Assessment of conformational ensemble sizes necessary for specific resolutions of coverage of conformational space

The size of conformational ensembles required for regular coverage of the conformational space of druglike molecules was examined. Using the conformer generation program Omega, the number of regularly distributed conformers (NRC) of flexible compounds was determined as a function of the root-mean-square deviation (RMSD) resolution of coverage. A regression equation was developed predicting the NRC of a molecule as a function of RMSD. The model yielded R(2) of 0.91 for both training and test sets, which consisted of 3414 and 3352 compounds, respectively. Utilizing 14 504 ligands from the Protein Data Bank with experimentally determined 3-D conformations, the regression equation was applied to the estimation of the NRC and the success rate of reproduction of experimental conformations from a theoretical conformation ensemble as a function of RMSD and flexibility was explored.     

Tetranuclear copper(I) clusters: impact of bridging carboxylate ligands on solid state structure and photoluminescence

The X-ray crystallographic characterization and solid state photoluminescence (PL) study of three new tetranuclear copper(I) clusters, [Cu4(O2CR)4], R = (3-F)C6H4 (1), (2,3,4-F)3C6H2 (2), and CF3/C6F5 (3), revealed a dependence of PL on the structural type.     

A straightforward preparation of benzo[f]naphtho[b][1,4]oxazepines from TNT

2,4,6-Trinitrotoluene readily reacts with 1-nitroso-2-naphthol to afford 9,11-dinitrobenzo[f]naphtho[2,1-b][1,4]oxazepine. The nitro groups of the latter undergo displacement by O- and S-nucleophiles with preferential substitution of the 11-NO₂ (peri-nitro group). The structures of the substitution products are confirmed by X-ray diffraction and ¹H NMR NOE experiments.     

C,N-Diarylformamidines as Valuable Building Blocks in the Synthesis of Heterocyclic Compounds

Obtaining highly functionalized heterocyclic structures is an important topic of modern organic synthesis, as it reveals the possibility of constructing more complex systems and therefore, expanding the range of various drugs. Aiming at synthesizing complex molecules from simple and readily available reagents, the modification of C,N-diarylformamidines, well known in medicinal chemistry, is of great interest. This article reviews comprehensively the field of C,N-diarylformamidine chemistry and covers publications on this topic from 1999 to 2022.     

Impact of oil composition on formation and stability of emulsions produced by spontaneous emulsification

In this study, triglycerides of different chain lengths were mixed with paraffin oil, and their effectiveness in forming emulsions produced by spontaneous emulsification upon the addition of water was investigated. The emulsion droplet size exhibited a similar trend as a function of the triglyceride/paraffin oil composition for medium-chain (MCTs) (C8–C10) and long-chain (C18) triglycerides (LCTs). However, emulsions formulated with MCTs and LCTs have a much smaller droplet size (about 50?nm) than emulsions based upon short-chain (C4) triglycerides (SCTs). The addition of SCTs resulted in droplet sizes around 800?nm and the emulsions formed were very unstable. The droplet size, polydispersity index, zeta potential, and emulsion stability of these systems will be described as a function of the oil phase composition.     

Structural Variability of R2C Adducts of 3a,6a‐Diaza‐1,4‐diphosphapentalene: Tuning the N→P Bonding

3a,6a‐Diaza‐1,4‐diphosphapentalene (DDP) reacts with hexachlorocyclopentadiene to form a stable adduct (ClC)₄C=DDP ( 4 ). The phosphorus atom involved into coordination has a pyramidal arrangement but retains partial double bonding with carbon [1.752(3) Å]. At the same time, the P–N bond remains covalent [1.824(3) Å]. The adduct 4 is better described as a zwitterionic compound with strongly delocalized positive and negative charges. A similar zwitterionic adduct DDP=C(CN)₂ was prepared by the reactions of dichloro‐DDP ( 7 ) with malononitrile in the presence of Et₃N. DFT calculations showed that related structures are formed in the case of the substituents (ClC)₄C=, (HC)₄C=, (NC)₂C=, and (MeCO)₂C=, possessing electron‐delocalizing properties. Compounds with other R₂C groups (R = Ph, Me, C₆F₅, Cl), possessing electronegative properties as well, but insufficient e‐delocalization, demonstrate the noncovalent P–N bonding and a little shorter R₂C–P bond lengths (ca. 1.70 Å).     

Improving the robustness of the control volume finite element method with application to multiphase porous media flow

Control volume finite element methods (CVFEMs) have been proposed to simulate flow in heterogeneous porous media because they are better able to capture complex geometries using unstructured meshes. However, producing good quality meshes in such models is nontrivial and may sometimes be impossible, especially when all or parts of the domains have very large aspect ratio. A novel CVFEM is proposed here that uses a control volume representation for pressure and yields significant improvements in the quality of the pressure matrix. The method is initially evaluated and then applied to a series of test cases using unstructured (triangular/tetrahedral) meshes, and numerical results are in good agreement with semianalytically obtained solutions. The convergence of the pressure matrix is then studied using complex, heterogeneous example problems. The results demonstrate that the new formulation yields a pressure matrix than can be solved efficiently even on highly distorted, tetrahedral meshes in models of heterogeneous porous media with large permeability contrasts. The new approach allows effective application of CVFEM in such models.     

Strikingly High Activity of 15-Lipoxygenase Towards Di-Polyunsaturated Arachidonoyl/Adrenoyl-Phosphatidylethanolamines Generates Peroxidation Signals of Ferroptotic Cell Death

The vast majority of membrane phospholipids (PLs) include two asymmetrically positioned fatty acyls: oxidizable polyunsaturated fatty acids (PUFA) attached predominantly at the sn2 position, and non-oxidizable saturated/monounsaturated acids (SFA/MUFA) localized at the sn1 position. The peroxidation of PUFA-PLs, particularly sn2-arachidonoyl(AA)- and sn2-adrenoyl(AdA)-containing phosphatidylethanolamines (PE), has been associated with the execution of ferroptosis, a program of regulated cell death. There is a minor subpopulation (≈1–2 mol %) of doubly PUFA-acylated phospholipids (di-PUFA-PLs) whose role in ferroptosis remains enigmatic. Here we report that 15-lipoxygenase (15LOX) exhibits unexpectedly high pro-ferroptotic peroxidation activity towards di-PUFA-PEs. We revealed that peroxidation of several molecular species of di-PUFA-PEs occurred early in ferroptosis. Ferrostatin-1, a typical ferroptosis inhibitor, effectively prevented peroxidation of di-PUFA-PEs. Furthermore, co-incubation of cells with di-AA-PE and 15LOX produced PUFA-PE peroxidation and induced ferroptotic death. The decreased contents of di-PUFA-PEs in ACSL4 KO A375 cells was associated with lower levels of di-PUFA-PE peroxidation and enhanced resistance to ferroptosis. Thus, di-PUFA-PE species are newly identified phospholipid peroxidation substrates and regulators of ferroptosis, representing a promising therapeutic target for many diseases related to ferroptotic death.     

Role of Mono- and Disaccharide Combination in Cryoprotective Medium for Rooster Semen to Ensure Cryoresistance of Spermatozoa

The combination of saccharides in the composition of a cryopreservation medium may represent a promising method for the preservation of the reproductive cells of male birds. In the current study, cryoprotective media with a combined composition of mono- and di-saccharides were developed. The degree of penetration of reducing saccharide molecules (maltose—Mal20 medium) and non-reducing disaccharide molecules (trehalose—Treh20 medium) from the cryoprotective medium into the cytosol of rooster spermatozoa was studied. LCM control media without disaccharides were used as the control. The number of maltose molecules penetrating from the outside into the cytosol of the spermatozoon was 1.06 × 10⁴, and the number of trehalose molecules was 3.98 × 10⁴. Using a combination of maltose and fructose, the progressive motility of frozen/thawed semen and the fertility rates of eggs were significantly higher ((p < 0.05) 40.2% and 68.5%, respectively) than when using a combination of trehalose and fructose in a cryoprotective diluent (33.4% and 62.4%, respectively). A higher rate of chromatin integrity at the level of 92.4% was obtained when using Treh20 versus 74.5% Mal20 (p < 0.05). Maltose positively affected the preservation of frozen/thawed sperm in the genital tract of hens. On the seventh day from the last insemination when using Mal20, the fertilization of eggs was 42.6% and only 27.3% when using Treh20. Despite the same molecular weight, maltose and trehalose have different physicochemical and biological properties that determine their function and effectiveness as components of cryoprotective media.