Pratibha Mehta Luthra

Demethoxycurcumin induces Bcl-2 mediated G2/M arrest and apoptosis in human glioma U87 cells

Docking analysis of curcumin (C1), demethoxycurcumin (C2) and bisdemethoxycurcumin (C3) with Bcl-2 illustrated that among the three curcuminoids, C2 binds more efficiently into its putative active site. C1, C2 and C3 were purified from turmeric rhizomes to demonstrate the molecular mechanism of their anticancer activity on human glioma U87 cells. Human glioma U87 cells treated with curcuminoids resulted in activation of Bcl-2 mediated G2 checkpoint, which was associated with the induction of G2/M arrest and apoptosis. The binding of C1, C2 and C3 with Bcl-2 protein was confirmed with circular dichroism (CD) spectroscopy. Present work revealed that C2 induced Bcl-2 mediated G2/M arrest and apoptosis most effectively.

Synthesis of novel 7-imino-2-thioxo-3,7-dihydro-2H-thiazolo [4,5-d] pyrimidine derivatives as adenosine A2A receptor antagonists

Novel bicyclic thiazolopyrimidine compounds (15-26) were synthesized to develop adenosine A(2A) receptor (A(2A)R) antagonist for the treatment of Parkinsons disease (PD). The binding affinity of the compounds (15-26) with A(2A)R was evaluated using radioligand binding assay on isolated membranes from stably transfected HEK293 cells. Selectivity of the compounds towards A(2A)R was assessed by comparing their binding affinities with A(1) receptors (A(1)R). cAMP concentrations were measured from HEK293 cells treated with compounds (15-26) as compared to NECA (A(2A)R agonist). The compound (16) possessed strongest A(2A)R binding affinity (K(i) value=0.0038 nM) and selectivity (737-fold) versus A(1)R. Decrease in A(2A)R-coupled release of endogenous cAMP from HEK293 cells treated with compounds (15-26) is evocative of their potential as A(2A)R antagonist.

Prospective of curcumin, a pleiotropic signalling molecule from Curcuma longa in the treatment of Glioblastoma

GBM (Glioblastoma) is the most malignant human brain tumor with median survival of one year. The treatment involves surgery, radiotherapy and adjuvant chemotherapy mostly with the alkylation agents such as temozolomide (TMZ). Dietary polyphenol curcumin, isolated from the rhizome of the Curcuma longa (turmeric), has emerged as remarkable anti-cancer agent in the treatment of various peripheral cancers such as blood, lymphomas, multiple myeloma, melanoma as well as skin, lung, prostate, breast, ovarian, bladder, liver, gastrointestinal tract, pancreatic and colorectal epithelial cancers with a pleiotropic mode of action and also showed promise in alleviation of GBM. In this review, the mechanism of anticancer effect of curcumin in GBM has been discussed extensively. The clinical safety and pharmacokinetics of curcumin has been scrutinized to combat the challenges for the treatment of GBM.

Aqua mediated synthesis of 2-amino-6-benzothiazol-2-ylsulfanyl-chromenes and its in vitro study, explanation of the structure–activity relationships (SARs) as antibacterial agent

Multi-component reaction (MCR) involves coupling of p-bromophenol with 2-Benzothiazolethiol, malononitrile and substituted aldehydes in aqueous K(2)CO(3) as green base to synthesize 2-amino-6-benzothiazol-2-ylsulfanyl-chromenes. This multi-component reaction thus offers a higher yield and versatility in the preparation of densely functionalized oxygen heterocycles. The newly synthesized compounds were screened for their antibacterial activities against positive and gram negative pathogenic strains to bacteria. SAR analysis was performed to explore comprehensive structure-activity relationships and a statistically reliable model to explain their antibacterial activities.

8-(Furan-2-yl)-3-phenethylthiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidine-2(3H)-thione as novel, selective and potent adenosine A2A receptor antagonist

Antagonism of the human A2A receptor has been implicated to alleviate the symptoms associated with Parkinsons disease. The present finding reveals the potential of PTTP (8-(furan-2-yl)-3-phenethylthiazolo[1,2,4]triazolo[1,5-c]pyrimidine-2(3H)-thione) as novel and potent A2AR antagonist. In radioligand binding assay, PTTP showed significantly high binding affinity (Ki 6.3 nM) and selectivity with A2AR (A1R/A2AR=4603) which was comparable to the results of docking analysis (Ki=1.6 nM, ΔG=-14.52 Kcal/mol). PTTP antagonized (0.46 pmol/ml) the effect of NECA-induced increase in cAMP concentration (0.65 pmol/ml) better than SCH58261 (0.55 pmol/ml) in HEK293T cells. Haloperidol and NECA-induced mice pre-treated with PTTP at 10mg/kg showed attenuation in catalepsy and akinesia without significant neurotoxicity in rotarod test at 20mg/kg. Essentially, novel compound demonstrated remarkable potential as A2AR antagonist in the therapy of PD.

Efficient entry to diversely functionalized spirooxindoles from isatin and their biological activity

A collection of structurally complex and chemically diverse small molecules is a useful tool to explore cell circuitry. In this article, we have reported the two step synthesis of diverse spirooxindoles. The key reaction to assemble the spirooxindole core is a Lewis acid catalyzed three component coupling. The final library of compounds was then analyzed for their cytotoxic activity against U87 human glioma cells. It is noteworthy to mention that this is the first report on the pharmaceutical evaluation of such compounds. Although the activity is moderate, it opens the door for new chemical modifications of spirooxindoles.Graphical abstract

Novel 8-(furan-2-yl)-3-substituted thiazolo [5,4-e][1,2,4] triazolo[1,5-c] pyrimidine-2(3H)-thione derivatives as potential adenosine A2A receptor antagonists

Novel thiazolotriazolopyrimidine derivatives (23-33) designed as potential adenosine A(2A) receptor (A(2A)R) antagonists were synthesized. Molecular docking studies revealed that all compounds (23-33) exhibited strong interaction with A(2A)R. The strong interaction of the compounds (23-33) with A(2A)R in silico was confirmed by their high binding affinity with human A(2A)R stably expressed in HEK293 cells using radioligand-binding assay. The compounds 24-26 demonstrated substantial binding affinity and selectivity for A(2A)R as compared to SCH58261, a standard A(2A)R antagonist. Decrease in A(2A)R-coupled release of endogenous cAMP in treated HEK293 cells demonstrated in vitro A(2A)R antagonist potential of the compounds 24-26. Attenuation in haloperidol-induced motor impairments (catalepsy and akinesia) in Swiss albino male mice pre-treated with compounds 24-26 further supports their role in the alleviation of PD symptoms.

Antagonism of haloperidol-induced swim impairment in L-dopa and caffeine treated mice: a pre-clinical model to study Parkinson's disease.

Parkinsons disease (PD) exhibits symptoms of motor dysfunction such as tremor, akinesia and rigidity. Agents that selectively disrupt or destroy catecholaminergic systems, such as reserpine, methamphetamine, 6-hydroxydopamine and 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine, have been used to develop PD models and to study the animal behavior like catalepsy, akinesia, swim-test, etc. The major apprehension while working with these chemicals is their irreversible neuro-toxic effect. Haloperidol is a classical antipsychotic drug, which produces extra-pyrimidal Parkinsons symptoms (EPS). Measuring catalepsy and akinesia in the treated mice monitored the haloperidol-induced EPS. Alternatively, swimming disability was tested as a new parameter to monitor haloperidol-induced EPS. The results showed that the restoration of swimming disability in haloperidol-induced L-dopa and caffeine pre-treated mice could be used as pre-clinical model to study PD.

High-performance liquid chromatography separation of enantiomers of mandelic acid and its analogs on a chiral stationary phase

The enantiomers of mandelic acid and its analogs have been chromatographically separated on a chiral stationary phase (CSP) derived from 4-(3,5-dinitrobenzamido) tetrahydrophenanthrene. The rationale of separations of these compounds is discussed with respect to the method development for determining enantiomeric purity and possibility of obtaining enantiomerically pure materials by high-pressure liquid chromatography. The relationship of analyte structure to the extent of enantiomeric separation has been examined and separation factors (alpha) are presented for various groups of structurally related compounds. Chiral recognition models have been suggested to account for the observed separations. These models provide mechanistic insights into the chiral recognition process.

Therapeutic uses ofCurcuma longa (turmeric).

Curcuma longa commonly known as tumeric is traditionally used as a spice in Indian food. A wide range of biological activities e.g. anticancer, antimicrobial, antiinflammatory and free radical scavenging activity of the plant suggests a logical basis for its traditional use in foodstuff. Various phytothreapeutic uses ofCurcuma longa have been reviewed.