Publications by authors named "Amit K Keshari"

20 Publications

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Author Correction: Novel Indole-fused benzo-oxazepines (IFBOs) inhibit invasion of hepatocellular carcinoma by targeting IL-6 mediated JAK2/STAT3 oncogenic signals.

Sci Rep 2020 Feb 6;10(1):2391. Epub 2020 Feb 6.

Department of Pharmaceutical Sciences, Babasaheb Bhimrao Ambedkar University, Vidya Vihar, Raibareli Road, Lucknow, 226025, India.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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http://dx.doi.org/10.1038/s41598-020-59134-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7002741PMC
February 2020

Novel Indole-fused benzo-oxazepines (IFBOs) inhibit invasion of hepatocellular carcinoma by targeting IL-6 mediated JAK2/STAT3 oncogenic signals.

Sci Rep 2018 04 12;8(1):5932. Epub 2018 Apr 12.

Department of Pharmaceutical Sciences, Babasaheb Bhimrao Ambedkar University, Vidya Vihar, Raibareli Road, Lucknow, 226025, India.

Inspired by the well-documented tumor protecting ability of paullones, recently, we synthesized novel paullone-like scaffolds, indole-fused benzo-oxazepines (IFBOs), and screened them against hepatocellular carcinoma (HCC) specific Hep-G2 cells. Three of the synthesized compounds significantly attenuated the progression of HCC in vitro. By computational studies, we further discovered that IFBOs exhibited a stable binding complex with the IL-6 receptor. In this context, we investigated in vivo study using the nitrosodiethyl amine (NDEA)-induced HCC model, which strengthened our previous findings by showing the blockade of the IL-6 mediated JAK2/STAT3 oncogenic signaling pathway. Treatment with IFBOs showed remarkable attenuation of cellular proliferation, as evidenced through a decrease in the number of nodules, restoration of body weight, oxidative stress parameters, liver marker enzymes and histological architecture. Interestingly, using a metabolomic approach we further discovered that IFBOs can restore the perturbed metabolic profile associated with the HCC condition to normalcy. Particularly, the efficacy of compound 6a for an anti-HCC response was significantly better than the marketed chemotherapeutic drug, 5-fluorouracil. Altogether, these remarkable findings open up possibilities of developing IFBOs as novel future candidate molecules for plausible alternatives for HCC treatment.
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http://dx.doi.org/10.1038/s41598-018-24288-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5897576PMC
April 2018

Novel 1,3,4-thiadiazoles inhibit colorectal cancer via blockade of IL-6/COX-2 mediated JAK2/STAT3 signals as evidenced through data-based mathematical modeling.

Cytokine 2019 06 23;118:144-159. Epub 2018 Mar 23.

Department of Pharmaceutical Sciences, Babasaheb Bhimrao Ambedkar University, Vidya Vihar, Raibareli Road, Lucknow 226025, India. Electronic address:

We attempted a preclinical study using DMH-induced CRC rat model to evaluate the antitumor potential of our recently synthesized 1,3,4-thiadiazoles. The molecular insights were confirmed through ELISA, qRT-PCR and western blot analyses. The CRC condition was produced in response to COX-2 and IL-6 induced activation of JAK2/STAT3 which, in turn, was due to the enhanced phosphorylation of JAK2 and STAT3. The treatment with 1,3,4-thiadiazole derivatives (VR24 and VR27) caused the significant blockade of this signaling pathway. The behavior of STAT3 populations in response to IL-6 and COX-2 stimulations was further confirmed through data-based mathematical modeling using the quantitative western blot data. Finally, VR24 and VR27 restored the perturbed metabolites associated to DMH-induced CRC as evidenced through H NMR based serum metabolomics. The tumor protecting ability of VR24 and VR27 was found comparable or to some degree better than the marketed chemotherapeutics, 5-flurouracil.
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http://dx.doi.org/10.1016/j.cyto.2018.03.026DOI Listing
June 2019

Poly(lactic--glycolic acid)-loaded nanoparticles of betulinic acid for improved treatment of hepatic cancer: characterization, in vitro and in vivo evaluations.

Int J Nanomedicine 2018 16;13:975-990. Epub 2018 Feb 16.

Department of Pharmaceutical Sciences, Babasaheb Bhimrao Ambedkar University, Vidya Vihar, Lucknow, Uttar Pradesh, India.

Purpose: The application of betulinic acid (B), a potent antineoplastic agent, is limited due to poor bioavailability, short plasma half-life and inappropriate tissue distribution. Thus, we aimed to prepare novel 50:50 poly(lactic--glycolic acid) (PLGA)-loaded B nanoparticles (BNP) and to compare its anti-hepatocellular carcinoma (HCC) activity with parent B.

Methods: BNP were synthesized and characterized using different methods such as scanning electron microscopy (SEM), fourier-transform infrared (FTIR) spectrometry and particle size analyses. Particle size of BNP was optimized through the application of the stabilizer, polyvinyl alcohol (PVA). The anti-HCC response was evaluated through in vitro cell line study using Hep-G2 cells, confocal microscopy, in vivo oral pharmacokinetics and animal studies. Further, quantitative reverse transcription polymerase chain reaction (qRT-PCR) analysis was conducted to observe the changes in the expression of specific genes.

Results: Particle size of BNP was optimized through the application of the stabilizer, polyvinyl alcohol. Physicochemical characterization exhibited particle size of 257.1 nm with zeta potential -0.170 mV (optimized batch B, BNP). SEM and FTIR analyses of BNP showed that cylindrical particles of B converted to spherical particles in BNP and there were no interaction between B and used polymers. The release study of optimized BNP was highest (≥80%) than any other formulation. Later, in vitro cell culture analysis using Hep-G2 cells and confocal microscopy studies revealed that BNP had the highest inhibition and penetration properties than parent B. Oral pharmacokinetics studies using albino Wistar rats at single 100 mg dose again exhibited BNP had the higher 50% of plasma concentration (t), a higher maximum plasma concentration () and took longer to reach the maximum plasma concentration (T) than parent B. Next, our in vivo study using nitrosodiethyl amine (NDEA)-induced HCC model documented BNP decreased in number of nodules, restored body weight, oxidative stress parameters, liver marker enzymes and histological architecture than parent B. Lastly, qRT-PCR studies further demonstrated that anti-HCC properties of BNP may be due to over expression of antiapoptotic caspases i.e., caspase 3 and 8.

Conclusion: The prepared BNP showed a better therapeutic response against HCC and could be attributed as future candidate molecule for HCC treatment.
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http://dx.doi.org/10.2147/IJN.S157391DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5818879PMC
May 2018

6,7-dimethoxy-1,2,3,4-tetrahydro-isoquinoline-3-carboxylic acid attenuates colon carcinogenesis via blockade of IL-6 mediated signals.

Biomed Pharmacother 2018 Apr 16;100:282-295. Epub 2018 Feb 16.

Department of Pharmaceutical Sciences, Babasaheb Bhimrao Ambedkar University, Vidya Vihar, Raibareli Road, Lucknow 226025, India. Electronic address:

In this study, we investigated the in vivo antiproliferative activity of 6,7-dimethoxy-1,2,3,4-tetrahydro-isoquinoline-3-carboxylic acid (M1) in dimethylhydrazine (DMH) induced colorectal carcinoma (CRC) using albino Wistar rats. M1 was administered to DMH induced CRC rats at 10 and 25 mg/kg doses for 15 days. Various physiological, oxidative parameters, histopathology, ELISA, gene and protein expression studies were conducted to evaluate the anti-CRC potential of M1. The histopathology and biochemical tests indicated the protective action of M1 in DMH-induced colon cancer. ELISA confirms that M1 reduced the increased concentration of IL-6 more prominently than those of IL-2 and COX-2. Gene expression analysis revealed that M1 attenuated the increased mRNA over-expression of IL-6, JAK2 and STAT3. The result obtained from quantitative western blot analysis demonstrated that the CRC condition was produced by the IL-6 induced activation/phosphorylation of JAK2 and STAT3 and further down-regulated with M1 treatment. This evidence was supported well with the application of data-based mathematical modeling. Applying the fitted model, we predicted the quantitative behavior of STAT3 populations not accessible to experimental measurement. Later, H NMR based serum metabolic profiling was carried out using rat sera to investigate the impact of M1 on CRC-induced metabolic alterations. M1 showed its ability to restore the perturbed metabolites in CRC condition. Altogether, our study provided the first time evidence that M1 exhibits anti-CRC potential through the blockade of IL-6/JAK2/STAT3 oncogenic signaling.
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http://dx.doi.org/10.1016/j.biopha.2018.02.009DOI Listing
April 2018

Novel 1,4-benzothazines obliterate COX-2 mediated JAK-2/STAT-3 signals with potential regulation of oxidative and metabolic stress during colorectal cancer.

Pharmacol Res 2018 06 8;132:188-203. Epub 2017 Dec 8.

Department of Pharmaceutical Sciences, Babasaheb Bhimrao Ambedkar University, Vidya Vihar, Raebareli Road, Lucknow 226025, India. Electronic address:

1,4-benzothiazines have ameliorative effects through inhibition of COX-2 mediated STAT-3 pathways at G-protein couple receptor site. As per this scenario, we recently prepared and tested novel 1,4-benzothiazine derivatives against HT-29 human colon cancer cell line. Two compounds namely AR13 and AR15 showed higher inhibitions among all the synthesized compounds. In the present context, we conducted the in vivo antiproliferative action and identified the molecular mechanism associated to cytotoxic action of AR13 and AR15 in dimethylhydrazine (DMH) induced colorectal carcinoma (CRC) model. Various physiological, oxidative stress, histopathology, ELISA, qRT-PCR, western blot and NMR-based metabolomics were accomplished to evaluate the anticancer effect of titled compounds. Both compounds were subjected to histological and biochemical tests to observe the protective action of the compounds. ELISA showed potential role of these compounds to normalize increased levels of IL-2, IL-6 and COX-2 mediators. This action was more pronounced for COX-2 rather than IL-2 and IL-6. Gene expression analyses further revealed that both of them attenuated the over-expressed COX-2 gene. Furthermore, it was confirmed that these compounds exerted antitumor potential via preventing COX-2 induced JAK-2 and STAT-3 phosphorylation. This action was substansiated by immunohistochemistry using JAK2, p-JAK2, STAT3 and p-STAT3 targets in colon tissue. Finally, score plots of PLS-DA models exhibited significant metabolic discriminations between the treated and CRC groups, and both compounds showed ability to restore the imbalance of multiple metabolites during CRC. In conclusion, our study provided the evidence towards better antiproliferative effect of AR13 and AR15 in DMH-induced CRC through the blockade of COX-2/JAK-2/STAT-3 signal transduction pathway and could be demonstrated as useful anti-CRC candidate molecules for future anticancer therapy.
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http://dx.doi.org/10.1016/j.phrs.2017.12.010DOI Listing
June 2018

Isolated mangiferin and naringenin exert antidiabetic effect via PPAR/GLUT4 dual agonistic action with strong metabolic regulation.

Chem Biol Interact 2018 Jan 6;280:33-44. Epub 2017 Dec 6.

Department of Pharmaceutical Sciences, Babasaheb Bhimrao Ambedkar University, Vidya Vihar, Raebareli Road, Lucknow 226025, Uttar Pradesh, India. Electronic address:

In this study, we isolated two compounds from the leaves of Salacia oblonga (SA1, mangiferin and SA2, naringenin), and their structures were confirmed by infrared spectroscopy, nuclear magnetic resonance (NMR) spectroscopy, and mass spectrometry. SA1 and SA2 were orally administered to streptozotocin-induced diabetic rats at 50 and 100 mg/kg daily for 15 days. Blood glucose level, serum lipid profile, oxidative stress parameters, histopathology, docking, molecular parameters, and NMR-based metabolic perturbation studies were performed to investigate the pharmacological activities of SA1 and SA2. Results suggested that both compounds reduced blood glucose level, restored body weight, and normalized lipid concentrations in the serum and oxidative stress biomarkers in the liver and pancreas. In addition, the docking study on several diabetes-associated targets revealed that both compounds had a strong binding affinity towards peroxisome proliferator-activated receptor gamma (PPAR) and glucose transporter type 4 (GLUT4). Further real-time reverse transcription polymerase chain reaction and western blot analyses were performed to confirm the gene and protein expression levels of PPAR and GLUT4 in the pancreatic tissues. Data obtained from the molecular studies showed that both compounds exhibited antidiabetic effects through dual activation of PPAR/GLUT4 signaling pathways. Finally, the NMR-based metabolic studies showed that both compounds normalized the diabetogenic metabolites in the serum. Altogether, we concluded that SA1 and SA2 might be potential antidiabetic lead compounds for future drug development.
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http://dx.doi.org/10.1016/j.cbi.2017.12.007DOI Listing
January 2018

5H-benzo[h]thiazolo[2,3-b]quinazolines ameliorate NDEA-induced hepatocellular carcinogenesis in rats through IL-6 downregulation along with oxidative and metabolic stress reduction.

Drug Des Devel Ther 2017 13;11:2981-2995. Epub 2017 Oct 13.

Department of Pharmaceutical Sciences, Babasaheb Bhimrao Ambedkar University.

5H-benzo[h]thiazolo[2,3-b]quinazoline scaffold is known to have an antitumor effect on certain types of malignancies; however, its effect on hepatocellular carcinoma (HCC) remains unclear. Previously, we reported -toluenesulfonic acid-promoted syntheses, molecular modeling and in vitro antitumor activity of 5H-benzo[h]thiazolo[2,3-b]quinazoline against human hepatoma (Hep-G2) cells where compounds and were found to be potent inhibitors among the series. In continuation to our previous effort to develop novel therapeutic strategies for HCC treatment, here we investigated the in vivo antitumor activity and the mechanism underlying the effects of and in N-nitrosodiethylamine (NDEA)-induced HCC using male Wistar rats. NDEA was administered weekly intraperitoneally at a dose of 100 mg/kg for 6 weeks. Various physiological and morphological changes, oxidative parameters, liver marker enzymes and cytokines were assessed to evaluate the antitumor effect of and . In addition, proton nuclear magnetic resonance-based serum metabolomics were performed to analyze the effects of and against HCC-induced metabolic alterations. Significant tumor incidences with an imbalance in carcinogen metabolizing enzymes and cellular redox status were observed in carcinogenic rats. Tumor inhibitory effects of and were noted by histopathology and biochemical profiles in NDEA-induced hepatic cancer. Compounds and had a potential role in normalizing the elevated levels of inflammatory mediators such as interleukin-1β (IL-1β), IL-2, IL-6 and IL-10. At molecular level, the real-time quantitative reverse-transcribed polymerase chain reaction analysis revealed that and attenuated the gene overexpression in hepatic cancer. Further, orthogonal partial least squares discriminant analysis scores plot demonstrated a significant separation of and -treated groups from carcinogen control group. Both the compounds have potential to restore the imbalanced metabolites due to HCC, signifying promising hepatoprotective activities. All these findings suggested that and could be potential drug candidates to treat HCC.
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http://dx.doi.org/10.2147/DDDT.S143075DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5648320PMC
July 2018

Novel Mannich-bases as Potential Anticonvulsants: Syntheses, Characterization and Biological Evaluation.

Cent Nerv Syst Agents Med Chem 2017 ;17(3):219-228

Faculty of Pharmacy, Babu Banarasi Das Northern India Institute of Technology, Sector-2, Dr. Akhilesh Das Nagar, Faizabad Road, Lucknow, 226028, U.P.. India.

Background: Mannich bases are known to be an important pharmacophore or bioactive leads in the synthesis of various potential agents that have a variety of therapeutic activities like anticancer, antipsychotic, anticonvulsant, antimalarial, anti-inflammatory, antibacterial and so forth. Thus, in the present research, conjugation of moieties like 1,5-benzoxazepines and 1,5-benzothiazepines with secondary amines like piperazine, methyl piperazine and morpholine was carried out in a Mannich base with an anticipation of good anticonvulsant activity.

Objective: Synthesis, characterization, structure activity relationship and anticonvulsant activity of the Mannich bases of 1,5-benzothiazepine and 1,5-benzoxazepine derivatives.

Methods: All the derivatives were synthesized in three steps. In the first step, substituted 4-hydroxy chalconylbenzene was synthesized by the reaction of 4-hydroxyacetophenone and substituted benzaldehyde, in the presence of potassium hydroxide. In the second step, 2,3-dihydro- 1,5- benzothiazepines and 2,3-dihydro-1,5-benzoxazepines were synthesized by the reaction of 2- thio/aminophenol with chalcones in the presence of glacial acetic acid. In the third step, these compounds finally underwent Mannich reaction with different secondary amines to the respective title compounds. All the synthesized derivatives were characterised and evaluated for anticonvulsant activity using MES (Maximal Electroshock Induced Seizure) and INH (Isoniazide Induced Convulsion) models.

Results: The synthesized derivatives were found to be more active in the MES model than INH model, with phenytoin and diazepam being the standards respectively. Accordingly, the mode of action of the synthesized compounds may be similar to phenytoin. The methyl piperazine containing compound, at a dose of 30 mg/kg., was found to be the most active and promising compound in the series.

Conclusion: The benzothiazepine derivatives showed better anticonvulsant activity than the benzoxazepines derivatives.
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http://dx.doi.org/10.2174/1871524917666170717113524DOI Listing
June 2018

-TSA-promoted syntheses of 5H-benzo[h] thiazolo[2,3-b]quinazoline and indeno[1,2-d] thiazolo[3,2-a]pyrimidine analogs: molecular modeling and in vitro antitumor activity against hepatocellular carcinoma.

Drug Des Devel Ther 2017 29;11:1623-1642. Epub 2017 May 29.

Department of Pharmaceutical Sciences, Babasaheb Bhimrao Ambedkar University, Vidya Vihar, Raebareli Road, Lucknow, Uttar Pradesh.

In our efforts to address the rising incidence of hepatocellular carcinoma (HCC), we have made a commitment to the synthesis of novel molecules to combat Hep-G2 cells. A facile and highly efficient one-pot, multicomponent reaction has been successfully devised utilizing a -toluenesulfonic acid (-TSA)-catalyzed domino Knoevenagel/Michael/intramolecular cyclization approach for the synthesis of novel 5H-benzo[h]thiazolo[2,3-b]quinazoline and indeno[1,2-d] thiazolo[3,2-a]pyrimidine analogs bearing a bridgehead nitrogen atom. This domino protocol constructed one new ring by the concomitant formation of multiple bonds (C-C, C-N, and C=N) involving multiple steps without the use of any metal catalysts in one-pot, with all reactants effi-ciently exploited. All the newly synthesized compounds were authenticated by means of Fourier transform infrared spectroscopy, liquid chromatography-mass spectrometry, proton nuclear magnetic resonance spectroscopy, and carbon-13 nuclear magnetic resonance spectroscopy, together with elemental analysis, and their antitumor activity was evaluated in vitro on a Hep-G2 human cancer cell line by sulforhodamine B assay. Computational molecular modeling studies were carried out on cancer-related targets, including interleukin-2, interleukin-6, Caspase-3, and Caspase-8. Two compounds (4A and 6A) showed growth inhibitory activity comparable to the positive control Adriamycin, with growth inhibition of 50% <10 μg/mL. The results of the comprehensive structure-activity relationship study confirmed the assumption that two or more electronegative groups on the phenyl ring attached to the thiazolo[2,3-b]quinazoline system showed the optimum effect. The in silico simulations suggested crucial hydrogen bond and π-π stacking interactions, with a good ADMET (absorption, distribution, metabolism, excretion, and toxicity) profile and molecular dynamics, in order to explore the molecular targets of HCC which were in complete agreement with the in vitro findings. Considering their significant anticancer activity, 4A and 6A are potential drug candidates for the management of HCC.
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http://dx.doi.org/10.2147/DDDT.S136692DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5459977PMC
April 2018

Pharmacophore, 3D-QSAR Models and Dynamic Simulation of 1,4-Benzothiazines for Colorectal Cancer Treatment.

Comb Chem High Throughput Screen 2017 ;20(8):658-674

Department of Pharmaceutical Sciences, Babasaheb Bhimrao Ambedkar University, Vidya Vihar, Rae Bareli Road, Lucknow 226025, India.

Aim And Objective: Interleukin-6 has become an attractive protein target. This is found in the progression of colon cancer. It performs various functions in the colon cancer cells such as inflammation, activates various cell types signaling and also promotes proliferation in colon cancer cells. It is a valid target to develop anticolon cancer drug. The purpose of our study is to develop the Three-dimensional Quantitative Structure-Activity Relationship (3D-QSAR) models, pharmacophore modeling and docking study as well as MD simulation to find out the novel potent inhibitors that bind with Interleukin-6 in colon cancer treatment.

Material And Methods: In this study, common pharmacophore models and atom-based 3D-QSAR studies were carried out by using 1,4-benzothiazine derivatives with their experiential GI50values towards HT-29 human colon cancer cell line.

Results: The common pharmacophore model (ADHR26) was developed and the survival score was found to be 3.828. The generated pharmacophore-based alignment was used to develop a predictive atom-based 3D-QSAR model by using Partial Least Square (PLS) method. Phase predictable activity and LogGI50 also exhibited the most significant atomic position in the backbone structure of ligands for anticolon cancer activity. Molecular dynamic and docking studies for the IL-6 target provide key framework of ligand for the anticolon cancer activity.

Conclusion: Finally, results generated from the work data, that exhibited the pharmacophore models and 3D-QSAR hypothesis might be a path of milestone in the area of medicinal chemistry to researchers for further design of new and potent IL-6 inhibitors.
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http://dx.doi.org/10.2174/1386207320666170509153137DOI Listing
December 2018

Discovery of Novel 2-Amino-5-(Substituted)-1,3,4-Thiadiazole Derivatives: New Utilities for Colon Cancer Treatment.

Anticancer Agents Med Chem 2018 ;18(5):719-738

Department of Pharmaceutical Sciences, Babasaheb Bhimrao Ambedkar University, Vidya Vihar, Raebareli Road, Lucknow 226025, India.

Background: Colon cancer is one of the most widespread disease, the mortality rate is high due to cancer metastasis and the development of drug resistance. In this regards, new chemotherapeutic agents with specific mechanisms of action and significant effect on patient's survival are the new era for the colon cancer drug development.

Objective: The main objective of present study was to design, synthesize of a novel series of 1,3,4-thiadiazole derivatives (VR1 to VR35) and screen them against HT-29 human colon cancer cell line.

Method: Newly 1,3,4-thiadiazole scaffold were designed, synthesized and further, characterized by FTIR, NMR (1H and 13C), MS and elemental analyses. Before the synthesis, molecular dynamic simulation and ADME studies were performed to find out the most potent lead compounds. Later, SRB assay using HT-29 cells and ELISA assays were performed to explore activity and molecular targets of VR24 and VR27 and find out whether in silico data had a similar pattern in the molecular level.

Results: The results of docking study revealed that both VR24 and VR27 had interaction energy >-5 kcal/mol with various assigned molecular targets and the ligand-protein complexes were found to be stable with IL-6. The computational analysis of molecules showed good ADMET profiling. Later, the in vitro anticancer study was conducted where VR24 and VR27 were found to be active against HT-29 cells (GI50<10 µM). Finally, ELISA assays revealed that both the compounds had higher inhibition properties to various biomarker of colon cancer like IL-6 and COX-2.

Conclusion: Collectively, these result suggested that VR24 and VR27 inhibited the assigned molecular targets, imparting their ameliorative effects against colon cancer. Due to these encouraging results, we concluded that both VR24 and VR27 may be effective against colon cancer therapy in future.
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http://dx.doi.org/10.2174/1871520617666170419122916DOI Listing
June 2019

Ameliorative effects of pyrazinoic acid against oxidative and metabolic stress manifested in rats with dimethylhydrazine induced colonic carcinoma.

Cancer Biol Ther 2017 05 30;18(5):304-313. Epub 2017 Mar 30.

a Department of Pharmaceutical Sciences , Babasaheb Bhimrao Ambedkar University , Vidya Vihar, Lucknow , India.

Pyrazinoic acid (PA) is structurally similar to nicotinic acid which acts on G-protein-coupled receptor (GPR109A). GPR109A expresses in colonic and intestinal epithelial sites, and involves in DNA methylation and cellular apoptosis. Therefore, it may be assumed that PA has similar action like nicotinic acid and may be effective against colorectal carcinoma (CRC). CRC was produced via subcutaneous injection of dimethylhydrazine (DMH) at 40 mg/kg body weight once in a week for 4 weeks. After that, PA was administered orally at 2 doses of 10 and 25 mg/kg daily for 15 d to observe the antiproliferative effect. Various physiologic, oxidative stress, molecular parameters, histopathology, RT-PCR and NMR based metabolomics were performed to evaluate the antiproliferative potential of PA. Our results collectively suggested that PA reduced body weight, tumor volume and incidence no. to normal. It restored various oxidative stress parameters and normalized IL-2, IL-6, and COX-2 as compared with carcinogen control. In molecular level, overexpressed IL-6 and COX-2 genes became normal after PA administration. Again, normal tissue architecture was prominent after PA administration. Score plots of PLS-DA models exhibited that PA treated groups were significantly different from CRC group. We found that CRC rat sera have increased levels of acetate, glutamine, o-acetyl-glycoprotein, succinate, citrulline, choline, o-acetyl choline, tryptophan, glycerol, creatinine, lactate, citrate and decreased levels of 3-hydroxy butyrate, dimethyl amine, glucose, maltose, myoinositol. Further the PA therapy has ameliorated the CRC-induced metabolic alterations, signifying its antiproliferative properties. In conclusion, our study provided the evidence that PA demonstrated good antiproliferative effect on DMH induced CRC and thus demonstrated the potential of PA as a useful drug for future anticancer therapy.
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http://dx.doi.org/10.1080/15384047.2017.1310341DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5499763PMC
May 2017

Indole-fused benzooxazepines: a new structural class of anticancer agents.

Future Sci OA 2017 Mar 4;3(1):FSO168. Epub 2017 Jan 4.

Department of Pharmaceutical Sciences, Babasaheb Bhimrao Ambedkar University, Vidya Vihar, Rae Bareli Road, Lucknow 226025, India.

Aim: A new series of compounds () bearing indole-fused benzooxazepine was synthesized, characterized and evaluated for anticancer activity.

Materials & Methods: In this study, all the synthesized compounds were screened via anticancer testing on Hep-G2 cancer cell line. A computational study was carried out on cancer-related targets including IL-2, IL-6, COX-2 Caspase-3 and Caspase-8.

Results: Some of the synthesized compounds effectively controlled the growth of cancerous cells.

Conclusion: The most active compounds - , , , and - exemplify notable anticancer profile with GI <10 μg/ml. Preliminary structure-activity relationship among the tested compounds can produce an assumption that the electronegative groups at phenyl ring attached with indole-fused benzooxazepine are instrumental for the activity. Molecular docking study showed crucial hydrogen bond and π-π stacking interactions, with good ADMET profiling and molecular dynamic simulation.
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http://dx.doi.org/10.4155/fsoa-2016-0079DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5351710PMC
March 2017

H NMR-based serum metabolomics reveals erythromycin-induced liver toxicity in albino Wistar rats.

J Pharm Bioallied Sci 2016 Oct-Dec;8(4):327-334

Centre of Biomedical Research, Sanjay Gandhi Post Graduate Institute of Medical Sciences Campus, Lucknow, Uttar Pradesh, India.

Introduction: Erythromycin (ERY) is known to induce hepatic toxicity which mimics other liver diseases. Thus, ERY is often used to produce experimental models of drug-induced liver-toxicity. The serum metabolic profiles can be used to evaluate the liver-toxicity and to further improve the understanding of underlying mechanism.

Objective: To establish the serum metabolic patterns of Erythromycin induced hepatotoxicity in albino wistar rats using H NMR based serum metabolomics.

Experimental: Fourteen male rats were randomly divided into two groups ( = 7 in each group): control and ERY treated. After 28 days of intervention, the metabolic profiles of sera obtained from ERY and control groups were analyzed using high-resolution 1D H CPMG and diffusion-edited nuclear magnetic resonance (NMR) spectra. The histopathological and SEM examinations were employed to evaluate the liver toxicity in ERY treated group.

Results: The serum metabolic profiles of control and ERY treated rats were compared using multivariate statistical analysis and the metabolic patterns specific to ERY-induced liver toxicity were established. The toxic response of ERY was characterized with: (a) increased serum levels of Glucose, glutamine, dimethylamine, malonate, choline, phosphocholine and phospholipids and (b) decreased levels of isoleucine, leucine, valine, alanine, glutamate, citrate, glycerol, lactate, threonine, circulating lipoproteins, N-acetyl glycoproteins, and poly-unsaturated lipids. These metabolic alterations were found to be associated with (a) decreased TCA cycle activity and enhanced fatty acid oxidation, (b) dysfunction of lipid and amino acid metabolism and (c) oxidative stress.

Conclusion And Recommendations: Erythromycin is often used to produce experimental models of liver toxicity; therefore, the established NMR-based metabolic patterns will form the basis for future studies aiming to evaluate the efficacy of anti-hepatotoxic agents or the hepatotoxicity of new drug-formulations.
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http://dx.doi.org/10.4103/0975-7406.199339DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5314833PMC
February 2017

Bridgehead Nitrogen Thiazolo[3,2-a]pyrimidine: A Privileged Structural Framework in Drug Discovery.

Mini Rev Med Chem 2017 ;17(15):1488-1499

Department of Pharmaceutical Sciences, Babasaheb Bhimrao Ambedkar University, Vidya Vihar, Raebareli Road, Lucknow-226025. India.

Background: Thiazolopyrimidine derivatives containing bridgehead nitrogen atom are nowa- days attracting the attention of many medicinal chemists throughout the world to explore this framework for its potential. This biologically important scaffold is formed by the fusion of two aromatic rings, thiazole and pyrimidine, in such a way that one carbon atom at the ring junction is replaced by a nitrogen atom and is, therefore, being common for both the heterocyclic rings. One of the most common example of this type of fusion is thiazolo[3,2-a]pyrimidine which is being used perpetually with tremendous success in various fields of therapeutic applications.

Method: Despite the outstanding researches on thiazolo[3,2-a]pyrimidines in the literature, hardly there is a comprehensive review on the chemistry and medicinal values of present scaffold. This review is, therefore, to endow with highlights on assorted progress made over the recent past on the basis of the development of new synthetic strategies, structure of various synthesized molecules and their promising medicinal attributes.

Conclusion: In addition, we have undertaken various scientific reports in depth, to explain spectral characterization (UV, IR, Mass, NMR and X-ray crystallography) and stereochemistry, particularly of thiazolo[3,2-a]pyrimidines.
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http://dx.doi.org/10.2174/1389557517666170216142113DOI Listing
October 2017

An Updated Review on the Phytochemistry, Pharmacology, and Clinical Trials of .

Pharmacogn Rev 2016 Jul-Dec;10(20):109-114

Department of Pharmaceutical Sciences, Babasaheb Bhimrao Ambedkar University, Lucknow, Uttar Pradesh, India.

(), a perennial herb, has been used for thousands of years in ayurvedic medicine and is closely associated with prevention, treatment, and cure of various human ailments such as obesity and diabetes. A vast and wide range of chemical compounds such as polyphenols, friedelane-type triterpenes, norfriedelane-type triterpenes, eudesmane-type sesquiterpenes including various glycosides had been isolated from this plant. This review is aimed to survey the literature covering the phytochemistry and pharmacology of and to review the scientific data including active components and their multi-targeted mechanisms of action against various metabolic syndromes. We also included clinical trials related to this plant in this review. The overview would assist researchers to gather scientific information related to in future.
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http://dx.doi.org/10.4103/0973-7847.194046DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5214554PMC
January 2017

Human Metabolic Enzymes Deficiency: A Genetic Mutation Based Approach.

Scientifica (Cairo) 2016 9;2016:9828672. Epub 2016 Mar 9.

Department of Pharmaceutical Sciences, Babasaheb Bhimrao Ambedkar University, Raebareli Road, Vidyavihar, Lucknow 226025, India.

One of the extreme challenges in biology is to ameliorate the understanding of the mechanisms which emphasize metabolic enzyme deficiency (MED) and how these pretend to have influence on human health. However, it has been manifested that MED could be either inherited as inborn error of metabolism (IEM) or acquired, which carries a high risk of interrupted biochemical reactions. Enzyme deficiency results in accumulation of toxic compounds that may disrupt normal organ functions and cause failure in producing crucial biological compounds and other intermediates. The MED related disorders cover widespread clinical presentations and can involve almost any organ system. To sum up the causal factors of almost all the MED-associated disorders, we decided to embark on a less traveled but nonetheless relevant direction, by focusing our attention on associated gene family products, regulation of their expression, genetic mutation, and mutation types. In addition, the review also outlines the clinical presentations as well as diagnostic and therapeutic approaches.
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http://dx.doi.org/10.1155/2016/9828672DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4804091PMC
April 2016

Isolated flavonoids from Ficus racemosa stem bark possess antidiabetic, hypolipidemic and protective effects in albino Wistar rats.

J Ethnopharmacol 2016 Apr 8;181:252-62. Epub 2016 Feb 8.

Department of Pharmaceutical Sciences, Babasaheb Bhimrao Ambedkar University, Vidya Vihar, Raebareli Road, Lucknow 226025, India. Electronic address:

Ethnopharmacological Relevance: Ficus racemosa (FR) has been used for thousands of years in Ayurvedic system of medicine in India and is closely associated with prevention, treatment and cure of various human ailments like obesity and diabetes. It is popularly known as gular. A vast and wide range of chemical compounds like polyphenols, friedelane-type triterpenes, norfriedelane type triterpene, eudesmane-type sesquiterpene including various glycosides had been isolated from this plant. However, no detail studies related to isolation of flavonoids has been reported previously with their antidiabetic, hypolipidemic and toxicological consequences.

Aim Of The Study: The present study was undertaken to evaluate antidiabetic, hypolipidemic and toxicological assessments of flavonoids isolated from Ficus racemosa (FR) stem bark.

Materials And Methods: We isolated four flavonoids from stem bark of FR and structures were confirmed by Infrared spectroscopy (IR), Nuclear Magnetic Resonance (NMR) (both 1D and 2D), mass spectroscopy (MS). Later, these flavonoids were administered to streptozotocin (STZ) rats once in a day for a period of seven days at 100mg/kg dose. We measured blood glucose level and body weight changes at different days (1st, 3rd, 5th and 7th days). Serum lipid profiles were also estimated to investigate the hypolipidemic potential of flavonoids in the similar experiment. Various oxidative stress parameters in pancreas and liver and hepatic biomarker enzymes in plasma were also determined to investigate the toxicity potential of isolated flavonoids. Finally, we performed docking studies to find out the mechanism of action.

Results: Our results collectively suggested that four flavonoids reduced blood glucose level and restored body weight, signifying antidiabetic action. There were reduction of other lipid profile parameters and increase of high density lipoprotein (HDL) during administration of flavonoids, also signifying hypolipidemic action. Various oxidative stress biomarkers and hepatic enzymes levels were also normalized with respect to diabetic control at the same time. Docking studies revealed that isolated flavonoids showed their antidiabetic potential via binding to PPARγ and GLUT1 receptors.

Conclusion: The isolated four flavonoids demonstrated good antidiabetic, hypolipidemic and antioxidant properties in STZ diabetic rats which supported the use of FR stem bark as useful supplementary drug for future antidiabetic therapy.
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http://dx.doi.org/10.1016/j.jep.2016.02.004DOI Listing
April 2016

Antiproliferative effect of isolated isoquinoline alkaloid from Mucuna pruriens seeds in hepatic carcinoma cells.

Nat Prod Res 2016 16;30(4):460-3. Epub 2015 Mar 16.

a Department of Pharmaceutical Sciences , Babasaheb Bhimrao Ambedkar University , Vidya Vihar, Raebareli Road, Lucknow 226025 , India.

The present study was undertaken to investigate the antiproliferative action of isolated M1 (6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid) from Mucuna pruriens seeds using human hepatic carcinoma cell line (Huh-7 cells). Initially, docking studies was performed to find out the binding affinities of M1 to caspase-3 and 8 enzymes. Later, cytotoxic action of M1 was measured by cell growth inhibition (MTT), followed by caspase-3 and 8 enzymes assay colorimetrically. Our results collectively suggested that M1 had strong binding affinity to caspase-8 in molecular modelling. M1 possessed antiproliferative activity on Huh-7 cells (EC50 = 13.97 μM) and also inhibited the action of caspase-8 enzyme, signified process of apoptosis. M1 was active against Huh-7 cells that may be useful for future hepatic cancer treatment.
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http://dx.doi.org/10.1080/14786419.2015.1020489DOI Listing
October 2016