Co(III)-Catalyzed Regioselective Functionalization of Isoquinolones with Naphthoquinones.

A strategy for Co(III)-catalyzed C(sp2)-H alkenylation of N-protected isoquinolones with 1,4-naphthoquinones has been disclosed. The developed protocol was efficiently applied for diversely substituted isoquinolones. Preliminary mechanistic experiments revealed the involvement of a five-membered cobaltacycle as an intermediate. Deuterium labeling experiments suggested the reversible nature of the C-H activation step. The scale-up reaction was also carried out, and the product was utilized as a chemosensor to detect Fe3+ ions.

Inherent directing group-enabled Co(III)-catalyzed C-H allylation/vinylation of isoquinolones.

Co(III)-catalysed site-selective C8-allylation and vinylation of isoquinolones with allyl acetate and vinyl acetates has been accomplished. The oxo group of isoquinolone has been utilised as an inherent directing group. Based on preliminary mechanistic studies, a plausible mechanism for the developed reaction has also been delineated. Broad substrate scope with good to excellent yields and post-synthetic transformations of allylated and vinylated isoquinolines highlight the importance of the reaction.

Construction of unsymmetrical heterobiaryls via the Cp*Rh(III)-catalysed C-H/C-H coupling of heteroarenes.

Herein, a concise method for the Rh(III)-catalyzed, directing-group-assisted C-H/C-H cross-coupling of N-heterocycles (quinolines, indolines, indoles, pyridines, pyrimidines, pyrazoles) with other heteroarenes (benzoxazoles, benzofurans, and thiophenes) is disclosed for the synthesis of unsymmetrical heterobiaryl compounds in good to excellent yields. A plausible catalytic cycle has been delineated based on experimental and computational mechanistic studies.

Rh(III)-Catalyzed Alkylation of 8-Methylquinolines with Oxabenzonorbornadienes.

Herein, a concise Rh(III)-catalyzed C(sp3)-H alkylation of 8-methylquinolines with oxabenzonorbornadiene scaffolds and other strained olefins has been disclosed. The retention of the oxabenzonorbornadiene skeleton, broad substrate scope, and wide-ranging functional group tolerance are the key features of the developed catalytic methodology. Mechanistic studies revealed that the reaction does not involve a radical pathway, and the five-membered rhodacycle is the key intermediate. This is the first report on the C(sp3)-H alkylation of 8-methylquinolines with strained oxabenzonorbornadiene scaffolds (with ring retention).

A DFT study of Se n Te n clusters.

First principles calculations have been performed to study the characteristic properties of Se n Te n (n = 5-10) clusters. The present study reveals that the properties of these small clusters are consistent with the properties of Se-Te glassy systems. Several hundred equilibrium structures obtained from a genetic algorithm based USPEX code are relaxed to their minimum energy using the VASP code. Most of the lowest energy buckled ring-like structures are formed from Se-Te heteropolar bonds. Detailed structural analysis and distance energy plots unveil that many equilibrium structures are close in energy to their global minimum. The computed Raman and IR spectra show the dominance of Se-Te heteropolar bonds, consistent with earlier simulation and experimental findings in Se1-x Te x glass materials. Low frequency vibrational modes observed in small clusters are characteristic features of amorphous materials. Non-bonding orbitals (lone pair) are observed in the HOMO, whereas the LUMO is formed from purely antibonding orbitals. The dielectric functions corroborate the bonding mechanism and slightly polar nature of Se n Te n clusters. The energy loss and absorption coefficient indicate the presence of π-plasmons in the UV-visible region. Furthermore, it is ascertained that the use of a hybrid functional (B3LYP) does not affect the properties of small clusters appreciably, except causing a blue shift in the optical spectra. Hence, we find that the small clusters have bearing on the formation of glassy Se-Te systems.

Development, Characterization and In Vitro Antimicrobial Evaluation of Novel Flavonoids Entrapped Micellar Topical Formulations of Neomycin Sulfate.

Flavonoids are the secondary metabolites widely used in pharmaceutical industries due to their several health benefits. Quercetin and rutin, well known flavonoids possesses various pharmacological properties but the constraints of poor aqueous solubility and impermeability across cell membranes restricts their use in formulation development. Moreover, the rising problem of antimicrobial resistance has also caused a serious threat to human life, thus demanding the urgent need of developing more effective antimicrobial formulations. In view of this, the present research work is focused on utilizing the most feasible flavonoid-surfactant concentrations obtained from the already reported physico-chemical analysis in developing an improved neomycin topical formulation through drug combinatorial approach. The formulations were subjected for assessment of physical parameters such as determination of pH, viscosity and spreadability. The drug release profile of the formulations was studied through different mathematical models. After evaluation of all the parameters, two best formulations (NQ-T2 [HE] and NR-T1 [HE]) were selected for antimicrobial evaluation studies against different bacterial and fungal clinical isolates. Among the two formulations, NQ-T2 [HE] showed excellent antibacterial activity against the bacterial strains while NR-T1 [HE] also exhibited promising results when compared with the standard formulations. Overall, this study represents a possible solution to enhance the antimicrobial efficacy of neomycin formulations by combining them with flavonoids through micelles assisted drug combination approach.

Repurposing of FDA Approved Drugs Against SARS-CoV-2 Papain-Like Protease: Computational, Biochemical, and in vitro Studies.

The pandemic caused by SARS-CoV-2 (SCoV-2) has impacted the world in many ways and the virus continues to evolve and produce novel variants with the ability to cause frequent global outbreaks. Although the advent of the vaccines abated the global burden, they were not effective against all the variants of SCoV-2. This trend warrants shifting the focus on the development of small molecules targeting the crucial proteins of the viral replication machinery as effective therapeutic solutions. The PLpro is a crucial enzyme having multiple roles during the viral life cycle and is a well-established drug target. In this study, we identified 12 potential inhibitors of PLpro through virtual screening of the FDA-approved drug library. Docking and molecular dynamics simulation studies suggested that these molecules bind to the PLpro through multiple interactions. Further, IC50 values obtained from enzyme-inhibition assays affirm the stronger affinities of the identified molecules for the PLpro. Also, we demonstrated high structural conservation in the catalytic site of PLpro between SCoV-2 and Human Coronavirus 229E (HCoV-229E) through molecular modelling studies. Based on these similarities in PLpro structures and the resemblance in various signalling pathways for the two viruses, we propose that HCoV-229E is a suitable surrogate for SCoV-2 in drug-discovery studies. Validating our hypothesis, Mefloquine, which was effective against HCoV-229E, was found to be effective against SCoV-2 as well in cell-based assays. Overall, the present study demonstrated Mefloquine as a potential inhibitor of SCoV-2 PLpro and its antiviral activity against SCoV-2. Corroborating our findings, based on the in vitro virus inhibition assays, a recent study reported a prophylactic role for Mefloquine against SCoV-2. Accordingly, Mefloquine may further be investigated for its potential as a drug candidate for the treatment of COVID.

The medicolegal importance of establishing human identity by using dactyloscopy and rugoscopy: A comparative study.

BACKGROUND: Palatal rugae are irregular and asymmetric mesenchymal ridges that extend in a lateral direction away from the incisive papilla and mid-palatine raphe. Their unique characteristics and environmental stableness justify their inclusion in forensic investigations. Dermatoglyphics or fingerprint patterns are epidermal ridges, which are genetically controlled and are specific to an individual. Hence they are used as a forensic tool. OBJECTIVES: The study aimed to assess the reliability of Rugoscopic and Dermatoglyphic patterns for gender identification. MATERIALS AND METHODS: A total of 200 subjects were recruited in this prospective study. All subjects were between the age range of 18 and 55 years. The subjects were categorized into 100 males and 100 females. Fingerprint dermatoglyphic patterns were recorded using stamp pad, ink, and A4 size white sheets. A subject's fingers were pressed onto the stamped ink pad and lightly pressed over a sheet of paper. Obtained patterns were coded and analyzed as per Galton's criteria into arch, loop, and whorl patterns. Palatal rugae patterns were obtained by making alginate impression material and impression trays. Obtained casts were analyzed for rugae pattern analysis using Kapali's classification. An unpaired t test was used as a statistical tool. RESULTS: On analyzing dermatoglyphic patterns, the arch pattern was most common among male subjects, whereas loop pattern was found to be most common among females. On rugoscopic pattern analysis, Straight pattern was most frequent among males, whereas the circular pattern was common among females. CONCLUSION: A statistically significant difference was noted between gender and rugoscopic patterns (P = 0.02) and dermatoglyphic patterns (P = 0.03).

Effect of different irrigating solutions with surfactants on the microhardness and smear layer removal of root canal dentin: An in vitro study.

AIM: The present in vitro study was undertaken to check the effect of the different irrigating solutions with surfactants, i.e., sodium hypochlorite-(Naocl)-Extra, chlorhexidine (CHX)-Ultra, ethylenediaminetetraacetic acid (EDTA), QMix, and BioPure MTAD on the microhardness and smear layer removal of root canal dentin. MATERIALS AND METHODS: A total of 120 straight rooted lower premolars were collected and were randomly divided into 2 equal groups of 60 each (n = 60). The microhardness of the samples was evaluated by Vickers hardness tester and the removal of smear layer by scanning electron microscope after irrigation of the samples with the tested solutions. RESULTS: CHX-Ultra showed the least microhardness reduction, and EDTA showed the maximum microhardness reduction in all the tested groups. BioPure MTAD showed the maximum removal of smear layer in the apical third, and CHX-Ultra showed the minimal smear layer removal in the apical third. CONCLUSION: During smear layer removal, irrigating solutions cause alterations in the chemical composition of dentin, which may decrease the microhardness of the root dentin causing erosion and affecting the clinical performance of the endodontically treated teeth. Irrigating solution with maximum smear layer removal with minimum changes in microhardness should be used.

Proteasome inhibition induces IKK-dependent interleukin-8 expression in triple negative breast cancer cells: Opportunity for combination therapy.

Triple negative breast cancer (TNBC) cells express increased levels of the pro-inflammatory and pro-angiogenic chemokine interleukin-8 (IL-8, CXCL8), which promotes their proliferation and migration. Because TNBC patients are unresponsive to current targeted therapies, new therapeutic strategies are urgently needed. While proteasome inhibition by bortezomib (BZ) or carfilzomib (CZ) has been effective in treating hematological malignancies, it has been less effective in solid tumors, including TNBC, but the mechanisms are incompletely understood. Here we report that proteasome inhibition significantly increases expression of IL-8, and its receptors CXCR1 and CXCR2, in TNBC cells. Suppression or neutralization of the BZ-induced IL-8 potentiates the BZ cytotoxic and anti-proliferative effect in TNBC cells. The IL-8 expression induced by proteasome inhibition in TNBC cells is mediated by IκB kinase (IKK), increased nuclear accumulation of p65 NFκB, and by IKK-dependent p65 recruitment to IL-8 promoter. Importantly, inhibition of IKK activity significantly decreases proliferation, migration, and invasion of BZ-treated TNBC cells. These data provide the first evidence demonstrating that proteasome inhibition increases the IL-8 signaling in TNBC cells, and suggesting that IKK inhibitors may increase effectiveness of proteasome inhibitors in treating TNBC.

Vitamin D and gastrointestinal cancer.

Vitamin D serves as a precursor to the potent steroid hormone calcitriol, which has widespread actions throughout the body. Calcitriol regulates numerous cellular pathways that could have a role in determining cancer risk and prognosis. Low Vitamin D levels have been implicated in numerous disease processes including fracture risk, falls, cardiovascular disease, hypertension, diabetes mellitus, and cancers. Metabolite of 1, 25-dihydroxyvitamin D3 (1,25[OH]2D3) regulates numerous genes that control gut physiology and homeostasis. 1,25(OH)2D3 serves various functions such as maintaining the integrity of epithelial barrier and absorption of calcium and phosphate, and the host's defense against pathogens, and the inflammatory response by several types of secretory and immune cells. Although epidemiological data remain inconsistent, and randomized control trials in humans do not yet exist to conclusively support a beneficial role for Vitamin D, results from some correlating studies strongly suggest that Vitamin D deficiency increases the risk of developing cancer and that avoiding deficiency and adding Vitamin D supplements might be an economical and safe way to reduce cancer incidence and improve cancer prognosis and outcome. The present review highlights the role of Vitamin D in cancer of the gastrointestinal tract including esophagus, gastric (stomach), liver, pancreas, and colon.

Emergence of micronuclei as a genomic biomarker.

The presence of micronuclei (MN) in mammalian cells is related to several mutagenetic stresses. MN are formed as a result of chromosome damage and can be readily identified in exfoliated epithelial cells. MN is chromatin particles derived from acentric chromosomal fragments, which are not incorporated into the daughter nucleus after mitosis. It can be visualized by chromatin stains. A variety of factors influences the formation of MN in cells such as age, sex, genetic constitution, physical and chemical agents, adverse habits such as tobacco, areca nut chewing, smoking, and alcohol consumption. Micronucleation has important implications in the genomic plasticity of tumor cells. The present paper reviews the origin, fate and scoring criteria of MN that serves as a biomarker of exposure to genetic toxins, and for the risk of cancer.