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Li M.-H.,Center for Vascular Biology | Swenson R.,Arroyo Biosciences LLC | Harel M.,Connecticut Childrens Medical Center | Jana S.,TCG Life science Ltd | And 5 more authors.
Journal of Pharmacology and Experimental Therapeutics | Year: 2015

The bioactive lipid sphingosine-1-phosphate (S1P) and its receptors (S1P1-5) play critical roles in many pathologic 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 pharmacological tools. One of the JTE-013 derivatives, AB1 [N-(1H-4-isopropyl- 1-allyl-3-methylpyrazolo[3,4-b]pyridine-6-yl)-amino-N9-(2,6- dichloropyridine-4-yl) urea], exhibited improved S1P2 antagonism compared with JTE-013. Intravenous 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 molecules 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, intravenous pharmacokinetics, cellular activity, and antitumor activity in NB and may have enhanced clinical and experimental applicability. Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics.


Barik R.,Jadavpur University | Barik R.,TCG Life science Ltd | Sarkar R.,Jadavpur University | Biswas P.,Jadavpur University | And 7 more authors.
Oriental Pharmacy and Experimental Medicine | Year: 2013

Bruguiera gymnorrhiza is a mangrove plant of the family Rhizophoraceae. The roots and leaves of the plant have traditionally been used for treating burns and mild inflammatory lesions. In the present study an attempt was made to evaluate the anti-inflammatory activity of the Bruguiera gymnorrhiza leaves. The methanolic fraction of Bruguiera gymnorrhiza leaves (BRG) was evaluated using different in vitro and in vivo models to evaluate the anti-inflammatory properties and also to obtain an insight on the probable mechanism of such activity. The leaf extract produced significant inhibition of both carrageenan induced rat paw oedema and acetic Acid induced peritoneal capillary permeability. The above observations were further supported by our findings from in vitro experimental models, where the plant extract produced significant inhibition of both cyclooxygenase (COX) and lipoxygenase (LOX) enzymes. Moreover, BRG inhibited the production of proinflammatory cytokines (TNF- α, IL-6 and IL-1β) in lipopolysaccharide (LPS)-stimulated peripheral blood mononuclear cells (PBMCs) in a dose dependent manner. It was also found to possess significant free radical (DPPH, superoxide and oxygen radical) scavenging activity. From the results obtained from the various in vitro and in vivo test models, it may be concluded that the methanolic extract of Bruguiera gymnorrhiza leaves display significant anti-inflammatory properties, probably mediated through blockade of both COX - LOX pathway, coupled with scavenging effect on free radicals. © 2013 Institute of Oriental Medicine, Kyung Hee University.


Malhotra R.,Guru Jambheshwar University of Science and Technology | Dey T.K.,Guru Jambheshwar University of Science and Technology | Dey T.K.,TCG Life science Ltd | Dutta S.,TCG Life science Ltd | And 2 more authors.
Organic and Biomolecular Chemistry | Year: 2014

First regioselective ring opening of serine derived cyclic sulfamidate by hard nucleophiles like ArONa is developed, where β-elimination of serine sulfamidate ester by stronger nucleophiles is overcome by reversal of the electronic effect of the carboxylate anion. This method provides easy and direct access to a variety of N-Boc- and N-PMB protected β-aryloxy-α-amino acids with complete retention of enantiopurity in moderate to high yields. © the Partner Organisations 2014.


Malhotra R.,Guru Jambheshwar University of Science and Technology | Chakrabarti S.,Guru Jambheshwar University of Science and Technology | Chakrabarti S.,TCG Life science Ltd | Dey T.K.,Guru Jambheshwar University of Science and Technology | And 6 more authors.
Tetrahedron | Year: 2013

Protection group of amino- and tethered o-arene functionality of 1,4-aryl-2-amino-1-butanol derived from l-serine dictates the cyclization mode under acidic conditions leading to reverse diastereoselectivity. N-Boc and acetal protected amino alcohol undergo cascade cyclization providing exclusively cis-dihydrexidine via reduction, where formation of C-ring (isoquinoline unit) prior to Friedel-Crafts cyclization control the cis-stereochemistry of the B-ring. N-Cbz and O-benzyl protection direct first F-C cyclization yielding the trans-1-aryl-2-aminotetralin and subsequent deprotection-cyclization forming the C-ring afforded dihydrexidine. © 2013 Elsevier Ltd. All rights reserved.


Malhotra R.,Guru Jambheshwar University of Science and Technology | Ghosh A.,Guru Jambheshwar University of Science and Technology | Ghosh A.,TCG Life science Ltd | Ghosh R.,Guru Jambheshwar University of Science and Technology | And 9 more authors.
Tetrahedron Asymmetry | Year: 2011

A scalable asymmetric synthesis of trans-2-amino-6,7-dimethoxy-1- phenyltetralin 2 and its N-nosyl derivative 12 have been achieved from Garner aldehyde derived from easily available d-serine using a stereoselective PhMgBr addition, Wittig reaction and TFA-mediated Friedel-Crafts cyclization as the key steps. The synthesis of dihydrexidine is accomplished from the N-nosyl-2-amino-1-phenyltetralin 12. © 2011 Elsevier Ltd. All rights reserved.

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