Synthesis of 2-aryl substituted 2,3-dihydroquinazoline-4(1H)-ones under solvent free conditions using ionic liquid as a mild and efficient catalyst

A simple, green and environmentally benign procedure has been developed for the synthesis of 2,3-dihydroquinazoline-4(1H)-ones in basic ionic liquid via the cyclocondensation of 2-amino benzamide with an aldehyde. This offers several advantages such as high yields, simple procedure, low cost, short reaction times, mild and solvent free condition

Synthesis and biological evaluation of theophylline acetohydrazide hydrazone derivatives as antituberculosis agents

A series of small molecules, theophylline acetohydrazide hydrazone derivatives were obtained via condensation of theophylline-7-acetohydrazide with different aromatic/heterocyclic aldehydes. The compounds were synthesized and characterized by using conventional methods. Further, the compounds and standard drugs were evaluated against Mycobacterium tuberculosis H37Rv strain, the activity obtained was varying depending on the functional group attached to theophylline acetohydrazide hydrazone compounds. Among these, Br-substituted compounds showed more potent against M. tuberculosis with MIC 3.6-4 mu M and better than the reference drugs used. The molecular docking studies have shown the possible binding modes of the compounds with protein (PDB ID: 4RHX); the compound 4h has shown highest glide score and binding energy. For all compounds, ADME properties were predicted

Synthesis and Biological Evaluation of Theophylline Methyl 1,3,4-Oxadiazole as Anticancer Agents

A series of theophylline methyl 1,3,4-oxadiazole small molecules were obtained via cyclization of theophylline-7-acetohydrazide with different benzoic acids. The compounds (IVa-j) were synthesized and characterized by using conventional methods. The new compounds obtained were evaluated for their cytotoxic effect in three different cancer lines, the activity obtained varies depending upon the structure of a molecule. The compound (IVb) and (IVf) showed promising effect than other compounds of the series. Thus, these two derivatives have the potential for developing as anticancer agents

Intramolecular [3 + 2]-Cycloadditions of Azomethine Ylides Derived from Secondary Amines via Redox-Neutral C–H Functionalization

Azomethine ylides are accessed under mild conditions via benzoic acid catalyzed condensations of 1,2,3,4-tetra­hydro­iso­quinolines or trypto­lines with aldehydes bearing a pendent dipolarophile. These intermediates undergo intramolecular [3 + 2]-cycloadditions in a highly diastereoselective fashion to form polycyclic amines with four new stereogenic centers. Challenging substrates such as piperidine, morpholine, and thiomorpholine undergo the corresponding reactions at elevated temperatures

Identification and characterization of novel SCR7-based small-molecule inhibitor of DNA end-joining, SCR130 and its relevance in cancer therapeutics

Targeting DNA repair with small-molecule inhibitors is an attractive strategy for cancer therapy. Majority of DNA double-strand breaks in mammalian cells are repaired through nonhomologous end-joining (NHEJ). It has been shown that small-molecule inhibitors of NHEJ can block efficient repair inside cancer cells, leading to cell death. Previously, we have reported that SCR7, an inhibitor of NHEJ can induce tumor regression in mice. Later studies have shown that different forms of SCR7 can inhibit DNA end-joining in Ligase IV-dependent manner. Recently, we have derivatized SCR7 by introducing spiro ring into core structure. Here, we report the identification of a novel inhibitor of NHEJ, named SCR130 with 20-fold higher efficacy in inducing cytotoxicity in cancer cell lines. SCR130 inhibited DNA end-joining catalyzed by rat tissue extract. Specificity analysis revealed that while SCR130 was specific to Ligase IV, it showed minimal or no effect on Ligase III and Ligase I mediated joining. Importantly, SCR130 exhibited the least cytotoxicity in Ligase IV-null cell line as compared with wild type, confirming Ligase IV-specificity. Furthermore, we demonstrate that SCR130 can potentiate the effect of radiation in cancer cells when used in combination with gamma-radiation. Various cellular assays in conjunction with Western blot analysis revealed that treatment with SCR130 led to loss of mitochondrial membrane potential leading to cell death by activating both intrinsic and extrinsic pathways of apoptosis. Thus, we describe a novel inhibitor of NHEJ with higher efficacy and may have the potential to be developed as cancer therapeutic

N-Heterocyclic Carbene Mediated Organocatalysis Reactions

Arduengo et al., isolated the first ‘bottleable’ carbene, the first N-heterocyclic carbene (NHC) 1,3-di(adamantyl)imidazol-2-ylidene resulted to an explosion of experimental and theoretical studies of novel NHCs being synthesized and analyzed have huge practical significance. These compounds emerged as successful ligands for coordinating transition metals, the complexes with NHC show diverse applications in the field of catalysis and organic transformation, NHC as ligand to main group elements and their properties and applications. Here this chapter provides the concise overview of N-heterocycle carbene as an organocatalyst that provides different organic transformation on to a carbonyl group. The majority of the NHC catalyzed reactions are employed in the phenomenon of reversing the electrophilic character of carbonyl carbon to nucleophilic carbon (umpolung activity) on coordination suggests benzoin, Stetter and hydroacylation reactions. Also, non-umpolung activity of bis-electrophile α,β-unsaturated acylazoliums reaction with suitable bis-nucleophiles in the organic synthesis have been studied

Combinatorial Study of a Novel Poly (ADP-ribose) Polymerase Inhibitor and an HDAC Inhibitor, SAHA, in Leukemic Cell Lines

Cancer is a multifactorial disease, which makes it difficult to cure. Since more than one defective cellular component is often involved during oncogenesis, combination therapy is gaining prominence in the field of cancer therapeutics. The purpose of this study was to investigate the combinatorial effects of a novel PARP inhibitor, P10, and HDAC inhibitor, SAHA, in leukemic cells. Combinatorial effects of P10 and SAHA were tested using propidium iodide staining in different leukemic cells. Further, flowcytometry-based assays such as calcein-AM/ethidium homodimer staining, annexin-FITC/PI staining, and JC-1 staining were carried out to elucidate the mechanism of cell death. In addition, cell-cycle analysis, immunocytochemistry studies, and western blotting analysis were conducted to check the combinatorial effect in Nalm6 cells. Propidium iodide staining showed that P10 in combination with SAHA induced cell death in Nalm6 cells, in which PARP expression and activity is high with a combination index of < 0.2. Annexin-FITC/PI staining, JC-1 staining, and other biochemical assays revealed that P10 in combination with SAHA induced apoptosis by causing a change in mitochondrial membrane potential in > 65 % cells. Importantly, combinatorial treatment induced S phase arrest in 40-45 % cells due to DNA damage and plausible replicative stress. Finally, we demonstrated that treatment with P10 led to DNA strand breaks, which were further potentiated by SAHA (p < 0.01), leading to activation of apoptosis and increased cell death in PARP-positive leukemic cells. Our study reveals that coadministration of PARP inhibitor with SAHA could be used as a combination therapy against leukemic cells that possess high levels of intrinsic PARP activity

Discovery of Novel Approach for Regioselective Synthesis of Thioxotriaza-Spiro Derivatives via Oxalic Acid

A vital approach for the synthesis of a range of novel thioxotriaza-spiro derivatives is described. These new heterocyclic systems are obtained via oxalic acid catalyzed reaction of alpha,beta-unsaturated ketones in the presence of 5,6-diamino-2-mercaptopyrimidine-4-ols; thus, spiro rings are constructed in one step. Notably, this transformation involves condensation of an amino group followed by enamine reaction with alkenes and subsequent reaction promoted by oxalic acid to afford spiro compounds with excellent regioselectivity

Raman and surface enhanced Raman spectroscopic studies of specific, small molecule activator of histone acetyltransferase p300

We report for the first time, the Raman and Surface Enhanced Raman Scattering (SERS) studies of N-(4-chloro-3-trifluoromethyl-phenyl)-2-ethoxy-benzamide (CTB). This molecule is specific activator of Human Histone Acetyltransferase (HAT), p300 and serves as lead molecule to design anti-neoplastic therapeutics. A detailed Raman and SERS band assignments have been performed for CTB, which are compared with the density functional theory calculations. The observed red shift of N H stretching frequency from the computed wavenumber indicates the weakening of N H bond resulting from proton transfer to the neighboring oxygen atom. We observe Ag N vibrational mode at 234 cm⁻¹ in SERS of CTB. This indicates there is a metal–molecule bond leading to chemical enhancement in SERS. We also observe, enhancement in the modes pertaining to substituted benzene rings and methyl groups. Based on SERS analysis we propose the adsorption sites and the orientation of CTB on silver surface