[Show abstract][Hide abstract] ABSTRACT: An efficient one-pot three-component stepwise approach for the synthesis of N-2-substituted-1,2,3-triazoles from chalcones, sodium azide and esters has been developed using a recoverable and reusable ZrO 2 nanoparticle-supported Cu(II)–b-cyclodextrin complex as a catalyst. N-2 alkylation of triazoles using different aryl–alkyl esters without any additives has been achieved for the first time. The one-pot operation, atom-economical nature, regioselectivity and good yields are the noteworthy features of this protocol. The reusability of the prepared nanocatalyst was successfully examined four times without any appreciable loss in catalytic activity.
[Show abstract][Hide abstract] ABSTRACT: An efficient one-pot three-component stepwise approach for the synthesis of N-2-substituted-1, 2, 3-triazoles from chalcones, sodium azide and esters has been developed using recoverable and reusable ZrO2 nanoparticle-supported Cu (II)-β-cyclodextrin complex as a catalyst. N-2 alkylation of triazoles using different aryl-alkyl esters without any additives has been achieved for the first time. One-pot operation, atom-economical, regioselectivity and good yields are the noteworthy features of this protocol. The reusability of the prepared nanocatalyst was successfully examined four times without any appreciable loss in catalytic activity.
[Show abstract][Hide abstract] ABSTRACT: Signal Transducer and Activator of Transcription 3 (STAT3) is a transcription factor that regulates genes involved in cell growth, proliferation and survival, and given its association with many types of cancers it recently emerged as a promising target for therapy. In this work, we present the synthesis of N-substituted azaspirane derivatives and their biological evaluation against HCC cells (IC50 = 7.3 μM), thereby identifying CIMO as a potent inhibitor of the JAK-STAT pathway with selectivity over normal LO2 cells (IC50 = >100 μM). The lead compound, CIMO, suppresses proliferation of HCC cells, and achieves this effect by reducing both constitutive and inducible phosphorylation of JAK1, JAK2 and STAT3. Interestingly, CIMO displayed inhibition of Y705 phosphorylation which is required for nuclear translocation of STAT3, but it has no effect on S727 phosphorylation. CIMO accumulates cancer cells in the sub-G1 phase and decreases STAT3 in the nucleus, and thereby causes downregulation of genes regulated via STAT3. Suppression of STAT3 phosphorylation by CIMO and knock down of STAT3 mRNA using siRNA transfection displayed a similar effect on viability of HCC cells. Furthermore, CIMO significantly decreased the tumor development in an orthotopic HCC mouse model through the modulation of phospho-STAT3, Ki-67 and cleaved caspase-3 in tumor tissues. Thus, CIMO represents a chemically novel and biologically in vitro and in vivo validated compound, which targets the JAK-STAT pathway as a potential cancer treatment.
Journal of Biological Chemistry 10/2014; · 4.65 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Cholinesterase plays a vital role in the decline of cholinergic transmission and thus can contribute to the development of Alzheimer’s disease (AD). Thus, compounds that can inhibit acetylcholinesterase (AChe) and butyrylcholinesterase (BuChe) are the potential drugs for the treatment of AD. A series of novel pyrrolopyrimidine derivatives was synthesized and evaluated for their inhibitory activity against cholinesterase by Ellman method. Among the ten newly synthesized compounds, 4-(4-((4-(difluoromethoxy)phenyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)benzoate was the most potent molecule identified with the IC50 values of 18 µM and 17 µM on AChe and BuChe respectively.
Letters in Drug Design & Discovery 10/2014; 11(10):1143-1148. · 0.85 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Bismuth oxide was synthesized via simple, rapid and energy efficient solution combustion synthesis (SCS) by employing sucrose as a fuel. This SCS- Bi2O3 was characterized by analytical techniques such as PXRD, SEM, EDX, UV- Visible and BET surface area measurement. Using the prepared SCS-Bi2O3, several classes of heterocyclic compounds were synthesized in good yields via Suzuki-coupling reaction in aqueous medium. Interestingly, the recovered SCS-Bi2O3 could be reused three times without a significant loss of catalytic activity. Further, the synthesized compounds were tested for cytotoxic activity against a human hepatoma cancer cell line (HepG2). Among these, the compound 3n effectively inhibited the proliferation of these cells with an IC50 value of 8.4 μM. Thus, this paper describes the preparation of highly effective Bi2O3, which can be used for synthesizing various classes of heteocycles, including those having anti-cancer property.
[Show abstract][Hide abstract] ABSTRACT: Various tumor cells exhibit structural alterations in the sulfated modifications to glycosaminoglycans (GAGs). The altered expression of chondroitin sulfate (CS) and heparan sulfate (HS) on the surfaces of tumor cells is known to play a key role in malignant transformation and tumor metastasis. The receptor molecule for the CS chains containing E-disaccharide units (CS-E) expressed on Lewis lung carcinoma (LLC) cells was recently revealed to be Receptor for Advanced Glycation End-products (RAGE). RAGE is also involved in the development of various pathological conditions including aging, infection, pulmonary fibrosis, diabetes, and Alzheimer's disease, by binding to a wide range of ligands. RAGE binds strongly not only to CS-E, but also to HS-expressing LLC cells. Recombinant RAGE bound CS-E and HS with high affinity. Furthermore, in a mouse model, the colonization of the lungs by LLC cells was inhibited by intravenously injected CS-E, an anti-CS-E antibody, or an anti-RAGE antibody. These findings demonstrated that RAGE is at least one of the critical receptors for CS and HS chains expressed on the tumor cell surface and is involved in experimental lung metastasis, and also that CS/HS and RAGE are potential molecular targets for the treatment of pulmonary metastasis. We, hence, reviewed these findings and also several chemically synthesized small GAGmimetics that exhibit potent anti-metastatic and/or anti-tumor activities.
[Show abstract][Hide abstract] ABSTRACT: TNF is a pleotropic cytokine known to be involved in the progression of several pro-inflammatory disorders. Many therapeutic agents have been designed to counteract the effect of TNF in rheumatoid arthritis as well as a number of cancers. In the present study we have synthesized and evaluated the anti-cancer activity of novel biscoumarins in vitro and in vivo. Among new compounds, BIHC was found to be the most cytotoxic agent against the HepG2 cell line while exhibiting less toxicity towards normal hepatocytes. Furthermore, BIHC inhibited the proliferation of various HCC cells in a dose- and time-dependent manner. Subsequently, using in silico target prediction, BIHC was predicted as a TNF blocker. Experimental validation was able to confirm this hypothesis, where BIHC could significantly inhibit the recombinant mouse TNF-α binding to its antibody with an IC50 of 16.5 micromolar. Furthermore, in silico docking suggested a binding mode of BIHC similar to a ligand known to disrupt the native, trimeric structure of TNF, and also validated with molecular dynamics simulations. Moreover, we have demonstrated the downregulation of p65 phosphorylation and other NF-κB regulated gene products upon BIHC treatment, and on the phenotypic level the compound shows inhibition of CXCL-12 induced invasion of HepG2 cells. Also, we demonstrate that BIHC inhibits infiltration of macrophages to the peritoneal cavity, and suppresses the activity of TNF-α in vivo in mice primed with thioglycollate broth and lipopolysaccharide. We comprehensively validated the TNF-α inhibitory efficacy of BIHC in inflammatory bowel disease model.
[Show abstract][Hide abstract] ABSTRACT: Hepatocellular carcinoma, a fatal liver cancer, affects 600,000 people annually and ranks third in cancer-related lethality. In this work we report the synthesis and related biological activity of novel dihydropyrimidones. Among the tested compounds, 5-acetyl-4-(1H-indol-3-yl)-6-methyl-3,4-dihydropyrimidin-2(1H)-one (4g) was found to be most active towards the HepG2 cell line (IC50=17.9 μM), being at the same time 7.6-fold selective over normal (LO2) liver cells (IC50=136.9 μM). Subsequently, we identified peroxisome proliferator-activated receptor γ as target of compound 4g using an in silico approach, and confirmed this mode-of-action experimentally.
[Show abstract][Hide abstract] ABSTRACT: A new strategy was developed to synthesize 1,2-disubstituted 4-quinolones in good yield starting from 1,3-bisaryl-monothio-1,3-diketone substrates. The synthesized compounds were evaluated for antimalarial activity using Plasmodium falciparum strains. All compounds, except two, showed good activity. Of these, seven compounds exhibited excellent antimalarial activity (IC50, <2 µM). More importantly, all seven compounds were equally effective in inhibiting the growth of both chloroquine-sensitive and chloroquine-resistant strains. The cytotoxicity assessment using a carcinoma and a non-carcinoma human cell lines revealed that almost all synthesized compounds were minimally cytotoxic (IC50, >50 µM).
[Show abstract][Hide abstract] ABSTRACT: One step synthesis of 2,3-dihydroquinazolin-4(1H)-ones from gem-dibromomethylarenes using 2-aminobenzamide is described. Gem-dibromomethylarenes are used as aldehyde equivalent for the efficient synthesis of 2,3-dihydroquinazolin-4(1H)-ones, this synthesis takes shorter reaction time with quick isolation and excellent product yield.
[Show abstract][Hide abstract] ABSTRACT: Secretory Phospholipases A2 (sPLA2's) are present in snake venoms, serum, biological fluids of patients with various inflammatory, autoimmune and allergic disorders. Lipid mediators, in the inflammatory processes have potential value of controlling phospholipids metabolism through sPLA2 inhibition. Thus it demands the need for screening of potential leads for sPLA2 inhibition. Till date, sPLA2 activity has been assayed using expensive radioactive or chromogenic substrates, thereby, limiting a large number of assays. In this study a simple-sensitive Nanodrop assay was developed using non-fluorogenic and non-chromogenic phospholipid substrate 1, 2-Dimyristoyl-sn-glycero-3-phosphocholine (DMPC) and ANS as interfacial hydrophobic probe is advantageous. The modified assay required 10ng concentration of sPLA2. ANS being a strong anion binds predominantly to cationic groups of choline head of DMPC through ion pair formation, imparting hydrophobicity and lipophilicity resulting in increase in fluorescence. Triton X-100 imparts correct geometrical space during sPLA2 catalyzing DMPC, releasing lysophospholipid and acidic myristoyl acid which in turn alters the hydrophobic environment, prevailed around ANS-DMPC, which leads to weakening the electrostatic ion pair interaction between DMPC and ANS, ensuing decrease in fluorescence. These characteristic, fluorescence changes between DMPC-ANS in response to sPLA2 catalysis is well documented and validated in this study.
[Show abstract][Hide abstract] ABSTRACT: Thirteen 2-oxazine-based small molecules were synthesized targeting 5-lipoxygenase (LOX), and acetylcholinesterase (AChE). The test revealed that the newly synthesized compounds had potent inhibition towards both 5-LOX and AChE in lower micro molar concentration. Among the tested compounds, the most active compound, 2-[(2-acetyl-6,6-dimethyl-4-phenyl-5,6-dihydro-2H-1,2-oxazin-3-yl)methyl]-1H-isoindole-1,3(2H)-dione (2a) showed inhibitory activity towards 5-LOX and AChE with an IC50 values of 1.88, and 2.5μM, respectively. Further, the in silico molecular docking studies revealed that the compound 2a bound to the catalytic domain of AChE strongly with a highest CDOCKER score of -1.18kcal/mol when compared to other compounds of the same series. Additionally, 2a showed a good lipophilicity (logP=2.66), suggesting a potential ability to penetrate the blood-brain-barrier. These initial pharmacological data revealed that the compound 2a could serve as a drug-seed in developing anti-Alzheimer's agents.
[Show abstract][Hide abstract] ABSTRACT: The present work reveals the synthesis and antiproliferative effect of a series of 2, 3 disubstituted 4-thiazolidinone analogues on human leukemic cells. The chemical structures of newly synthesized compounds were confirmed by IR, (1)H NMR, (13)C NMR and mass spectral analysis. Compound methyl 3-methoxy-4-(4-oxo-3-(5-(piperazin-1-yl)pyridin-2-yl)thiazolidin-2-yl)benzoate (5) displayed potent activity (IC509.71, 15.24 and 19.29 μM) against Nalm6, K562, Jurkat cells. Cell cycle analysis and mitochondrial membrane potential further confirmed that compound 5 is cytotoxic and able to induce cell death.
European Journal of Medicinal Chemistry 05/2014; 81C:341-349. · 3.43 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Four nickel complexes with β-(oximinoalkyl)amine ligands OxnHn containing one (Ox1H1), two (Ox2H2), four (Ox4H4) and six (Ox6H6) oxime groups were synthesized and characterized by elemental analysis, FTIR, HRMS and single crystal X-ray diffraction. β-Oximinoalkylamines OxnHn act as polydentate ligands forming five-membered chelate rings, in which nickel is coordinated with both amine and oxime nitrogen atoms. In all structurally characterized complexes, OH-groups of oximes arms are involved in hydrogen bonding with counterions (Cl−), which are located in the inner or outer coordination sphere of the nickel atom. Two new structural types of pseudo-octahedral Ni(II) β-oximinoalkylamine complexes containing two ligands per one nickel ion (Ni(Ox1H1)2Cl2 and Ni(Ox2H2)2Cl2) were identified. Dioxygen reactivity of the obtained complexes in aerobic oxidation of triphenylphosphine was studied. Bis-oxime complex Ni(Ox2H2)2Cl2 was found to be the most active promoter of triphenylphosphine oxidation among the synthesized nickel complexes.
[Show abstract][Hide abstract] ABSTRACT: Although arthritis is primarily a joint disorder that mainly targets the articular cartilage and subchondral bone, several recent investigations have reported oxidative burst and vital organ damage that are being considered as secondary complications of arthritis. The continuous generation of free radicals like reactive oxygen and nitrogen species is considered as a key culprit in the initiation and propagation of oxidative damage. In addition, activation of T and B cells, macrophages, inflammatory mediators such as TNF-α, IL-1β and IL-6 aggravates the oxidative damage of the vital organs, particularly the liver. The current piece of work demonstrates oxidative stress in the liver of arthritic rats and its amelioration by the procyanidin-rich tamarind seed extract (TSE). The arthritic liver homogenate, mitochondrial and cytosolic fractions were found with increased levels of oxidative stress markers including free radicals. As a consequence, depletion in the levels of glutathione, total thiols, glutathione peroxidase and reductase was evident. Furthermore, the activities of endogenous antioxidant enzymes like superoxide dismutase, catalase and glutathione-S-transferase were found to be significantly altered. The increased and decreased activity of transaminases respectively in serum and liver, along with histological observations, further confirms the liver damage. Unfortunately, the commonly used drugs like NSAIDs and DMARDs have failed to prevent oxidative damage, rather they were found to be the inducers themselves. Interestingly, TSE supplementation was found to significantly inhibit oxidative burst in the liver and maintain homeostasis. Thus, the study clearly demonstrates the protective efficacy of TSE against arthritis-associated oxidative liver damage, including mitochondrial oxidative burst and its associated secondary complications.
[Show abstract][Hide abstract] ABSTRACT: Efficient routes for the regioselective synthesis of 3,5-bis(het)arylisoxazoles with complementary regioselectivity have been developed. The methods involve the cyclocondensation of hydroxylamine hydrochloride with either 1,3-bis(het)aryl-monothio-substituted 1,3-diketones 1 or with 3-methylthio-1,3-bis(het)aryl-2-propenones 2 under various reaction conditions. In the first protocol, diketones 1 were treated with hydroxylamine hydrochloride in the presence of sodium acetate/acetic acid (pH 2.2) in refluxing ethanol/benzene to give 3,5-bis(het)arylisoxazoles 5, in which the het(aryl) moiety attached to thiocarbonyl group of the monothio-substituted 1,3-diketones is installed at the 3-position. On the other hand, the reaction of hydroxylamine hydrochloride with 3-(methylthio)-1,3-bis(het)aryl-2-propenones 2 in the presence of barium hydroxide in refluxing ethanol gave 3,5-bis(het)arylisoxazoles 6 with complementary regioselectivity in high yields. A probable mechanism for the formation of regioisomeric isoxazoles 5 and 6 from precursors 1 and 2 has been suggested.
Annalen der Chemie und Pharmacie 01/2014; · 3.10 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: A series of new 4-thiazolidinone-, pyridine- and piperazine-based conjugates were synthesized, characterized and screened for their anticancer activity against nalm6, k562 and Jurkat cell lines. Few of them showed good potency to induce apoptosis in leukemia cells.
European Journal of Medicinal Chemistry 01/2014; 81:341–349. · 3.43 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Thrombocytopenia is a serious issue connected with the pathogenesis of several human diseases including chronic inflammation, arthritis, Alzheimer's disease, cardiovascular diseases (CVDs) and other oxidative stress-associated pathologies. The indiscriminate use of antibiotics and other biological drugs are reported to result in thrombocytopenia, which is often neglected during the treatment regime. In addition, augmented oxidative stress induced by drugs and pathological conditions has also been shown to induce thrombocytopenia, which seems to be the most obvious consequence of elevated rate of platelet apoptosis. Thus, blocking oxidative stress-induced platelet apoptosis would be of prime importance in order to negotiate thrombocytopenia and associated human pathologies. The current study presents the synthesis and platelet protective nature of novel ibuprofen derivatives. The potent anti-oxidant ibuprofen derivative 4f was selected for the study and the platelet protective efficacy and platelet aggregation inhibitory property has been demonstrated. The compound 4f dose dependently mitigates the oxidative stress-induced platelet apoptosis in both platelet rich plasma and washed platelets. The platelet protective nature of compound 4f was determined by assessing various apoptotic markers such as ROS generation, cytosolic Ca2+ levels, PS externalization, cytochrome C translocation, Caspase activation, mitochondrial membrane depolarization, cytotoxicity, LDH leakage and tyrosine phosphorylation of cytosolic proteins. Furthermore, compound 4f dose dependently ameliorated agonist induced platelet aggregation. Therefore, compound 4f can be estimated as a potential candidate in the treatment regime of pathological disorders associated with platelet activation and apoptosis. In addition, compound 4f can be used as an auxiliary therapeutic agent in pathologies associated with thrombocytopenia.
PLoS ONE 01/2014; 9(9):e107182. · 3.53 Impact Factor