Manu Jaggi

Dabur Research Foundation, Ghazibad, Uttar Pradesh, India

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Publications (64)156.36 Total impact

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    ABSTRACT: Background: There is an increased interest in understanding the molecular mechanisms by which herbal mixtures elicit their effects with the hope that they can be translated into new anticancer therapies. A novel herbal decoction 3HX was formulated that exerted excellent anticancer activity in preclinical models, specifically AML and melanoma. The present study explored the anticancer mechanism of 3HX. Methods: Cell lines SK-MEL-2 and THP-1 were treated with 3HX followed by analysis of apoptotic markers. Angiogenesis was evaluated by proliferation, migration and VEGF estimation in human endothelial cells EA.hy926. Kinase inhibition was assessed by Z' Lyte assays. Topoisomerase II activity was determined by Kinetoplast DNA Cleavage assay. NFkB signaling assay was done using NFkB-bla THP-1. Immunostimulatory assays were done by estimation of MIP-1-α, TNF-α and IL-1-β in murine splenocytes. Anti-metastatic activity was assessed by lung colonization assay. Results: 3HX induced strong apoptotic signaling in tumor cell lines mediated by ROS generation, PS externalization, mitochondrial membrane depolarization, caspase-3 activation, DNA fragmentation and cell cycle arrest. Considerable inhibition of proliferation, migration and VEGF release was recorded in treated endothelial cells. Further inhibitory effect was observed on all the 8 kinases - AKT1 (PKB alpha), ERBB2 (HER2), FLT3, MAPK1 (ERK2), PRKCA (PKC alpha), BRAF, BRAF V599E and MAP2K1 (MEK1) with > 50% inhibition at 1:10 dilution in all except MAPK1 (ERK2). Inhibition of Topoisomerase II and NFkB signaling was also observed. 3HX also increased the levels of cytokines especially MIP-1-α and TNF-α. Metastatic assays revealed inhibition of melanoma nodule count and decrease in melanin content at 2 doses of 500 mg/kg and 250 mg/kg respectively administered orally. Conclusions: 3HX exerts anticancer action by multi-target and multi-signal pathways involving apoptosis; anti-angiogenesis; anti-metastasis; inhibition of signaling kinases, topoisomerase II and modulation of tumor microenvironment by enhancement of immune function and suppression of inflammation.
    2015 ASCO Annual Meeting; 05/2015
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    ABSTRACT: The oral absorption of etoposide is mainly limited by its active efflux out of the cells by P-glycoprotein (P-gp) and metabolized by cytochrome P450. Therefore, an attempt was aimed to investigate the effect of etoposide-loaded self-nanoemulsifying drug delivery system (SNEDDS) on the absorption of etoposide. The transport of SNE3 formulation across rat intestine was significantly (p < 0.001) higher than that of drug solution alone as well as in presence of verapamil, used as P-gp inhibitor. Results of fluorescence activating cell sorting assay showed a 61.3 ± 2.56% intracellular uptake of fluorescence marker Rhodamine B loaded in SNEDDS while plain Rhodamine B solution showed only a 15.3 ± 1.62 % uptake. Confocal laser scanning microscopy study showed significantly higher penetration i.e., 83.71 μm across the GI membrane as compared to plain Rhodamine B solution which showed penetration up to 21.67 μm. Mechanism of P-gp inhibition was confirmed by measuring ATPase activity in the DC-3F/ADX cell model. Moreover, histopathology revealed that epithelial membrane of rat intestine treated with SNE3 was free of abrasion and atrophy. The aforementioned results suggest that the inhibitory effect of SNEDDS on the activity of both P-gp and cytochrome P450 may enhance the oral absorption of etoposide.
    Journal of Drug Delivery Science and Technology 05/2015; 28. DOI:10.1016/j.jddst.2015.05.003 · 0.48 Impact Factor
  • 04/2015; 3(1). DOI:10.5599/admet.3.1.154
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    Indian journal of experimental biology 03/2015; 53(03):158-163. · 0.84 Impact Factor
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    ABSTRACT: Chyawanprash is an ayurvedic formulation used in Indian traditional medicinal system for its beneficial effect on human health. We investigated the immunostimulatory effects of Chyawanprash (CHY) using in vitro assays evaluating the secretion of cytokines such as Tumor Necrosis Factor-alpha (TNF-α), Interleukin-1beta (IL-1β) and Macrophage Inflammatory Protein-1-alpha (MIP-1-α) from murine bone marrow derived Dendritic Cells (DC) which play pivotal role in immunostimulation. The effects of CHY on phagocytosis in murine macrophages (RAW264.7) and Natural Killer (NK) cell activity were also investigated. At non-cytotoxic concentrations (20-500 μg/ml), CHY enhanced the secretion of all the three cytokines from DC. CHY also stimulated both, macrophage (RAW264.7) as well as NK cell activity, in vitro. In conclusion, the data substantiates the immunoprotective role of CHY at cellular level mediated by immunostimulation in key immune cells viz. dendritic Cells, macrophages and NK cells.
    Indian journal of experimental biology 03/2015; 53(03):158-163. · 0.84 Impact Factor
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    ABSTRACT: Imatinib mesylate has been evaluated for possible potential in treatment of colon cancer in recent times. However, due to significant reporting of P-gp expression in colon cancer, it can come across set back due to MDR. Therefore, in present work the liposomal formulation containing imatinib-bile salt conjugate was developed and investigated for its comparative performance in MDR colon cancer cellsand surface modified with hyaluronic acid for achieving low hemotoxicity with stealth characteristics. Imatinib was successfully conjugated with sodium-deoxycholate by charged conjugation and evaluated through FTIR, DSC and PXRD. The developed conjugate (IM-SD) was encapsulated in liposomes and the conditions were optimized by Box-Behnken statistical design to achieve a size of 56.56±1.23nm along with 99.11±0.89% entrapment efficiency (LIPO). The liposomes were surface modified with hyaluronic acid and the size was enhanced to 159.14±3.2nm (HA-LIPO). Flow cytometric studies demonstrated the enhanced uptake of P-gp substrate rhodamine dye in P-gp positive colo 320 colon cancer cells. In addition, an enhanced cellular internalization of HA-LIPO in CD-44 positive HT-29 and colo 320 cells indicates the targeting attributes of the hyaluronan coated liposomes. Finally, the hyaluronan coated liposomes were also found to have low opsonization activity. Copyright © 2014. Published by Elsevier B.V.
    International Journal of Biological Macromolecules 12/2014; 73. DOI:10.1016/j.ijbiomac.2014.11.026 · 2.86 Impact Factor
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    ABSTRACT: Over expression of P-glycoprotein (P-gp) in cancer cells often results in highly aggressive, multi-drug resistant (MDR) phenotype. Such tumors are very difficult to treat with conventional therapy and often lead to failure of the treatment. In this work, we fabricated surface engineered hybrid lipid nanoparticles grafted with novel AL–HA polymer by mineralization technique. AL–HA graft polymer was prepared by covalent conjugation of alendronate sodium and hyaluronic acid. Compritol ATO 888 and capmule MCM C8 hybrid lipid mix was employed to prepare irinotecan containing nanostructured lipid carrier (NLC) by using functional excipients with P-gp inhibition activity. AL–HA was successfully grafted over NLC-Ir (uncoated irinotecan loaded NLC) by calcium-assisted mineralization. HA-NLC-Ir (hyaluronic acid coated irinotecan loaded NLC) particles have a nanoscale size of 386 ± 2.2 nm along with a zeta potential value of 19.7 ± 1.2 mV. NLC-Ir as well as HA-NLC-Ir showed a slow and sustained drug release. In vitro cell line studies performed on HT-29 and Colo-320 colon cancer cells revealed a reduced IC50 even in MDR cells. Flowcytometry studies demonstrated the capability of the developed nanocarriers to deliver the P-gp substrate moieties in MDR cancer cells. Furthermore, the targeting potential of HA-NLC was confirmed by CLSM studies. The cell line studies also revealed that NLC formulation had a potential of inhibiting P-gp by affecting ATPase activity and MDR1 gene expression.
    Colloids and surfaces B: Biointerfaces 10/2014; 123. DOI:10.1016/j.colsurfb.2014.09.062 · 4.15 Impact Factor
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    ABSTRACT: Irinotecan loaded nanostructured lipid carrier (NLC-Ir) was surface decorated with hyaluronic acid graft polymer. Hyaluronic acid is a biocompatible, non-antigenic and hydrophilic, CD-44 ligand that can impart many useful features to the nanocarrier for anticancer drug delivery. The present investigation demonstrated that hyaluronic acid coated HA-NLC had significantly lower haemolytic potential as compared to uncoated NLC. Further, HA-NLC had a reduced plasma protein interaction and low macrophage uptake. The in vivo tumor targeting and pharmacodynamics efficacy of HA-NLC was studied in Ehrlich's Ascites Tumor (EAT) allograft model. Radio scintigraphic biodistribution studies revealed that HA-NLC carrier got accumulated in the tumor tissues in good proportion. Additionally, the content of radioactivity associated with tumor tissues remained constant at 2, 4 and 24h (2.41, 2.48 and 2.47%, respectively), while it got reduced in other organs. Furthermore, tumor to muscle ratio of radioactivity suggested a better accumulation of HA-NLC in tumor tissues that was significantly enhanced (P<0.05) with time. In vivo antitumor activity of hyaluronan coated HA-NLC-Ir was 5.8 and 2.6 times higher as compared to control and free drug solution respectively. Furthermore, encapsulation of irinotecan in HA-NLC-Ir nanocarrier was found to have reduced the thrombocytopenia and neutropenia associated with free irinotecan. Thus, it can be inferred that the hyaluronic acid decorated nanocarrier can provide a haemo-compatible, non-toxic and target based delivery system for the effective management of cancer. Copyright © 2014 Elsevier B.V. All rights reserved.
    Colloids and surfaces B: Biointerfaces 10/2014; 123. DOI:10.1016/j.colsurfb.2014.09.061 · 4.15 Impact Factor
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    ABSTRACT: Purpose: The purpose of this study is to build up the 3D pharmacophore of Monoacylglycerol lipase (MAGL) inhibitor and to provide the basis to design the novel and potent MAGL inhibitors. Material and Method: A 3D-QSAR study on benztriazol-1-yl carboxamide derivatives as monoacylglycerol lipase (MAGL) inhibitors was successfully performed by means of pharmacophore mapping using PHASE 3.5 module of Schrφdinger-9.4. Result: The 3D-QSAR obtained from APRRR-105 hypothesis was found to be statistically good with r2 = 0.9228 and q2 = 0.871, taking PLS factor 4. The statistical significance of the model was also confirmed by a high value of Fisher's ratio of 82.8 and a very low value of root-mean-square error (RMSE) 0.2564. Another parameter which signifies the model predictivity is Pearson R. Its value of 0.9512 showed that the correlation between predicted and observed activities for the test set compounds is excellent. Conclusion: The study suggested that one H-bond acceptor, one positive center, and proper positioning of hydrophobic groups near the distal aromatic ring C are the crucial determinants for MAGL inhibition. Thus, it can be assumed that the present QSAR analysis is enough to demonstrate MAGL inhibition with the help of APRRR-105 hypothesis and will be helpful in designing novel and potent MAGL inhibitors.
    Journal of Pharmacy & Bioallied Sciences 10/2014; 6(4):260-6. DOI:10.4103/0975-7406.142957
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    ABSTRACT: In present investigation, we developed a novel hyaluronated cationic nanostructured lipid carrier (CNLCs) which contains CPT-11/irinotecan to target CD44 biomarker which commonly overexpresses on colon cancer. The cationic core NLCs was developed by using Capmule MCM and Compritol as mix lipid phase with 150± 2.5nm particles size and 93.98±2.5% entrapment efficiency. The cationic core NLCs were coated with hyaluronic acid by ionic conjugation. The particle size of hyaluronated CNLCs was enhanced to255±4.2nm. In-vitro drug release studies revealed a slow and sustain release of the drug and a practically no leaching of coumarin-6. The confocal laser microscopy studies were performed with developed CNLCs in two CD44 overexpressing cell lines (HT-29 and Colo-320). The studies revealed marked uptake of the CNLCs by both the cell lines in just two hours. The results were comparable to the FITC conjugated CD44 antibodies. Therefore, the developed dual purpose CNLCs were found to be highly specific for CD44 biomarker. The developed formulations were found to be compatible with blood components. The MTT assay revealed that the developed particles had enhanced cytotoxicity against non-MDR as well MDR cancer cells.
    International Journal of Biological Macromolecules 09/2014; 72. DOI:10.1016/j.ijbiomac.2014.09.005 · 2.86 Impact Factor
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    ABSTRACT: The advent of Camptothecin added a new dimension in the field anticancer drug development containing quinoline motif. Quinoline scaffold plays an important role in anticancer drug development as their derivatives have shown excellent results through different mechanism of action such as growth inhibitors by cell cycle arrest, apoptosis, inhibition of angiogenesis, disruption of cell migration, and modulation of nuclear receptor responsiveness. The anti-cancer potential of several of these derivatives have been demonstrated on various cancer cell lines. In this review we have compiled and discussed specifically the anticancer potential of quinoline derivatives, which could provide a low-height flying bird's eye view of the quinoline derived compounds to a medicinal chemist for a comprehensive and target oriented information for development of clinically viable anticancer drugs.
    European Journal of Medicinal Chemistry 07/2014; 97(32). DOI:10.1016/j.ejmech.2014.07.044 · 3.45 Impact Factor
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    ABSTRACT: Monoacylglycerol lipase (MAGL) is one of the key enzymes of the endocannabinoid system (ECS). It hydrolyzes one of the major endocannabinoid, 2-arachidonoylglycerol (2-AG), an endogenous full agonist at G protein coupled cannabinoid receptors CB1 and CB2. Numerous studies showed that MGL inhibitors are potentially useful for the treatment of pain, inflammation, cancer and CNS disorders. These provocative findings suggested that pharmacological inhibition of MAGL function may confer significant therapeutic benefits. In this study, we presented hybrid ligand and structure-based approaches to obtain a novel set of virtual leads as MAGL inhibitors. The constraints used in this study, were Glide score, binding free energy estimates and ADME properties to screen the ZINC database, containing approximately 21 million compounds. A total of seven virtual hits were obtained, which showed significant binding affinity towards MAGL protein. Ligand, ZINC24092691 was employed in complex form with the protein MAGL, for molecular dynamics simulation study, because of its excellent glide score, binding free energy and ADME properties. The RMSD of ZINC24092691 was observed to stay at 0.1nm (1Å) in most of the trajectories, which further confirmed its ability to inhibit the protein MAGL. The hits were then evaluated for their ability to inhibit human MAGL. The compound ZINC24092691 displayed the noteworthy inhibitory activity reducing MAGL activity to 21.15% at 100nM concentration, with an IC50 value of 10nM.
    Bioorganic & Medicinal Chemistry Letters 06/2014; 24(16). DOI:10.1016/j.bmcl.2014.06.029 · 2.42 Impact Factor
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    02/2014; 1(1). DOI:10.14440/jbm.2014.12
  • Colloids and surfaces B: Biointerfaces 01/2014; · 4.15 Impact Factor
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    ABSTRACT: Multidrug resistance (MDR) is an area of concern for the drug developers as well as clinical practitioners. This phenomenon is putting an emance pressure on treatment modalities of many diseases as well as posing a grave danger over clinically accepted drugs as well as molecules under clinical development. P-glycoprotein (P-gp) mediated efflux of xenobiotics is one of the major mechanisms involved in MDR. Hence, an effective modulation of P-gp may restore the potential of many substrate drugs. However, the non-specific P-gp modulation may be associated with many unwanted toxic effects. Therefore, an approach involving simultaneous exploitation of P-gp modulation as well as targeted delivery in a particulate carrier system may result in a more effective MDR reversal, accompanying a safer drug profile.
    Medical Hypotheses 12/2013; 82(2). DOI:10.1016/j.mehy.2013.12.006 · 1.07 Impact Factor
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    ABSTRACT: The present study investigates the screening of the formulation components as well as evaluates the quality issues of the nanostructured lipid carriers (NLCs) for the anticancer agent, CPT-11. The Stepwise screening of the components for the preparation of NLCs requires the selection of liquid lipid or oil, based on the relative solubility of CPT-11 in different oils. Maximum solubility of the CPT-11 was found in capmul MCM-C8 (81± 0.5mg/ml). Hence, it was selected as the liquid lipid for the development of NLCs. Solid lipids gelucire 39/1, glyceryl mono stearate (GSM) and compritol ATO 888 were observed to have good affinity for the drug on systematic screening of different solid lipids. However, gelucire 39/1 and GSM were found to have lower physical compatibility (miscibility) with capmul MCM C-8. Hence, compritol ATO 888 was selected as the solid lipid phase for the preparation of NLCs. Ratio of liquid lipid (oil) to solid lipid was optimized with the intention of maximizing the oil concentration (as oil was found to have higher solubility of drug) as well as producing a lipid mix with sufficient melting point to maintain solid state. The liquid-solid lipid mixture in the ratio up to 30:70 was observed to have sufficient melting point (52.48±1.2°C). Pluronic F-68 was selected as the main surfactant for the preparation of NLCs because of its good emulsification efficacy for the solid lipid liquid mix. The optimized formulation was also evaluated for the different quality issues. PXRD data revealed that the characteristic peaks of the compritol were present in the NLC samples and there was no appreciable polymorphic change when the formulation was stored for 6 months. Electron microscopic and DLS studies proved the absence of different colloidal species. Thermal analysis by DSC revealed that the lipid particles maintained sufficiently good melting point even after nanosizing. Absence of gelation on multiple syringing and resilience for the stress provided by autoclaving further established the quality of the developed NLCs.
    International Journal of Pharmaceutics 12/2013; 461(1). DOI:10.1016/j.ijpharm.2013.12.006 · 3.65 Impact Factor
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    ABSTRACT: Abstract To develop naphthyridine derivatives as anticancer candidates, pharmacokinetic (PK) evaluations of 10 novel derivatives of 1,4-dihydro-4-oxo-1-proparagyl-1,8-naphthyridine-3-carboxamide, with potent anticancer activity were done using in vitro ADME (absorption, distribution, metabolism, excretion) and pharmacokinetic--pharmcodynamic (PK/PD) assays. Only derivatives 5, 6, 9 and 10 showed better metabolic stability, solubility, permeability, partition coefficient and cytochrome P450 (CYP) inhibition values. PK of derivatives 5, 6, 9 and 10 in rat showed comparable PK profile for derivative 5 (C0 = 6.98 µg/mL) and 6 (C0 = 6.61 µg/mL) with no detectable plasma levels for derivatives 9 and 10 at 5.0 mg/kg i.v. dose. PK/PD assay of derivatives 5 and 6 in tumor-bearing mice (TBM) showed comparable PK but tumor plasma index (TPI) of derivative 6 (4.02) was better than derivative 5 (2.50), suggesting better tumor uptake of derivative 6. Derivative 6, as lead compound, showed highest tumor growth inhibition (TGI) value of 33.6% in human ovary cancer xenograft model.
    Journal of Enzyme Inhibition and Medicinal Chemistry 10/2013; 29(5). DOI:10.3109/14756366.2013.845817 · 2.33 Impact Factor
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    ABSTRACT: The present investigation was aimed to establish a validated stability-indicating liquid chromatographic method for the estimation of etoposide (ETP) in bulk drug and self-nano emulsifying formulation. ETP was successfully separated from the degradation products formed under stress conditions on LiChrospher 100 C18 reverse-phase column (a 250 mm × 4.6 mm i.d., 5-μm particle size) using 55:45 (v/v) acetonitrile-phosphate buffer saline (pH 4.5) as the mobile phase, at a flow rate of 1.0 mL min(-1) and detection at 283 nm. The response was a linear function of analyte concentration (R(2) > 0.9997) over the concentration range of 0.05-50 μg mL(-1). The method was validated for precision, accuracy, robustness, sensitivity and specificity. The % recovery of ETP at three different levels (50%, 100% and 150%) ranged between 93.84% and 100.06% in optimized self-nano emulsifying formulation, Etosid® soft-gelatin capsule and Fytosid® injection. First-order degradation kinetics of ETP were observed under acidic and alkaline conditions. The method was also applied for the stability assessment of self-nano emulsifying formulation under accelerated conditions, the formulation was found to be stable at all storage conditions with the shelf-life of 2.37 years at 25 °C. The method holds promise for routine quality control of ETP in bulk, pharmaceutical formulations as well as in stability-indicating studies.
    Saudi Pharmaceutical Journal 08/2013; 21(1):103-11. DOI:10.1016/j.jsps.2012.01.005 · 1.28 Impact Factor
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    ABSTRACT: The purpose of this work is intended to investigate the potential of self-nanoemulsifying (SNE) drug delivery system for enhanced oral bioavailability of etoposide by P-glycoprotein (P-gp) modulation. The components of SNE formulation were optimized by their solubilization and emulsification efficiency. The ternary phase diagrams provided nanoemulsion existence ranges and the corresponding formulations were developed and evaluated via thermodynamic and dispersibility tests. The successful formulations were characterized for various parameters including time required for self-emulsification, percentage transmittance, droplet size, surface morphology, zeta potential and in vitro release. The etoposide loaded SNE9 formulation showed 2.6- and 11-fold higher permeability coefficient in apical to basolateral direction across Caco-2 monolayers as compared to the Etosid and plain drug solution, respectively. The etoposide loaded SNE9 formulation showed a higher cytotoxicity at the highest tested concentration compared to the blank SNE9 formulation and the free etoposide. Furthermore, an in vivo pharmacokinetic study of etoposide in SNE9 formulation showed 3.2- and 7.9-fold increase in relative oral bioavailability compared with that of etoposide in Etosid and drug suspension, respectively. Thus, the developed SNE drug delivery system could be a valuable tool for the effective oral delivery of etoposide.
    Journal of Biomedical Nanotechnology 07/2013; 9(7):1216-29. DOI:10.1166/jbn.2013.1613 · 5.34 Impact Factor
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    ABSTRACT: We have previously synthesized a series of 1,8-naphthyridine-3-carboxamide derivatives to identify potential anti-cancer/anti-inflammatory compounds. Three derivatives, 7-chloro-N-(3-(cyclopentylamino)-3-oxo-1-phenylpropyl)-6-fluoro-4-oxo-1-(prop-2-yn-1-yl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide (C-22), 7-chloro-N-(2-hydroxy-3-oxo-1-phenyl-3-(phenylamino)propyl)-4-oxo-1-(prop-2-yn-1-yl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide (C-31) and 7-chloro-6-fluoro-N-(2-hydroxy-3-oxo-1-phenyl-3-(phenylamino)propyl)-4-oxo-1-(prop-2-yn-1-yl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide (C-34) demonstrated high cytotoxicity against a number of cancer cell lines and inhibited secretion of IL-1-β and IL-6. In the present study, C-22, C-31 and C-34 were assessed for modulation of pro-inflammatory cytokines, TNF-α and IL-8, chemokine RANTES and NO produced by lipopolysaccharide (LPS)-treated mouse Dendritic cells (DCs). Among the 3 compounds, C-34 showed the most potent inhibition of inflammatory markers in DC model at 0.2 and 2μM. C-34 also significantly downregulated the secretion of TNF-α, IL-1-β and IL-6 by murine splenocytes and THP-1 cells against LPS induced levels. In vitro effects of C-34 on bone marrow toxicity were assessed in CFU-GM assay. Human CFU-GM population was comparatively more sensitive to C-34 (0.1-10μM) than murine CFU-GM. IC(50) values for murine and human CFU-GM were not attained. C-34 was further examined for in vivo suppression of LPS induced cytokines in a mice model. At doses ranging from 1.25 to 5mg/kg, C-34 led to significant inhibition of TNF-α, IL-1-β, IL-6 and MIP-1-α. At the highest dose of 5mg/kg, C-34 also protected LPS-treated mice against endotoxin-induced lethality. In conclusion, C-34 demonstrates anti-inflammatory activity in vitro and in vivo in addition to cytotoxic properties. This finding suggests its potential for further development as a synthetic naphthyridine derivative with dual anti-cancer and anti-inflammatory (cytokine inhibition) properties.
    International immunopharmacology 01/2013; 15(3). DOI:10.1016/j.intimp.2013.01.011 · 2.47 Impact Factor

Publication Stats

676 Citations
156.36 Total Impact Points


  • 2006–2015
    • Dabur Research Foundation
      Ghazibad, Uttar Pradesh, India
  • 2011
    • Fresenius Kabi Oncology Limited
      Гургаон, Haryana, India
  • 2007
    • CSIR - National Chemical Laboratory, Pune
      Poona, Maharashtra, India
  • 2005
    • Indian Institute of Chemical Technology
      Bhaganagar, Andhra Pradesh, India