containing conjugates were cleaved in cell-free extract of C. albicans cells. These results suggest that a molecular umbrella can be successfully applied as a nanocarrier for the construction of cleavable antifungal conjugates.

Archaeal pseudomurein and bacterial murein cell wall biosynthesis share a common evolutionary ancestry

Bacteria near-universally contain a cell wall sacculus of murein (peptidoglycan), the synthesis of which has been intensively studied for over 50 years. In striking contrast, archaeal species possess a variety of other cell wall types, none of them closely resembling murein. Interestingly though, one type of archaeal cell wall termed pseudomurein found in the methanogen orders Methanobacteriales and Methanopyrales is a structural analogue of murein in that it contains a glycan backbone that is cross-linked by a L-amino acid peptide. Here, we present taxonomic distribution, gene cluster and phylogenetic analyses that confirm orthologues of 13 bacterial murein biosynthesis enzymes in pseudomurein-containing methanogens, most of which are distantly related to their bacterial counterparts. We also present the first structure of an archaeal pseudomurein peptide ligase from Methanothermus fervidus DSM1088 (Mfer336) to a resolution of 2.5 Å and show that it possesses a similar overall tertiary three domain structure to bacterial MurC and MurD type murein peptide ligases. Taken together the data strongly indicate that murein and pseudomurein biosynthetic pathways share a common evolutionary history.

Integral Structure Of Professional I-Concept

The paper considers the notion of “professional self-concept”. Its multilevel structure, in which components, modalities, levels, time components and distorting components are identified and described, is represented and substantiated. Professional self-concept is considered as a structural analogue of the general self-concept and the marked difference in the structures of the concepts is showed

Modelling the structural variation of quartz and germanium dioxide with temperature by means of transformed crystallographic data

The pseudocubic (PC) parameterization of O4 tetrahedra [Reifenberg & Thomas (2018). Acta Cryst. B74, 165–181] is applied to quartz (SiO2) and its structural analogue germanium dioxide (GeO2). In α-quartz and GeO2, the pseudocubes are defined by three length parameters, a PC, b PC and c PC, together with an angle parameter αPC. In β-quartz, αPC has a fixed value of 90°. For quartz, the temperature evolution of parameters for the pseudocubes and the silicon ion network is established by reference to the structural refinements of Antao [Acta Cryst. (2016), B72, 249–262]. In α-quartz, the curve-fitting employed to express the non-linear temperature dependence of pseudocubic length and Si parameters exploits the model of a first-order Landau phase transition utilized by Grimm & Dorner [J. Phys. Chem. Solids (1975), 36, 407–413]. Since values of tetrahedral tilt angles about 〈100〉 axes also result from the pseudocubic transformation, a curve for the observed non-monotonic variation of αPC with temperature can also be fitted. Reverse transformation of curve-derived values of [Si+PC] parameters to crystallographic parameters a, c, x Si, x O, y O and z O at interpolated or extrapolated temperatures is demonstrated for α-quartz. A reverse transformation to crystallographic parameters a, c, x O is likewise carried out for β-quartz. This capability corresponds to a method of structure prediction. Support for the applicability of the approach to GeO2 is provided by analysing the structural refinements of Haines et al. [J. Solid State Chem. (2002), 166, 434–441]. An analysis of trends in tetrahedral distortion and tilt angle in α-quartz and GeO2 supports the view that GeO2 is a good model for quartz at high pressure.

Synthesis of procaine analogues containing pentafluoroethoxy groups in the aromatic nucleus

In order to synthesize procaine analogs containing one or two pentafluoroethoxy groups, a method for the synthesis of benzoic acids containing a pentafluoroethoxy group in the ortho-position of the benzene nucleus has been developed. An effective method for the synthesis of procaine structural analogues containing one or two pentafluoroethoxy groups has been proposed. It has been shown that the replacement of the amino group by the pentafluoroethoxy group in the procaine molecule leads to a significant increase in the local anesthetic activity of the obtained compounds. The most active compound was a structural analogue of procainamide containing two pentafluoroethoxy groups in positions 2 and 4. The formation of fluorine-containing analogues of procaine was confirmed by 1H, 19F and 13C NMR spectroscopy and mass spectrometry.

A Concise Synthesis of 24,25-Dihydro-6-epi-Monanchosterol A

We report the first synthetic entry to a steroid with an unusual bicyclo[4.3.1]dec-3-en-10-one A/B ring substructure as a close structural analogue of the anti-inflammatory monanchosterols. Under optimized conditions, regioselective cis-dihydroxylation of the Δ5-double bond of 7-dehydrocholesterol and subsequent Criegee oxidation yields the corresponding 5,6-seco-steroid as a pure Z-isomer which upon treatment with K2CO3 in MeOH diastereoselectively affords 24,25-dihydro-6-epi-monanchosterol A through intramolecular aldol addition (cyclization). The developed three-step sequence proceeds in 17% overall yield without the need of any protecting group. The title compound was characterized by X-ray crystallography.

DSIP-Like KND Peptide Reduces Brain Infarction in C57Bl/6 and Reduces Myocardial Infarction in SD Rats When Administered during Reperfusion

A structural analogue of the DSIP, peptide KND, previously showed higher detoxification efficacy upon administration of the cytotoxic drug cisplatin, compared to DSIP. DSIP and KND were investigated using the model of acute myocardial infarction in male SD rats and the model of acute focal stroke in C57Bl/6 mice. A significant decrease in the myocardial infarction area was registered in KND-treated animals relative to saline-treated control animals (19.1 ± 7.3% versus 42.1 ± 9.2%). The brain infarction volume was significantly lower in animals intranasally treated with KND compared to the control saline-treated animals (7.4 ± 3.5% versus 12.2 ± 5.6%). Injection of KND in the first minute of reperfusion in the models of myocardial infarction and cerebral stroke reduced infarction of these organs, indicating a pronounced cardioprotective and neuroprotective effect of KND and potentiality for the treatment of ischemia-reperfusion injuries after transient ischemic attacks on the heart and brain, when administered during the reperfusion period. A preliminary pilot study using the model of myocardial infarction with the administration of DSIP during occlusion, and the model of cerebral stroke with the administration of KND during occlusion, resulted in 100% mortality in animals. Thus, in the case of ischemia-reperfusion injuries of the myocardium and the brain, use of these peptides is only possible during reperfusion.

Pregabalin abuse and toxicity and related factors

Pregabalin is one of a group of gabapentinoids approved by the Food and Drug Administration (FDA) in 2004. It is a capsule medication taken by mouth that is used for the treatment of neuropathic pain. It is a structural analogue of the neurotransmitter gamma-aminobutyric acid (GABA), and it appears to have a spectrum of benefits and harms similar to those of other adjuvant analgesics used to treat neuropathic pain. The most common side effects mentioned in peripheral neuropathy studies are dizziness and somnolence. Pregabalin could cause liver toxicity by increasing the levels of liver enzymes. It can potentially cause vasodilatation and fluid retention in the heart and blood vessels. It may also lead to addiction. The use of Pregabalin is common among patients with a history of substance abuse and psychoactive drug dependence, as euphoria is one of its main side effects. However, abrupt discontinuation from using Pregabalin may cause nausea, insomnia, or headache. The present review evaluates the significant impact of Pregabalin toxicity on liver and heart in patients and misusers. Keywords: Pregabalin, liver toxicity, alanine aminotransferase (ALT), aspartate aminotransferase (AST), creatine kinase (CK), heart failure, addiction.

Effects of L-alpha-aminoadipic acid on neurons and glia of the rat brain striatum

Introduction. Few published studies have examined the role of glia-neuron interactions in neurodegen-eration. In this regard, the search for new experimental models is important. L-alpha-aminoadipic acid (L-AA), being a structural analogue of glutamate with a selective toxic effect on astroglia, is of particular interest. However, morphological and neurochemical changes caused by L-AA still remain unclear. The aim of the study was to characterize immunomorphological changes of glia and neurons in the striata of rats after L-AA administration. Materials and methods. On days 3 and 12 after L-AA stereotaxic administration, we studied astrocytic pro-teins localization using immunofluorescence methods: GFAP, vimentin, glutamine synthetase, along with oligodendroglia (by cyclonucleotidphosphatase expression), microglia (IBA1 Ca-binding protein), neuronal nuclear protein NeuN, and the astroglia proliferative activity (based on Ki67 localization). Results. We detected astrocyte death and a decrease in glutamine synthetase immunoreactivity in the le-sioned area, but no changes in the microglia reaction and the L-AA effect on neurons and oligodendroglia. The astrocyte loss was replenished by proliferation and migration of newly formed immature astrocytes, and a glial scar formed on day 12 after the surgery. Conclusion. L-AA administration, which causes the death of striatum astrocytes in the injection area, can serve as a convenient model for studying reactive changes in astroglia and astrocytic dysfunction while revealing the pathogenetic patterns of neurodegenerative processes. Keywords: astrocytes, striatum, L-alpha-aminoadipic acid, gliosis, glial toxin

Rearrangement of substituted pyrimidin-4-ones under the Vilsmeier-Haack reaction

The article describes the result of our study on rearrangements of four heterocyclic systems with variation of oxygen and nitrogen atoms, in particular, the results of formylation of 2,2-disubstituted hydroquinazolones under the conditions of the Vilsmeier-Haack reaction. A new rearrangement of spiro derivatives of quinazolin-4(3H)-ones was discovered under the action of a formylating reagent with the formation of predicted 1-cyclohex(pent)-1-en-1-ylchinazolin-4-(1H)-ones. The absence of this rearrangement for 2,2-dimethyl-2,3-dihydroquinazolin-4(1H)-one is explained. 6',7',7'-Trimethyl-1',5',6',7'-tetrahydrospiro [cyclohexane-1,2'-pyrrolo[3,4-d]pyrimidine]-4'(3'H)-one is a structural analogue of spiro derivatives of quinazolin-4(3H)-ones; it undergoes a similar rearrangement with the formation of 1-cyclopent-1-en-1-yl-6,7,7-trimethyl-1,5,6,7-tetrahydro-4H-pyrrolo[3,4-d]pyrimidin-4-one when interacting with Vilsmeier-Haack reagent.