Pyridopyrimidinone Derivatives as ΙDNAG-Quadruplex-Stabilizing Agents: Design, Synthesis and Biophysical Studies

Published in: Journal, Volume : 2, Issue : 18, Pages : 5206-5213

DOI : 10.1002/slct.201700677

Author : Malhotra, Rajesh; Rarhi, Chhanda; Diveshkumar, K. V.; Bommisetti, P.; Pany, Sushree Prangya P.; Roy, Subho; Pradeepkumar, P. I.; Kundu, Mrinalkanti

Abstract : With an aim to engineer drug-like properties, pyridopyrimidinone based selective G4 DNA stabilizing agents, e.g., I were designed, synthesized and further they were evaluated for G4 DNA recognition properties. CD melting studies revealed the preferential stabilization of parallel topol. of promoter c-MYC and c-KIT G4 DNAs by the ligands, especially compound I and 4-[7-chloro-3-methyl-8-(4-methyl-piperazin-1-yl)-4-oxo-4H-pyrido[1,2-a]pyrimidin-2-yloxymethyl]-N-(2-dimethylamino-ethyl)-benzamide, over the different topologies of telomeric G4 DNA. UV melting experiments suggested that no significant stabilization was observed for duplex DNA. Further, the results from ITC experiments substantiated the preferential stabilization of parallel topol. of c-MYC G4 DNA over telomeric and duplex DNA by the ligands I. These data showed that ligand I has moderate binding affinity to the c-MYC G4 DNA and is ~49-fold and ~25-fold selective over the telomeric G4 DNA and the duplex DNA resp. The mol. modeling and dynamics studies of the ligand I in complex with c-MYC and c-KIT1 G4 DNAs showed that this ligand stacks on the 5′-quartet of c-MYC and 3′-quartet of c-KIT1 G4 DNA structures.

Pseudo five component reaction towards densely functionalized spiro[indole-3,2′-pyrrole] by picric acid, an efficient syn-diastereoselective catalyst: insight into the diastereoselection on C(sp3)-C(sp3) axial conformation

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.

In Vitro Mechanistic Study of the Anti-inflammatory Activity of a Quinoline Isolated from Spondias pinnata Bark

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.

Novel Benzylidene Thiazolidinedione Derivatives as Partial PPARg Agonists and their Antidiabetic Effects on Type 2 Diabetes

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.

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.