Published in: Journal, Article, Research Support, Non-U.S. Gov’t, Volume : 17, Issue : 5, Pages : 1254-1265
DOI : 10.1039/c8ob02849d
Author : Sengupta, Ayon; Maity, Suvendu; Mondal, Animesh; Ghosh, Prasanta; Rudra, Sonali; Mukhopadhyay, Chhanda
Abstract : A new series of highly-functionalized spiro compounds of pyrrole were synthesized by a one pot, step-economic condensation of isatin, arylamine and β-keto ester catalyzed by wet picric acid. Initially, the reaction is proposed with an expectation of the formation of a multi-spiro heterocyclic framework of highly-substituted piperidine. However, the isomeric compound was characterized to be a five-membered pyrrole derivative with a diverse scope of variations having different types of substituents in the three components, resp. The possibility of formation of various diastereomers around the hindered single bond and the spiro carbon was limited, as only syn products I and II [R1 = t-Bu, Et, Bn; R2 = H, 4-Me, 4-MeO, etc.; R3 = H, Me; R4 = H, Me, Bn, allyl] were isolated in all the reactions performed under the standard conditions. Probably the reactions were mediated by the si-facial formation of the bonds in a picric acid stabilized charge transfer complex transition state. Also, the manner a mol. achieves the most stabilized energy minimized arrangement with all its substituents in space was studied by DFT calculations where I was more stable than II. The studies on the formation of I and II were carried out by variation of electronic and steric factors in each of the components of the reactions.
Published in: Journal, Article, Research Support, Non-U.S. Gov’t Volume : 81, Issue : 9, Pages : 1956-1961
DOI : 10.1021/acs.jnatprod.8b00036
Author : Ghate, Nikhil B.; Chaudhuri, Dipankar; Panja, Sourav; Singh, Sudhir S.; Gupta, Gajendra; Lee, Chang Yeon; Mandal, Nripendranath
Abstract : The search for new plant-based anti-inflammatory drugs continues in order to overcome the detrimental side effects of conventional anti-inflammatory agents, both steroidal and nonsteroidal. This study involves the quinoline SPE2, 7-hydroxy-6-methoxyquinolin-2(1H)-one, isolated from the EtOAc fraction of Spondias pinnata bark. Structure elucidation was done using anal. spectroscopic methods including Fourier transform IR spectroscopy, high-resolution electrospray ionization mass spectrometry, NMR spectroscopy, and single-crystal X-ray crystallog. Theanti-inflammatory activity of SPE2 was evaluated in a lipopolysaccharide (LPS)-stimulated murine macrophage RAW 264.7 model. SPE2 effectively suppressed LPS-induced overproduction of pro-inflammatory mediators such as nitric oxide (NO), tumor necrosis factor (TNF)-α, interleukin (IL)-6, and IL-1β, and reactive oxygen species. Expression levels of NO synthesizing enzyme, cyclooxygenase-2, TNF-α, IL-6 and IL-1β were also determined to return to normal after SPE2 treatment. Localization of NF-κB was evaluated by confocal microscopy and Western blotting, which showed a dose-dependent reduction of NF-κB inside the nucleus and an increase in cytoplasmic NF-κB with SPE2 treatment. Collectively, the results suggest that SPE2 has anti-inflammatory activity via inhibition of NF-κB activation.
Published in: Journal, Article, Research Support, Non-U.S. Gov’t Volume : 7, Issue : 1, Pages : 1-17
DOI : 10.1038/s41598-017-14776-0
Author : Yasmin, Sabina; Capone, Fabio; Laghezza, Antonio; Piaz, Fabrizio Dal; Loiodice, Fulvio; Vijayan, Viswanathan; Devadasan, Velmurugan; Mondal, Susanta K.; Atli, Ozlem; Baysal, Merve; Pattnaik, Ashok K.; Jayaprakash, Venkatesan; Lavecchia, Antonio
Abstract : Peroxisome proliferator-activated receptor γ has received significant attention as a key regulator of glucose and lipid homeostasis. In this study, we synthesized and tested a library of novel 5-benzylidene-thiazolidin-2,4-dione (BTZD) derivatives bearing a substituent on nitrogen of TZD nucleus (compounds 1a-1k, 2i-10i, 3a, 6a, and 8a-10a). Three compounds (1a, 1i, and 3a) exhibited selectivity towards PPARγ and were found to be weak to moderate partial agonists. Surface Plasmon Resonance (SPR) results demonstrated binding affinity of 1a, 1i and 3a towards PPARγ. Furthermore, docking experiments revealed that BTZDs interact with PPARγ through a distinct binding mode, forming primarily hydrophobic contacts with the ligand-binding pocket (LBD) without direct H-bonding interactions to key residues in H12 that are characteristic of full agonists. In addition, 1a, 1i and 3a significantly improved hyperglycemia and hyperlipidemia in streptozotocin-nicotinamide (STZ-NA)-induced diabetic rats at a dose of 36 mg/kg/day administered orally for 15 days. Histopathol. investigations revealed that microscopic architecture of pancreatic and hepatic cells improved in BTZDs-treated diabetic rats. These findings suggested that 1a, 1i and 3a are very promising pharmacol. agents by selectively targeting PPARγ for further development in the clin. treatment of type 2 diabetes mellitus.
Published in: Journal, Article, Volume : 21, Issue : 3, Pages : 200-208
DOI : 10.1177/1087054713494004
Author : Das Bhowmik, Aneek; Sarkar, Kanyakumarika; Ghosh, Paramita; Das, Manali; Bhaduri, Nipa; Sarkar, Keka; Ray, Anirban; Sinha, Swagata; Mukhopadhyay, Kanchan
Abstract : OBJECTIVE: ADHD is frequently detected in boys though there is no established cause. One possibility is that genes predisposing to ADHD have sexually dimorphic effects. With an aim to find out the reason for this male biasness, contribution of 14 functional polymorphisms was investigated in ADHD subjects. METHOD: Genomic DNA of probands, their parents, and ethnically matched controls was subjected to analysis of single-nucleotide polymorphisms and variable number of tandem repeats (VNTRs). RESULTS: Case-control analysis revealed significant higher occurrence of DAT1 intron 8 VNTR “”5R”” allele ( p = .028), DBH rs1108580 “”A”” allele ( p = .027), and MAOA-u VNTR-rs6323 3R-T haplotype ( p = .007) in male probands. Family-based analysis showed significant preferential transmission of Dopamine receptor D4 exon 3 VNTR-rs1800955 7R-T haplotype from parents to male probands ( p = .008). Interaction between DBH gene variants and low enzymatic activity was also noticed, especially in male probands. CONCLUSION: Data obtained may partly answer the male biasness of ADHD.
Published in: Journal, Volume : 57, Issue : 29, Pages : 3140-3145
DOI : 10.1016/j.tetlet.2016.06.019
Author : Pai, Gita; Chattopadhyay, Asoke P.
Abstract : Cu nanoparticles promoted N-arylation of NH-heterocycles, e.g., I with aryl halides ArX [Ar = 4-H3CC6H4, 2,4-(Cl)2C6H3, 4-O2NC6H4, etc.; X = Cl, I] is an effective and inexpensive method. In this synthetic protocol, good to excellent yields are obtained. Both aryl iodide and aryl bromide are compatible with the reaction conditions.
Published in: Journal, Volume : 13, Issue : 2, Pages : 127-134
DOI : 10.2174/1570178613666151124200300
Author : Joardar, Soumen; Chakravorty, Santanu; Das, Sakti P.
Abstract : Simple, convenient, one step protocol for the synthesis of isobenzofuran-1(3H)-ones (phthalides) from phthalate esters in moderate to good yields were developed. Short and effective route to prepare two bioactive butyrolactones, viz., maculalactone A and B were also demonstrated.
Published in: Journal, Article, Volume : 59, Issue : 3, Pages : 1116-1139
DOI : 10.1021/acs.jmedchem.5b01704
Author : Igawa, Hideyuki; Takahashi, Masashi; Kakegawa, Keiko; Kina, Asato; Ikoma, Minoru; Aida, Jumpei; Yasuma, Tsuneo; Kawata, Yayoi; Ashina, Shuntaro; Yamamoto, Syunsuke; Kundu, Mrinalkanti; Khamrai, Uttam; Hirabayashi, Hideki; Nakayama, Masaharu; Nagisa, Yasutaka; Kasai, Shizuo; Maekawa, Tsuyoshi
Abstract : Aiming to discover melanin-concentrating hormone receptor 1 (MCHR1) antagonists with improved safety profiles, we hypothesized that the aliphatic amine employed in most antagonists reported to date could be removed if the bicyclic motif of the compound scaffold interacted with Asp123 and/or Tyr272 of MCHR1. We excluded aliphatic amines from our compound designs, with a cutoff value of pKa < 8, and explored aliphatic amine-free MCHR1 antagonists in a CNS-oriented chem. space limited by four descriptors (TPSA, ClogP, MW, and HBD count). Screening of novel bicyclic motifs with high intrinsic binding affinity for MCHR1 identified the imidazo[1,2-a]pyridine ring, and subsequent cyclization of the central aliphatic amide linkage led to the discovery of a potent, orally bioavailable MCHR1 antagonist 4-[(4-chlorobenzyl)oxy]-1-(2-cyclopropyl-3-methylimidazo[1,2-a]pyridin-6-yl)pyridin-2(1H)-one (I). It exhibited low potential for hERG inhibition and phospholipidosis induction as well as sufficient brain concentration to exert antiobesity effects in diet-induced obese rats.
Published in: Journal, Article, Research Support, Non-U.S. Gov’t Volume : 349, Issue : 1, Pages : 9-19
DOI : 10.1002/ardp.201500317
Author : Badavath, Vishnu N.; Baysal, Ipek; Ucar, Guelberk; Mondal, Susanta K.; Sinha, Barij N.; Jayaprakash, Venkatesan
Abstract : Ferulic acid has structural similarity with curcumin which is being reported for its monoamine oxidase (MAO) inhibitory activity. Based on this similarity, the authors designed a series of ferulic acid amides and tested for their inhibitory activity on human MAO (hMAO) isoforms. All the compounds were found to inhibit the hMAO isoforms either selectively or nonselectively. Nine compounds were found to inhibit hMAO-B selectively, whereas the other four were found to be nonselective. There is a gradual shift from hMAO-B selectivity to nonselectivity as there is an increase in chain length at the amino terminus. In case of compounds having an aromatic nucleus at the amino terminus, increasing the carbon number between N and the aromatic ring increases the potency as well as selectivity toward hMAO-B. Three compounds were subjected to membrane permeability and metabolic stability studies by in vitro assay methods. They were found to have a better pharmacokinetic profile than curcumin, ferulic acid, and selegiline. In order to understand the structural features responsible for the potency and selectivity of I, the authors carried out a mol. docking simulation study.
Published in: Journal, Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov’t, Volume : 354, Issue : 3, Pages : 261-268
DOI : 10.1124/jpet.115.224519
Author : BLi, Mei-Hong; Swenson, Rolf; Harel, Miriam; Jana, Sampa; Stolarzewicz, Erik; Hla, Timothy; Shapiro, Linda H.; Ferrer, Fernando
Abstract : The bioactive lipid sphingosine-1-phosphate (S1P) and its receptors (S1P1-5) play critical roles in many pathol. processes, including cancer. The S1P axis has become a bona fide therapeutic target in cancer. JTE-013 [N-(2,6-dichloro-4-pyridinyl)-2-[1,3-dimethyl-4-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridin-6-yl]-hydrazinecarboxamide], a known S1P2 antagonist, suffers from instability in vivo. Structurally modified, more potent, and stable S1P2 inhibitors would be desirable pharmacol. tools. One of the JTE-013 derivatives, AB1 [N-(1H-4-isopropyl-1-allyl-3-methylpyrazolo[3,4-b]pyridine-6-yl)-amino-N’-(2,6-dichloropyridine-4-yl) urea], exhibited improved S1P2 antagonism compared with JTE-013. I.v. pharmacokinetics indicated enhanced stability or slower clearance of AB1 in vivo. Migration assays in glioblastoma showed that AB1 was slightly more effective than JTE-013 in blocking S1P2-mediated inhibition of cell migration. Functional studies in the neuroblastoma (NB) cell line SK-N-AS showed that AB1 displayed potency at least equivalent to JTE-013 in affecting signaling mols. downstream of S1P2. Similarly, AB1 inhibition of the growth of SK-N-AS tumor xenografts was improved compared with JTE-013. Cell viability assays excluded that this enhanced AB1 effect is caused by inhibition of cancer cell survival. Both JTE-013 and AB1 trended to inhibit (C-C motif) ligand 2 expression and were able to significantly inhibit subsequent tumor-associated macrophage infiltration in NB xenografts. Interestingly, AB1 was more effective than JTE-013 in inhibiting the expression of the profibrotic mediator connective tissue growth factor. The terminal deoxynucleotidyl transferase-mediated digoxigenin-deoxyuridine nick-end labeling assay and cleaved caspase-3 detection further demonstrated that apoptosis was increased in AB1-treated NB xenografts compared with JTE-013. Overall, the modification of JTE-013 to produce the AB1 compound improved potency, i.v. pharmacokinetics, cellular activity, and antitumor activity in NB and may have enhanced clin. and exptl. applicability.
Published in: Journal, Article, Volume : 11, Issue : 42, Pages : 269-276
DOI : 10.4103/0973-1296.153078
Author : Chaudhuri, Dipankar; Ghate, Nikhil Baban; Singh, Sudhir Shankar; Mandal, Nripendranath
Abstract : Background:Spondias pinnata has been reported for its efficient anticancer effects, but the studies were mostly focused on its extract Objective: Since its bioactive compounds are largely unknown, this study was designed to characterize the lead components present in it and their anticancer activity against human glioblastoma cell line (U87). Materials and Methods: Major compounds from the Et acetate fraction were isolated by column chromatog. and their anticancer potentials against U87 cells were evaluated. Furthermore, flow cytometric and immunoblotting analyses were performed to demonstrate the mechanism of apoptosis inducing activity of Me gallate (MG) against U87 cell line. Results: Four major compounds were isolated from the Et acetate fraction. Amongst these, two compounds showed promising activities and with the help of different spectroscopic methods they were identified as gallic acid and MG. Flow cytometric studies revealed that MG-induced apoptosis in U87 cells dose-dependently; the same was confirmed by activation of caspases through cleavage of endogenous substrate poly (ADP-ribose) polymerase. MG treatment also induced the expression of p53 and B-cell lymphoma-2-associated X and cleavage of BH3 interacting-domain with a concomitant decrease in B-cell lymphoma-2 expression. Moreover, MG-induced sustained phosphorylation of extracellular signal-regulated kinase (ERK1/2) in U87 cells with no change in the phosphorylation of other mitogen-activated protein kinases (c-Jun N-terminal of stress-activated protein kinases, p38). Conclusion: MG is a potent antioxidant and it induces sustained ERK1/2 activation and apoptosis in human glioblastoma U87, and provide a rationale for evaluation of MG for other brain carcinoma cell lines for the advancement of glioblastoma therapy.
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