An integrated approach to understand the regulatory role of miR-27 family in breast cancer metastasis.

One of the prime reasons of increasing breast cancer mortality is metastasizing cancer cells. Owing to the side effects of clinically available drugs to treat breast cancer metastasis, it is of utmost importance to understand the underlying biogenesis of breast cancer tumorigenesis. In-silico identification of potential RNAs might help in utilizing the miR-27 family as a therapeutic target in breast cancer. The experimentally verified common interacting mRNAs for miR27 family are retrieved from three publicly available databases- TargetScan, miRDB and miRTarBase. Finally on comparing the common genes with HCMDB and GEPIA data, four breast cancer-associated differentially expressed metastatic mRNAs (GATA3, ENAH, ITGA2 and SEMA4D) are obtained. Corresponding to the miR27 family and associated mRNAs, interacting drugs are retrieved from Sm2mir and CTDbase, respectively. The interaction network-based approach was utilized to obtain the hub RNAs and triad modules by employing the 'Cytohubba' and 'MClique' plugins, respectively in Cytoscape. Further, sample-, subclass- and promoter methylation-based expression analyses reveals GATA3 and ENAH to be the most significant mRNAs in breast cancer metastasis having >10% genetic alteration in both METABRIC Vs TCGA datasets as per their oncoprint analysis via cBioPortal. Additionally, survival analysis in Oncolnc reveals SEMA4D as survival biomarker. Interactions among the miR27 family, their target mRNAs and drugs interacting with miRNAs and mRNAs can be extensively explored in both in-vivo and in-vitro setups to assess their therapeutic potential in the diminution of breast cancer.

Conversion of amino-terephthalonitriles to multi-substituted single benzene fluorophores with utility in bioimaging.

Substitution of two fluorine atoms of the tetrafluoroterephthalonitrile (TFTN) ring (ortho to each other) by amine nucleophiles through SNAr chemistry is achievable. However, tri- and tetra-substitution towards multi-substituted single benzene fluorophores (SBFs) is harder due to increased electron richness of the TFTN moiety. Tertiary amine donors promote the molecule towards such multi-substitution guided by the steric obstruction to intramolecular charge transfer to the TFTN ring. Contrarily, secondary amine substituents with better lone pair donation to the TFTN ring cannot induce the SNAr pathway and instead promote hydrolysis of the nitrile groups of the TFTN moiety. Theoretical investigations have helped unearth the reasons for this observed difference in chemical reactivities and also explain the differences in the emission spectra. Finally, the success of the synthetic method towards multi-substitution is showcased through creation of a highly lipophilic SBF bearing an octyl unit and demonstrating its utility in in vitro cellular imaging.

Diamino-Terephthalonitrile-based Single Benzene Fluorophores Featuring Strong Solution State Fluorescence and Large Stokes Shifts.

1°- and 2°-amines react with tetrafluoroterephthalonitrile through SNAr chemistry, creating the strongly emissive para-diamino-terephthalonitrile type single benzene fluorophores. The regioselectivity of reaction is dictated by the sterics of the initial secondary amine adduct. The molecules exhibit strong green-yellow emission and large (nearly 150 nm) Stokes shifts. Excited state analysis reveals a cooperative effect between the para-positioned amino groups through the electron-poor terephthalonitrile unit resulting in the fluorescence amplification.

Production and characterization of a novel poly amino acid from a thermophilic bacterium, and preliminary testing of its coagulating potential for imminent wastewater treatment application.

The increasing demand for biopolymers across diverse fields, such as food, medicine, cosmetics, and environmental applications, has prompted researchers to explore novel molecules with enhanced functionalities that meet these demands. In this study, a thermophilic strain of Bacillus licheniformis was employed to produce a unique polyamino acid. This thermophilic isolate exhibited rapid growth at 50 °C in a sucrose mineral salts medium, resulting in a biopolymer concentration of 7.4 g/L. Interestingly, the biopolymer produced at different temperatures exhibited varying glass-transition temperatures (ranging from 87.86 °C to 104.11 °C) and viscosities (7.5 cP to 16.3 cP), suggesting that the fermentation temperature significantly influenced the degree of polymerization. Furthermore, the biopolymer was characterized using various techniques, including Thin Layer Chromatography (TLC), Fourier Transform Infrared (FTIR) spectroscopy, Liquid Chromatography-Electrospray Ionization-Mass Spectroscopy (LC-ESI MS), Nuclear Magnetic Resonance (NMR), and Differential Scanning Calorimetry-Thermogravimetric Analysis (DSC-TGA). The results revealed that the obtained biopolymer was a poly amino acid, with poly-γ-glutamic acid as the major monomeric component in the polymer backbone with a few appendages of aspartic acid residues in its side chain. Finally, the biopolymer demonstrated significant coagulation potential for water treatment applications, as evidenced by coagulation studies conducted under varying pH conditions using kaolin-clay as a model precipitant.

Promising anode materials for alkali metal ion batteries: a case study on cobalt anti-MXenes.

There is continuous demand for energy storage devices with high energy densities in consumer electronics, electric vehicles, and the grid energy market. Although commercial lithium-ion batteries (LIBs) satisfy the current needs, the limited availability of their raw materials and the moderate specific charge capacities (SCCs) of LIBS have motivated scientists to search for alternate anode materials for LIBs and create technologies beyond LIBs. In this work, we studied the potential of six cobalt anti-MXenes (CoAs, CoB, CoP, CoS, CoSe, and CoSi), a class of newly discovered 2D materials, as anode materials for lithium, sodium, and potassium ion batteries (LIBs, NIBs, and KIBs). We found that these materials are good electrical conductors and have high adsorption stability for alkali metal ions, which helps to prevent the formation of dendrites and increase the cycle life of the battery. They also show moderate to low migration energy barriers (MEBs), indicating the potential for faster charge-discharge kinetics. We also explain the slightly counter-intuitive result of observing low MEBs along with high adsorption stability. Furthermore, Co-anti-MXenes can adsorb multiple alkali atoms per formula unit, resulting in high specific charge capacities and low average anodic voltages. For example, as anode materials for lithium-ion batteries, CoP and CoSi have SCC values of 1075.4 mA h g-1 and 934 mA h g-1, and anodic voltages as low as 0.28 V and 0.43 V, respectively. Moreover, even the maximally metalated Co-anti-MXenes did not show agglomeration tendency at room temperature. Furthermore, the volume expansion of these materials is minimum for both Li and Na adsorption. As a whole, we find that Co-anti-MXenes are promising as anode materials for alkali metal ion batteries.

Amino-Terephthalonitrile-Based Single Benzene Fluorophores with Large Stokes Shifts and Solvatochromic Behavior.

We have synthesized a small library of blue-to-green emissive single benzene-based fluorophores (SBFs) in a short synthetic sequence. The molecules exhibit good Stokes shift in the range of 60-110 nm and select examples also possess very high fluorescence quantum yields of up to 87%. Theoretical investigations into the ground state and excited state geometries of many of these compounds reveal that good degree of planarization between the electron donor secondary amines and electron accepting benzodinitrile units can be achieved under certain solvatochromic conditions, giving rise to the strongly fluorescent behavior. On the other hand, the excited state geometry which lacks co-planarity of the donor amine and the single benzene moiety can open up a non-fluorescent channel. Additionally, in molecules with a dinitrobenzene acceptor, the perpendicular nitro moieties render the molecules completely non-emissive.

An in silico discovery of potential 3CL protease inhibitors of SARS-CoV-2 based upon inactivation of the cysteine 145-Histidine 41 catalytic dyad.

Coronavirus disease 19 (COVID19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Currently, several countries are at risk of the pandemic caused by this virus. In the absence of any vaccine or virus-specific antiviral treatments, the need is to fast track search for potential drug candidates to combat the virus. Though there are known drugs that are being repurposed to fight against the SARS-CoV-2, there is a requirement for the virus-specific drugs at the earliest. One of the main drug targets of SARS-CoV-2 is an essential non-structural protein, 3CL protease, critical for the life cycle of the virus. We have used molecular docking studies to screen a chemically diverse set of small molecules to identify potential drug candidates to target this protein. Of the 22,630 molecules from varied small molecule libraries, based on the binding affinities and physicochemical properties, we finalized 30 molecules to be potential drug candidates. Eight of these molecules bind in a manner allowing for the scope of a nearly orthogonal backside nucleophilic attack on their suitably placed electrophilic carbonyl groups by the thiol group of cysteine residue 145, while remaining inside a 4 Ǻ distance range. It is interesting since carbonyl groups are known to be attacked in a similar fashion by external nucleophiles and can be relevant when considering these molecules as potential mechanism-based irreversible inhibitors of the 3CLPro. Further, ADMET analysis and Molecular dynamics simulations and available bioactive assays led to the identification of three molecules with high potential to be explored as drug candidates/lead molecules to target 3CLPro of SARS-CoV-2.Communicated by Ramaswamy H. Sarma.

Predicting Long-Term Outcome of Patients of Early Parkinsonism with Acute Levodopa Challenge Test.

OBJECTIVES: The aim of this study was to evaluate the sensitivity and specificity of various outcomes of acute levodopa challenge test (ALCT) namely improvement of motor function, development of dyskinesia and intolerance; to predict the diagnosis of idiopathic Parkinson's disease (IPD) or Parkinson-plus syndrome; to predict levodopa responsiveness and levodopa-induced dyskinesia (LID) during long-term therapy. METHODS: ALCT was performed on 89 patients with parkinsonism of <2 years and were followed up for 18 months. Improvement of UPDRSm by ≥30% was considered positive. RESULTS: The test was positive in 37 (43.5%) and negative in 48 (56.5%) of 85 patients completing it. Of the 75 patients completing 18 months' follow-up 34 (45.3%) were diagnosed as IPD. A positive ALCT predicted a clinical diagnosis of IPD with sensitivity and specificity of 97.4% and 70.7% respectively. The predictive value of ALCT for long-term levodopa responsiveness was less than predicting a diagnosis of IPD. While appearance of dyskinesia during ALCT had a low predictive value for future LID (sensitivity 14.3%), it had high predictive value for a diagnosis of multisystem atrophy (MSA) (91% specificity and 37.5% sensitivity). The appearance of symptoms of levodopa intolerance (SLI) during ALCT could predict a clinical diagnosis of MSA with high specificity (95.5%) and moderate sensitivity (50%). CONCLUSION: Levodopa responsiveness during ALCT was useful in predicting a diagnosis of IPD but not long-term response to levodopa. The development of dyskinesia during ALCT could not correctly predict LID, but could predict a diagnosis of MSA. The appearance of SLI during ALCT could also predict MSA correctly.

Spectroscopic and viscometric determination of DNA-binding modes of some bioactive dibenzodioxins and phenazines.

Push-pull dibenzodioxins and phenazines having 'anthracene-like' planar structures and good charge transfer character had been previously synthesised in our laboratory. The dibenzodioxins had earlier proven their anti-proliferative nature against HeLa tumor cell lines. Since phenazines are structural analogues of the former, these molecules were evaluated in course of the current study for their cytotoxic action against HeLa cell lines and they exhibited strong anti-tumor activity. This behavior could be related to their good DNA binding property. The DNA binding modes of molecules 1-4 (Fig. 1) were evaluated using various experimental techniques and they interacted with DNA in a non-covalently by both intercalative as well as groove binding mechanisms. Molecule 1 follows predominantly intercalative binding mode whereas molecules 2 and 3 have nearly equal and opposite preferences for both groove binding and intercalative modes. For molecule 4, groove binding is preferred mode of binding to DNA. A rationale for such differential binding behaviour is provided based on the subtle structural differences in our synthesised dibenzodioxins and phenazines. Elucidation of the mode of a molecule-DNA-binding event is relevant for understanding the mechanism of action of these molecules and will help promote further research into designing better DNA targeting small molecules.

Chorea-ballism as a dominant clinical manifestation in heteroplasmic mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes syndrome with A3251G mutation in mitochondrial genome: a case report.

BACKGROUND: Mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes, the most common maternally inherited mitochondrial disease, can present with a wide range of neurological manifestations including both central and peripheral nervous system involvement. The most frequent genetic mutation reported in mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes syndrome is A3243G in MT-TL1 gene. Stroke-like episodes, dementia, epilepsy, lactic acidemia, myopathy, recurrent headaches, hearing impairment, diabetes, and short stature constitute the known presentations in this syndrome. Among the abnormal involuntary movements in mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes syndrome, myoclonus is the commonest. Other movement disorders, including chorea, are rarely reported in this disorder. CASE PRESENTATION: A 14-year-old South Asian boy from rural Bengal (India), born of a second degree consanguineous marriage, with normal birth and development history, presented with abnormal brief jerky movements involving his trunk and limbs, with recurrent falls for 10 months. We present here a case of heteroplasmic mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes syndrome with A3251G mutation, in which the clinical picture was dominated by a host of involuntary abnormal movements including chorea-ballism, myoclonus, and oromandibular dystonia in a backdrop of cognitive decline, seizure, and stroke-like episode. A final diagnosis was established by muscle biopsy and genetic study. Haloperidol was administered to control the involuntary movements along with introduction of co-enzyme Q, besides symptomatic management for his focal seizures. Six months into follow-up his seizures and abnormal movements were controlled significantly with slight improvement of cognitive abilities. CONCLUSION: The dominance of hyperkinetic movements in the clinical scenario and the finding of a point mutation A3251G in MT-TL1 gene make this a rare presentation.

Type II diabetes mellitus and obesity: Common links, existing therapeutics and future developments.

Type II diabetes mellitus (T2DM) and obesity are two common pathophysiological conditions of metabolic syndrome (MetS), a collection of similar metabolic dysfunctions due to sedentary lifestyle and overnutrition. Obesity arises from improper adipogenesis which otherwise has a crucial role in maintaining proper metabolic functions. Downstream events arising from obesity have been linked to T2DM. The nuclear receptor peroxisome proliferator activator gamma (PPAR-γ), responsible for maintaining lipid and glucose homeostasis, is down-regulated under obesity leading to a weakened insulin sensitivity of the human body. In course of our review we will outline details of the down-regulation mechanism, provide an overview of the current clinical therapeutics and their shortcomings. Toxicity studies on the seminal drug troglitazone, belonging to the most effective glitazone anti-diabetic category, is also discussed. This will lead to an overview about structural adaptations on the existing glitazones to alleviate their side effects and toxicity. Finally, we forward a concept of novel therapeutics mimicking the glitazone framework, based on some design concepts and preliminary in silico studies. These could be later developed into dual acting drugs towards alleviating the deleterious effects of obesity on normal glucose metabolism, and address obesity in itself.

Synthesis and electronic properties of ester substituted 1,4-dicyanodibenzodioxins and evaluation of anti-proliferative activity of all isomeric 1,2-, 2,3- and 1,4-dicyanodibenzodioxins against HeLa cell line.

1,4-Dicyanodibenzodioxins bearing carboxy methyl ester groups were synthesized using our established one-step SNAr coupling reaction between ortho- and meta-ester substituted catechols and perfluorinated terephthalonitrile. These are the first examples of 1,4-dicyanodibenzodioxins substituted at both the benzene moieties. Optical spectra were similar to the earlier examples reported, with a marginal blue shift for the ester dibenzodioxins. Theoretical analysis of the molecular orbitals reveals modest destabilization of the frontier molecular orbitals of one carboxy methyl ester isomer over the other and overall higher HOMO-LUMO gap for both isomers when compared to the earlier published 1,4-dicyanodibenzodioxins. In vitro cytotoxicity against human cervical cancer HeLa cell line was evaluated for these two compounds and all other previously published dibenzodioxins from our laboratory (1,4-dicyano, 1,2-dicyano and 2,3-dicyano variants). A number of derivatives showed anti-tumor activity in µM ranges and also exhibited no cytotoxicity against normal HEK 293 cell line. Mechanistic investigation of cell death pathways indicated high levels of reactive oxygen species (ROS) in the dibenzodioxin treated tumor cell lines along with cellular nuclear fragmentation, both of which are markers of the apoptotic cell death pathway.

Fusion and Desulfurization Reactions of Thiomorpholinochlorins.

An unusually nonplanar, ruffled structure that had been suspected for the previously reported [2,3-bismethylenethiomorpholinochlorinato]nickel(II) complex was confirmed by determination of its crystal structure. Treatment of this thiomorpholinochlorin with acid converts the exocyclic double bonds to direct links to the ortho-positions of both adjacent meso-phenyl groups. The crystal structure of this product indicated that the introduction of these linkages did not change the overall conformation of the macrocycle. The reactivity of the bis-linked thiomorpholine moiety with respect to Raney-nickel-induced (hydro)desulfurization reactions was probed, forming a bis-phenyl-linked 2,3-dimethylchlorin, also characterized by X-ray diffraction, and a bis-indene-annulated porphyrin. We also report on the synthesis of the oxygen analogue to the bis-linked thiomorpholine by reaction of a secochlorin bisketone nickel complex with Woollins' reagent. We thus introduce novel methodologies toward the synthesis of porphyrinoids carrying ß-to-ortho-phenyl fusions and expand on the scope and limits of the chemistry and interconversion of pyrrole-modified porphyrins.

Synthesis and photophysical characterization of quasi push-pull dicyanodibenzodioxins and their anti-tumor activity against glioma cell line C6.

Dibenzodioxins bearing multiple electron withdrawing groups were synthesized using a simple one-step methodology including examples of molecules possessing electron acceptor groups in both ends. As a consequence internal charge delocalization occurs and the optical spectra are found to be bathochromically shifted compared to similar examples known thus far. A theoretical analysis of the molecular orbitals reveals the origin of the peaks in the dibenzodioxin optical spectra. Select examples exhibit in vitro neuro-cytotoxicity against glioma cell line C6, a finding which enhances existing knowledge about the pharmacologically relevant structural motifs in dibenzodioxins.

Oxazolochlorins. 14. 8-Oxo-5,10,15,20-tetra­phenyl-7-oxa­porphyrin N(24)-oxide.

The structure of 8-oxo-5,10,15,20-tetraphenyl-7-oxaporphyrin N(24)-oxide, C43H28N4O3, (4B), shows that N-oxidation of the pyrrole opposite the oxazolidone group cants the pyrrole out of the mean plane of the chromophore. This also affects the oxazolidone group, which is also slightly canted out. This conformation is qualitatively similar to that of the parent meso-tetraphenylporphyrin N-oxide, but dissimilar to that of the porpholactone N-oxide isomer 8-oxo-5,10,15,20-tetraphenyl-7-oxaporphyrin N(22)-oxide, (4A), carrying the N-oxide at the oxazolidone group. While the degree of canting of the N-oxidized groups in both cases is comparable (and more pronounced than in the porphyrin N-oxide case), in (4A) the pyrrolic groups adjacent to the N-oxidized group are more affected than the opposing group. These differences in the conformational modes may contribute to rationalizing the distinctly different electronic properties of (4A) and (4B).

Helimeric porphyrinoids: stereostructure and chiral resolution of meso-tetraarylmorpholinochlorins.

The synthesis and chiral resolution of free-base and Ni(II) complexes of a number of derivatives of meso-tetraphenylmorpholinochlorins, with and without direct ß-carbon-to-o-phenyl linkages to the flanking phenyl groups, is described. The morpholinochlorins, a class of stable chlorin analogues, were synthesized in two to three steps from meso-tetraphenylporphyrin. The conformations and the relative stereostructures of a variety of free-base and Ni(II) complexes of these morpholinochlorins were elucidated by X-ray diffractometry. Steric and stereoelectronic arguments explain the relative stereoarray of the morpholino-substituents, which differ in the free-base and Ni(II) complexes, and in the monoalkoxy, ß-carbon-to-o-phenyl linked morpholinochlorins, and the dialkoxy derivatives. The Ni(II) complexes were all found to be severely ruffled whereas the free-base chromophores are more planar. As a result of the helimeric distortion of their porphyrinoid chromophores, the ruffled macrocycles possess a stable inherent element of chirality. Most significantly, resolution of the racemic mixtures was achieved, both by classical methods via diastereomers and by HPLC on a chiral phase. Full CD spectra were recorded and modeled using quantum-chemical computational methods, permitting, for the first time, an assignment of the absolute configurations of the chromophores. The report expands the range of known pyrrole-modified porphyrins. Beyond this, it introduces large chiral porphyrinoid π-systems that exist in the form of two enantiomeric, stereochemically stable helimers that can be resolved. This forms the basis for possible future applications, for example, in molecular-recognition systems or in materials with chiroptic properties.

OsO4-mediated dihydroxylation of meso-tetraphenylporphyrin N-oxide and transformation of the resulting diolchlorin N-oxide regioisomers.

The OsO(4)-mediated dihydroxylation of meso-tetraphenylporphyrin N-oxide yields two regioisomeric chlorin N-oxides. These chlorin N-oxides can be manipulated to provide pairs of regioisomers of pyrrole-modified porphyrin N-oxides. The UV-vis absorption and fluorescence emission spectra of the neutral and protonated regioisomers are distinct from each other, and generally different from the parent chromophore. The outcome of diol oxidation reactions of some N-oxide diolchlorins varies from the corresponding reactions of the parent diolchlorins. The crystal structure of a free base porpholactone N-oxide carrying the N-oxide on the oxazolone moiety is reported.

MTO/H2O2/pyrazole-mediated N-oxidation of meso-tetraarylporphyrins and -chlorins, and S-oxidation of a meso-tetraaryldithiaporphyrin and -chlorin.

The methyltrioxorhenium (MTO)/pyrazole-mediated H(2)O(2) oxidation of octaethylporphyrin and a number of meso-tetraarylporphyrins offers simple and good yielding access to the corresponding N-oxides, only few of which were prepared before. The crystal structure of a free base tetraarylporphyrin N-oxide demonstrates the degree to which the oxygenated pyrrole moiety is slanted with respect to the rest of the otherwise nearly planar macrocycle. The method is also suitable to the preparation of hitherto unknown chlorin N-oxides. Oxidation of meso-tetraphenyldithiaporphyrin and meso-tetraphenyldithiachlorin furnishes the corresponding novel S-oxides. The optical properties of the novel chromophores are described and rationalized.