Synthesis and Anticancer Evaluation of Disubstituted Benzimidazoles via One-Pot Telescopic Grinding Approach.

Benzimidazole compounds are known for their broad spectrum therapeutic potentials. A small library of benzimidazole derivatives were designed and synthesized via a one-pot telescopic grinding approach. The ability of these molecules as proposed anticancer agents were evaluated by their potential to bind to two important cancer pathway protein targets, human estrogen receptors and cyclin dependant kinases, 3ERT and 5FGK respectively.

Synthetic access to diverse thiazetidines a one-pot microwave assisted telescopic approach and their interaction with biomolecules.

A one-pot microwave assisted telescopic approach is reported for the chemo-selective synthesis of substituted 1,3-thiazetidines using readily available 2-aminopyridines/pyrazines/pyrimidine, substituted isothiocyanates and 1,2-dihalomethanes. The procedure involves thiourea formation from 2-aminopyridines/pyrazines/pyrimidine with the substituted isothiocyanates followed by a base catalysed nucleophilic attack of the CS bond on the 1,2-dihalomethane. Subsequently, a cyclization reaction occurs to yield substituted 1,3-thiazetidines.

An in silico approach to investigate the theranostic potential of coumarin-derived self-immolative luminescent probes.

Till date the challenge exists in the treatments of cancer for various reasons. Most importantly, the available diagnostics are expensive with research gap for enhancing the cancer detection sensitivity. Herein, a series of coumarin-derived fluorescent theranostic probes are reported that can serve as potent anticancer agents as well as in the detection of cancer cells.

Recent Advancements of Aptamers in Cancer Therapy.

Aptamers are chemical antibodies possessing the capability of overcoming the limitations posed by conventional antibodies, particularly for diagnostic, therapeutic, and theranostic applications in cancer. The ease of chemical modifications or functionalization, including conjugations with nucleic acids, drug molecules, and nanoparticles, has made these aptamers to gain priorities in research. In this Mini-review, various reports on therapeutics with aptamer-functionalized nanomaterials for controlled or multistep drug release, targeted delivery, stimuli-responsive drug release, are discussed.

Click-derived multifunctional metal complexes for diverse applications.

The Click reaction that involves Cu(I)-catalyzed azide-alkyne cycloaddition (CuAAC) serves as the most potent and highly dependable tool for the development of many complex architectures. It has paved the way for the synthesis of numerous drug molecules with enhanced synthetic flexibility, reliability, specificity and modularity. It is all about bringing two different molecular entities together to achieve the required molecular properties.

Photophysical evaluation on the electronic properties of synthesized biologically significant pyrido fused imidazo[4,5-c]quinolines.

A single pot microwave assisted method was employed to synthesize a series of novel pyrido fused imidazo[4,5-c]quinolines. The electronic properties of these derivatives were investigated by following their photophysical behaviour under isolated and solvated conditions via computational and experimental approaches. The solvatochromic effect of these derivatives was investigated in the ground and excited singlet states by following the absorption and fluorescence emission and excitation spectra.

2,3-Difunctionalized Benzo[]thiophene Scaffolds Possessing Potent Antiangiogenic Properties.

A new class of 2-anilino-3-cyanobenzo[]thiophenes (2,3-ACBTs) was studied for its antiangiogenic activity for the first time. One of the 2,3-ACBTs inhibited tubulogenesis in a dose-dependent manner without any toxicity. The 2,3-ACBTs significantly reduced neovascularization in both and angiogenic assays without affecting the proliferation of endothelial cells.

Antitumor Effects of Ir(III)-2-Indazole Complexes for Triple Negative Breast Cancer.

In this work, we have synthesized a series of novel C,N-cyclometalated 2-indazole-ruthenium(II) and -iridium(III) complexes with varying substituents (H, CH, isopropyl, and CF) in the R position of the phenyl ring of the 2-indazole chelating ligand. All of the complexes were characterized by H, C, high-resolution mass spectrometry, and elemental analysis. The methyl-substituted 2-indazole-Ir(III) complex was further characterized by single-crystal X-ray analysis.

Hepatoprotective and Antioxidant Capacity of Flower Extracts against Carbon Tetrachloride-Induced Hepatotoxicity in Rats.

The aim of the presented work involves the isolation, characterization, and evaluation of hepatoprotective potential of flower extracts. For this purpose, petroleum ether, chloroform, ethyl acetate, alcohol, and water extracts of flower were screened for the flavonoid and phenolic content and quantified. Various antioxidant activity assays including 2,2'-diphenyl-1-picrylhydrazyl (DPPH), nitric oxide (NO) radical scavenging, 2,2-azinobis (3-ethylbenzothiazoline-6-sulfonic acid) (ABTS), and reducing ability were carried out.

Overview of Pathogenesis, Diagnostics, and Therapeutics of Infectious Diseases: Dengue and Zika.

The emergence of more virulent SARS virus has made scientists look back at other so-called neglected diseases such as dengue, Zika, and chikungunya, etc. Until recently these neglected diseases have not received much attention for their control or elimination from society. Over the past decade several attempts to investigate the pathogenicity, diagnostic, and therapeutic strategies for flavivirus caused diseases have been made.

An Overview on the Therapeutics of Neglected Infectious Diseases-Leishmaniasis and Chagas Diseases.

Neglected tropical diseases (NTDs) as termed by WHO include twenty different infectious diseases that are caused by bacteria, viruses, and parasites. Among these NTDs, Chagas disease and leishmaniasis are reported to cause high mortality in humans and are further associated with the limitations of existing drugs like severe toxicity and drug resistance. The above hitches have rendered researchers to focus on developing alternatives and novel therapeutics for the treatment of these diseases.

Diversity-Oriented Synthesis of Thiazolidine-2-imines via Microwave-Assisted One-Pot, Telescopic Approach and Its Interaction with Biomacromolecules.

In this work, a one-pot, telescopic approach is described for the combinatorial library of thiazolidine-2-imines. The synthetic manipulation proceeds smoothly via the reaction of 2-aminopyridine/pyrazine/pyrimidine with substituted isothiocyanates followed by base catalyzed ring closure with 1,2-dibromoethane to obtain thiazolidine-2-imines with broad substrate scope and high functional group tolerance. The synthetic strategy merges well with the thiourea formation followed by base catalyzed ring closure reaction for the thiazolidine-2-imine synthesis in a more modular and straightforward approach.

Synthesis and Antitumor Activity Evaluation of Cyclometalated 2H-Indazole Ruthenium(II) and Iridium(III) Complexes.

In this work, a series of novel C-N cyclometalated 2H-indazole Ru(II) and Ir(III) complexes were synthesized, wherein chelating ligands with substituents like H, and isopropyl group in the R position of the phenyl ring of the 2H-indazole chelating ligand are present. The cytotoxicity of Ru(II) and Ir(III) complexes has been evaluated against different human cancer cell lines (HeLa, MCF-7, and A549) in a concentration-dependent manner. The new iridium complex with isopropyl substituent in the phenyl ring of the 2H-indazole moiety showed good cytotoxic activity against MCF-7 cells with an IC value 3.

Evolutionary approaches in protein engineering towards biomaterial construction.

The tailoring of proteins for specific applications by evolutionary methods is a highly active area of research. Rational design and directed evolution are the two main strategies to reengineer proteins or create chimeric structures. Rational engineering is often limited by insufficient knowledge about proteins' structure-function relationships; directed evolution overcomes this restriction but poses challenges in the screening of candidates.

One-Pot, Telescopic Approach for the Chemoselective Synthesis of Substituted Benzo[]pyrido/pyrazino/pyridazino[1,2-][1,2,4]thiadiazine dioxides and Their Significance in Biological Systems †.

The one-pot telescopic approach has been developed for the chemoselective synthesis of substituted benzo[]pyrido/pyrazino/pyridazino[1,2-][1,2,4]thiadiazine dioxides using readily available 2-aminopyridines/pyrazines/pyridazine and 2-chloro benzene sulfonyl chloride. This one-pot procedure involves the chemoselective sulfonylation of 2-aminopyridines/pyrazines/pyridazine with 2-chloro benzene sulfonyl chloride followed by a Cu(I)-catalyzed Ullmann-type C-N coupling reaction to obtain benzo[]pyrido/pyrazino/pyridazino[1,2-][1,2,4]thiadiazine dioxides with broad substrate scope and high functional group tolerance. The synthetic sequence merges well with the nucleophilic attack on the 2-amino group of pyridines/pyrazines/pyridazines on the 2-chloro benzene sulfonyl chloride, followed by Cu(I)-catalyzed ipso chloro displacement to C-N bond formation resulting in a more modular and straightforward approach.

Design, synthesis and identification of novel coumaperine derivatives for inhibition of human 5-LOX: Antioxidant, pseudoperoxidase and docking studies.

5-Lipoxygenase (5-LOX) is a key enzyme involved in the biosynthesis of pro-inflammatory leukotrienes, leading to asthma. Developing potent 5-LOX inhibitors especially, natural product based ones, are highly attractive. Coumaperine, a natural product found in white pepper and its derivatives were herein developed as 5-LOX inhibitors.

Revisiting the insights and applications of protein engineered hydrogels.

Utilization of protein-protein interactions or protein-peptide interactions has led to new crosslinking chemistries, resulting into protein hydrogels. Enzyme catalyzed crosslinking of specific amino acids has also been used to generate crosslinked protein hydrogels. Weak, temporary, reversible or non-covalently crosslinked protein gels as well as strong, permanent, irreversible or covalently crosslinked protein gels with mechanical strengths of varying degrees are generated by means of various crosslinking strategies.

Evaluation of WO2014121383 A1: a process for preparation of rufinamide and intermediates.

There is great potential in the synthetic development of rufinamide to treat childhood-onset epilepsy known as Lennox-Gastaut syndrome (LGS). Areas covered: 1,4-disubstituted triazole ring formed by 1,3-dipolar cycloaddition reaction is an important structural motif widely used to construct diverse chemotypes in chemical, biological, and material fields. 1,2,3-triazole ring containing rufinamide, an antiepileptic drug developed by Novartis, is useful in combination with other antiepileptic medicaments for the treatment of childhood-onset epilepsy known as LGS.

Evaluation of DNA/Protein interactions and cytotoxic studies of copper(II) complexes incorporated with N, N donor ligands and terpyridine ligand.

A series of four new copper(II) heteroleptic complexes, [Cu(2‴-pytpy) (L)] (NO)·2HO (1-4), where 2‴-pytpy=4'-(2'''-Pyridyl)-2, 2':6', 2''-terpyridine, L=bipyridyl (bpy), 1, 10 phenanthroline(phen), dipyridoquinoxaline(dpq) and dipyridophenazine (dppz) were synthesized and characterized by spectroscopic techniques. Further, the molecular structure of the complex (2) was confirmed by single crystal X-ray diffraction technique and the data revealed a penta coordinated, distorted square-pyramidal geometry with triclinic system. The interactions of four complexes with calf thymus DNA and bovine serum albumin (BSA) were investigated by electronic absorption, fluorescence and circular dichroism spectroscopy techniques.

Bacterial lipid modification of proteins requires appropriate secretory signals even for expression - implications for biogenesis and protein engineering.

Sec- and Tat-mediated bacterial lipid modification of proteins are important posttranslational processes owing to their vital roles in cellular functions, membrane targeting and biotechnological applications like ELISA, biosensor, adjuvant-free vaccines, liposomal drug delivery etc. However a better understanding of the tight coupling of secretory and lipid modification machineries and the processes associated will help unravel this essential biological event and utilize it for engineering applications. Further, there is a need for a systematic and convincing investigation into membrane targeting, solubilization and ease-of-purification of engineered lipoproteins to facilitate scientists in readily applying this new protein engineering tool.

Design and characterization of stabilized derivatives of human CD4D12 and CD4D1.

CD4 is present on the surface of T-lymphocytes and is the primary cellular receptor for HIV-1. CD4 consists of a cytoplasmic tail, one transmembrane region, and four extracellular domains, D1-D4. A construct consisting of the first two domains of CD4 (CD4D12) is folded and binds gp120 with similar affinity as soluble 4-domain CD4 (sCD4).

Ligand-modulated parallel mechanical unfolding pathways of maltose-binding proteins.

Protein folding and unfolding are complex phenomena, and it is accepted that multidomain proteins generally follow multiple pathways. Maltose-binding protein (MBP) is a large (a two-domain, 370-amino acid residue) bacterial periplasmic protein involved in maltose uptake. Despite the large size, it has been shown to exhibit an apparent two-state equilibrium unfolding in bulk experiments.

Mitochondrial NADH kinase, Pos5p, is required for efficient iron-sulfur cluster biogenesis in Saccharomyces cerevisiae.

In Saccharomyces cerevisiae, the mitochondrial inner membrane readily allows transport of cytosolic NAD(+), but not NADPH, to the matrix. Pos5p is the only known NADH kinase in the mitochondrial matrix. The enzyme phosphorylates NADH to NADPH and is the major source of NADPH in the matrix.

Designed biomaterials to mimic the mechanical properties of muscles.

The passive elasticity of muscle is largely governed by the I-band part of the giant muscle protein titin, a complex molecular spring composed of a series of individually folded immunoglobulin-like domains as well as largely unstructured unique sequences. These mechanical elements have distinct mechanical properties, and when combined, they provide the desired passive elastic properties of muscle, which are a unique combination of strength, extensibility and resilience. Single-molecule atomic force microscopy (AFM) studies demonstrated that the macroscopic behaviour of titin in intact myofibrils can be reconstituted by combining the mechanical properties of these mechanical elements measured at the single-molecule level.

Recombination of protein fragments: a promising approach toward engineering proteins with novel nanomechanical properties.

Combining single molecule atomic force microscopy (AFM) and protein engineering techniques, here we demonstrate that we can use recombination-based techniques to engineer novel elastomeric proteins by recombining protein fragments from structurally homologous parent proteins. Using I27 and I32 domains from the muscle protein titin as parent template proteins, we systematically shuffled the secondary structural elements of the two parent proteins and engineered 13 hybrid daughter proteins. Although I27 and I32 are highly homologous, and homology modeling predicted that the hybrid daughter proteins fold into structures that are similar to that of parent protein, we found that only eight of the 13 daughter proteins showed beta-sheet dominated structures that are similar to parent proteins, and the other five recombined proteins showed signatures of the formation of significant alpha-helical or random coil-like structure.