Significance of Dopaminergic Gene Variants in the Male Biasness of ADHD.

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.

N-Arylation of nitrogen containing heterocycles with aryl halides using copper nanoparticle catalytic system

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.

A Simple, Convenient, Highly Regioselective Synthesis of Isobenzofuran-1(3H)-ones (phthalides) as well as Maculalactone A & B, the Bioactive Butyrolactones

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.

Melanin-Concentrating Hormone Receptor 1 Antagonists Lacking an Aliphatic Amine: Synthesis and Structure-Activity Relationships of Novel 1-(Imidazo[1,2-a]pyridin-6-yl)pyridin-2(1H)-one Derivatives

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.

Monoamine Oxidase Inhibitory Activity of Ferulic Acid Amides: Curcumin-Based Design and Synthesis

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.

Antitumor activity of a novel sphingosine-1-phosphate 2 antagonist, AB1, in neuroblastoma

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.

Methyl gallate isolated from Spondias pinnata exhibits anticancer activity against human glioblastoma by induction of apoptosis and sustained extracellular signal-regulated kinase 1/2 activation

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.

EN3427: A Novel Cationic Aminoindane with Long-Acting Local Anesthetic Properties

Published in: Journal, Article, Research Support, Non-U.S. Gov’t, Volume : 120, Issue : 4, Pages : 941-949

DOI : 10.1213/ANE.0000000000000629

Author : Banerjee, Manish; Baranwal, Atul; Saha, Soumya; Saha, Ashis; Priestley, Tony

Abstract : Background: Currently approved local anesthetic drugs provide relatively brief local anesthesia that is appropriate and even desirable in some settings, but an extended duration of action beyond their capabilities would be a distinct benefit in other clin. situations. We implemented a drug discovery program that sought to identify novel local anesthetic mols. that specifically demonstrated a long-acting, preferential action on nociceptor sensory afferents that expressed transient receptor potential (TRP) channels. The hypothesis we tested was whether relatively membrane-impermeant local anesthetic mols. could confer long-lasting anesthesia if neuronal access was facilitated by TRP channel activation. The current work describes in vivo studies on a lead mol. that emerged from the discovery program, EN3427, in several rodent pain models. Methods: Studies were performed on male Sprague-Dawley rats using 2 models of acute mech. paw-pinch-evoked and pinprick-evoked nociceptive pain. Behavioral responses to noxious stimuli were assessed at baseline, i.e., before any pharmacol. intervention, and at various timepoints after a single perisciatic or s.c. administration of either EN3427 alone or in combination with lidocaine. Paw withdrawal thresholds or cutaneous trunci reflexes were quantified, and pre-post drug values were compared statistically with anal. of variance followed by post hoc Dunnett multiple range test. Results: A single perisciatic injection of lidocaine (2%) produced relief of paw-pinch-evoked pain that was significantly different from baseline through to the 1-h timepoint (Dunnett multiplicity-adjusted P = 0.0081), as assessed using paw withdrawal or vocalization end points. EN3427 (0.2%), in the same model, produced a long-lasting block, with pain thresholds being significantly above baseline through to the 18-h timepoint (Dunnett multiplicity-adjusted P = 0.0002); the combination of EN3427 (0.2%) plus lidocaine (2%) produced even longer lasting analgesia, with pain thresholds being significantly above baseline through to the 24-h timepoint (Dunnett multiplicity-adjusted P = 0.0073). Similar results were obtained with use of the pinprick approach. A single s.c. injection of lidocaine (2%) produced complete loss of sensation to cutaneous pinprick through 0.5 h, but sensitivity thresholds were no different to baseline by the 1-h timepoint, a similar injection of EN3427 alone (0.2%) produced a loss of sensation that was significantly different from baseline through the 8-h timepoint (Dunnett multiplicity-adjusted P = 0.0045), and the combination of lidocaine (2%) plus EN3427 (0.2%) appeared to further enhance duration of analgesia, although this was significantly different from baseline only through the 10-h timepoint (Dunnett multiplicity-adjusted P = 0.0048). Analgesic efficacy was dose related; using the combined injection approach, we found that increases in the dose of EN3427 with a fixed 2% lidocaine led to substantially extended analgesia and increasing doses of lidocaine combined with a fixed dose of EN3427 (0.2%) led to only modestly increased duration of action. Conclusions: The present studies demonstrate that a new mol. entity, EN3427, produces effective and long-lasting analgesia in 2 rodent pain models. The analgesic effects of EN3427 are significantly longer-lasting than lidocaine and are further extended when EN3427 is combined with lidocaine. The results are discussed with respect to a possible lidocaine-mediated TRP channel activation and facilitated neuronal access of EN3427, with subsequent entrapment conferring extended-duration efficacy.

Antimicrobial properties of Kalanchoe blossfeldiana: a focus on drug resistance with particular reference to quorum sensing-mediated bacterial biofilm formation

Published in: Journal, Article, Research Support, Non-U.S. Gov’t, Volume : 67, Issue : 7, Pages : 951-962

DOI : 10.1111/jphp.12397

Author : Sarkar, Ratul; Mondal, Chaitali; Bera, Rammohan; Chakraborty, Sumon; Barik, Rajib; Roy, Paramita; Kumar, Alekh; Yadav, Kirendra K.; Choudhury, Jayanta; Chaudhary, Sushil K.; Samanta, Samir K.; Karmakar, Sanmoy; Das, Satadal; Mukherjee, Pulok K.; Mukherjee, Joydeep; Sen, Tuhinadri

Abstract : This study investigates the antimicrobial properties of Kalanchoe blossfeldiana with a particular reference to quorum sensing (QS)-mediated biofilm formation. A methanol extract of K. blossfeldiana leaves (MEKB) was evaluated for antimicrobial properties including QS-controlled production of biofilm (including virulence factor, motility and lactone formation) in Pseudomonas aeruginosa. The methanol extract of K. blossfeldiana was also evaluated for anti-cytokine (tumor necrosis factor-alpha, interleukin-6 and interleukin-1 beta) properties in peripheral blood mononuclear cells (PBMC). The methanol extract of K. blossfeldiana exhibited an antimicrobial effect on clin. isolates, as well as standard reference strains. Pseudomonas aeruginosa exposed to MEKB [subminimum inhibitory concentration (MIC)] displayed reduced biofilm formation, whereas supra-MIC produced destruction of preformed biofilms. The methanol extract of K. blossfeldiana reduced the secretion of virulence factors (protease and pyoverdin) along with generation of acyl homoserine lactone (AHL). Confocal laser scanning microscopy images indicate reduction of biofilm thickness. The extract also reduced cytokine formation in lipopolysaccharide-stimulated PBMC. Thus, Kalanchoe blossfeldiana was found to interfere with AHL production, which in turn may be responsible for downregulating QS-mediated production of biofilm and virulence.