Department Of Pharmaceutical Sciences and Natural Products

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Augmented anticancer efficacy of doxorubicin-loaded polymeric nanoparticles after oral administration in a breast cancer induced animal model
(2011) Jain, A.K.; Swarnakar, N.K.; Das, M.; Godugu, C.; Singh, R.P.; Rao, P.R.; Jain, S.
The present investigation reports an extensive evaluation of in vitro and in vivo anticancer efficacy of orally administered doxorubicin-loaded poly(lactic-co-glycolic acid) (PLGA) nanoparticles (Dox-NPs) in a breast cancer induced animal model. Spherically shaped Dox-NPs were prepared with an entrapment efficiency and particle size of 55.40 ? 2.30% and 160.20 ? 0.99 nm, respectively, and freeze-dried with 5% trehalose using stepwise freeze-drying. Cytotoxicity, as investigated on C127I cell line, revealed insignificant differences between the IC 50 of free Dox and Dox-NPs treated cells in the first 24 h, while higher cytotoxicity was demonstrated by Dox-NPs, following 72 h of incubation. Confocal laser scanning microscopy (CLSM) imaging corroborated that nanoparticles were efficiently localized into the nuclear region of C127I cells. The cellular uptake profile of Dox-NPs revealed both time and concentration dependent increases in the Caco-2 cell uptake as compared to the free Dox solution. Further, Dox-NPs significantly suppressed the growth of breast tumor in female Sprague-Dawley (SD) rats upon oral administration. Finally, orally administered Dox-NPs showed a marked reduction in cardiotoxicity when compared with intravenously injected free Dox as also evident by the increased level of malondialdehyde (MDA), lactate dehydrogenase (LDH), and creatine phosphokinase (CK-MB) and reduced levels of glutathione (GSH) and superoxide dismutase (SOD). The reduced cardiotoxicity of orally administered Dox-NPs was also confirmed by the major histopathological changes in the heart tissue after the treatments of intravenously injected free Dox and orally delivered Dox-NPs. ? 2011 American Chemical Society.
Intracellular delivery of redox cycler-doxorubicin to the mitochondria of cancer cell by folate receptor targeted mitocancerotropic liposomes
(2012) Malhi, Sarandeep Singh; Budhiraja, Abhishek; Arora, Sumit; Chaudhari, Kiran R.; Nepali, Kunal; Kumar, Raj; Sohi, Harmik; Murthy, Rayasa S.R.
Cancer cells reflect higher level of ROS in comparison to the normal cell, so they become more vulnerable to further oxidative stress induced by exogenous ROS-generating agents. Through this a novel therapeutic strategy has evolved, which involves the delivery of redox cycler-doxorubicin (DOX) to the mitochondria of cancer cell where it acts as a source of exogenous ROS production. The purpose of this study is to develop a liposomal preparation which exhibits a propensity to selectively target cancer cell along with the potential of delivering drug to mitochondria of cell. We have rendered liposomes mitocancerotropic (FA-MTLs) by their surface modification with dual ligands, folic acid (FA) for cancer cell targeting and triphenylphosphonium (TPP) cations for mitochondria targeting. The cytotoxicity, ROS production and cell uptake of doxorubicin loaded liposomes were evaluated in FR (+) KB cells and found to be increased considerably with FA-MTLs in comparison to folic acid appended, mitochondria targeted and non-targeted liposomes. As confirmed by confocal microscopy, the STPP appended liposomes delivered DOX to mitochondria of cancer cell and also showed higher ROS production and cytotoxicity in comparison to folic acid appended and non-targeted liposomes. Most importantly, mitocancerotropic liposomes showed superior activity over mitochondria targeted liposomes which confirm the synergistic effect imparted by the presence of dual ligands - folic acid and TPP on the enhancement of cellular and mitochondrial delivery of doxorubicin in KB cells. ? 2012 Elsevier B.V. All rights reserved.
Cellular uptake, intracellular trafficking and cytotoxicity of silver nanoparticles
(2012) Singh, R.P.; Ramarao, P.
Silver nanoparticles (Ag NPs) are used in consumer products and wound dressings due to their antimicrobial properties. However, in addition to toxic effects on microbes, Ag NPs can also induce stress responses as well as cytotoxicity in mammalian cells. We observed that Ag NPs are efficiently internalized via scavenger receptor-mediated phagocytosis in murine macrophages. Confocal and electron microscopy analysis revealed that internalized Ag NPs localize in the cytoplasm. Ag NPs cause mitochondrial damage, induce apoptosis and cell death. These effects were abrogated in presence of Ag ion-reactive, thiol-containing compounds suggesting the central of Ag ions in Ag NP toxicity. Quantitative image analysis revealed that intracellular dissolution of Ag NPs occurs about 50 times faster than in water. In conclusion, we demonstrate for the first time that Ag NPs are internalized by scavenger receptors, trafficked to cytoplasm and induce toxicity by releasing Ag ions. ? 2012 Elsevier Ireland Ltd.
Surfactant-assisted dispersion of carbon nanotubes: Mechanism of stabilization and biocompatibility of the surfactant
(2013) Singh, R.P.; Jain, S.; Ramarao, P.
Nanoparticles (NPs) are thermodynamically unstable system and tend to aggregate to reduce free energy. The aggregation property of NPs results in inhomogeneous exposure of cells to NPs resulting in variable cellular responses. Several types of surfactants are used to stabilize NP dispersions and obtain homogenous dispersions. However, the effects of these surfactants, per se, on cellular responses are not completely known. The present study investigated the application of Pluronic F68 (PF68) for obtaining stable dispersion of NPs using carbon nanotubes as model NPs. PF68-stabilized NP suspensions are stable for long durations and do not show signs of aggregation or settling during storage or after autoclaving. The polyethylene oxide blocks in PF68 provide steric hindrance between adjacent NPs leading to stable NP dispersions. Further, PF68 is biocompatible in nature and does not affect integrity of mitochondria, lysosomes, DNA, and nuclei. Also, PF68 neither induce free radical or cytokine production nor does it interfere with cellular uptake mechanisms. The results of the present study suggest that PF68-assisted dispersion of NPs produced suspensions, which are stable after autoclaving. Further, PF68 does not interfere with normal physiological functions suggesting its application in nanomedicine and nanotoxicity evaluation. ? 2013 Springer Science+Business Media Dordrecht.
Accumulated polymer degradation products as effector molecules in cytotoxicity of polymeric nanoparticles
(2013) Singh, R.P.; Ramarao, P.
Polymeric nanoparticles (PNPs) are a promising platform for drug, gene, and vaccine delivery. Although generally regarded as safe, the toxicity of PNPs is not well documented. The present study investigated in vitro toxicity of poly-?-caprolactone, poly(DL-lactic acid), poly(lactide-cocaprolactone), and poly(lactide-co-glycide) NPs and possible mechanism of toxicity. The concentration-dependent effect of PNPs on cell viability was determined in a macrophage (RAW 264.7), hepatocyte (Hep G2), lung epithelial (A549), kidney epithelial (A498), and neuronal (Neuro 2A) cell lines. PNPs show toxicity at high concentrations in all cell lines. PNPs were efficiently internalized by RAW 264.7 cells and stimulated reactive oxygen species and tumor necrosis factor-alpha production. However, reactive nitrogen species and interleukin-6 production as well as lysosomal and mitochondrial stability remained unaffected. The intracellular degradation of PNPs was determined by monitoring changes in osmolality of culture medium and a novel fluorescence recovery after quenching assay. Cell death showed a good correlation with osmolality of culture medium suggesting the role of increased osmolality in cell death. ? The Author 2013. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved.
Chemical profiling of ganoderma lucidum of bathinda region
(Central University of Punjab, 2013) Gill, Balraj Singh; Kumar, Sanjeev
Ganoderma lucidum is a basidiomycete's fungus with numerous pharmacological properties. The important ingredients of Ganoderma lucidum are terpenoids and polysaccharides etc. which play momentous role in immunomodulating, anti-inflammatory, anti-cancer, anti-diabetic and anti-oxidative. Mechanism of anticancer is still unrevealed. Aim of the present study was to analyse phytochemical difference in the Ganoderma lucidum growing on different hosts in Malwa region. Biomolecules play an imperative role in growth and development. Stress condition remodels the physiology, morphology and development of plant. To combat with stress, plants evolve with time and synthesize secondary metabolites. Stress tolerance ability is generated by overexpression of isoenzyme, intracellular targeting of anti-oxidants and overexpression ability of anti-oxidative enzyme. Ganoderma lucidum was analysed for different parameters such as total sugars, reducing sugars, starch, proteins, phenols, antioxidant property and flavonoids by standard procedures which was collected in different stages of development on different hosts, such as Azadirachta, Acacia, Bauhinia, Melia, and Dalbergia spp. It manifests fungus-host relationship and amount of phytoconstituent synthesized. The biochemical estimation showed 38.1±0.0481 g/100g of total sugars, 19±5.925 g/100g of reducing sugars, 57.3±3.333 g/100g of starch, 42±4.2% of proteins, 9.7±0.066% of phenols, 86.31%±5.480 scavenging activity in term of % inhibition and 5.26 ±0.6 mg/g of flavonoids. Complete analysis shows that except flavonoids all phytochemicals content was exceptionally high. Terpenoids analysis showed variation within the different hosts. Ganoderic acid, which is most active anticancerous molecule showed variation within different hosts. It can be concluded from the preliminary studies that there are variations in the chemical constituents of GL with change in host which makes it a "chemovariant"
Synethesis and biochemical screening of novel non-purine based xanthine oxidase inhibitors
(Central University of Punjab, 2013) Kumar, Deependra; Kumar, Raj
Xanthine oxidase (XO), or xanthine oxidoreductase (XOR), is a complex molybdoflavoenzyme which, in humans, is recognized as the terminal enzyme of purine catabolism, catalysing the hydroxylation of purines to uric acid, overproduction of which usually leads to a pathological condition called hyperuricemia and gout. XO inhibitors (XOI) are proved to be promising urate lowering agents. Purine based XOI (allopurinol) however, are associated with various lethal side effects like hypersensitivity syndrome (Stevens Johnson syndrome and Tissue Epidermal Necrolysis), bone marrow depression, rash etc. On the other hand non-purine based XOI (febuxostat) are found to be safer and effective antihyperuricemic and antigout agents. Present investigation describes synthesis, characterization of some non-purine based compounds and their evaluation for xanthine oxidase inhibitory activity
Recent advancements in small molecule inhibitors of insulin-like growth factor-1 receptor (IGF-1R) tyrosine kinase as anticancer agents
(2013) Negi, A.; Ramarao, P.; Kumar, R.
Advancements in understanding of the genetics, genomics, biochemistry and the pharmacology of cancer in human, have driven the current cancer chemotherapy to intently focus on development of target-based approaches rather than conventional approaches. From among the various targets identified, validated and inhibited at different hallmarks of cancer, protein tyrosine kinases (PTKs) have been exploited the most. Insulin receptors (IRs), insulin like growth factor receptors (IGF-1R) and their hybrid receptors belong to tyrosine kinase receptor (TKR) family, constitute a structural homology among them and generate a growth promoting IGF system on binding with either insulin, IGF-1 or IGF-2. The system induces the mitogenic effects through a torrent of cell signals produced as a result of cross talk with other growth promoting peptides and steroidal hormones, ultimately resulting in hijacking apoptosis and increasing cell proliferation and cell survival in cancer cells. Various strategies such as anti-IGF-1R antibodies, IGF-1 mimetic peptides, antisense strategies, IGF-1R specific peptide aptamers, targeted degradation of IGF-1R and expression of dominant negative IGF-1R mutants have been explored to inhibit the IGF-1R signaling. However, targeting IGF-1R with small molecules has gained considerable attention in last few years due to their ease of synthesis, ease of optimization of absorption, distribution, metabolism, excretion and toxicity (ADMET) parameters, oral route of administration, lesser side effects and cost effectiveness. The present review provides a broad overview and discusses the highlights on discoveries, SAR studies and binding interactions of small molecules with either IGF-1R active or allosteric sites reported till date. ? 2013 Bentham Science Publishers.
Anticancer potential of new n-acetyl pyrazoline derivatives of 1,3 diaryl/hetroaryl propenoes: Synethesis and evaluation
(Central University of Punjab, 2013) Alex, Jimi Martin; Kumar, Raj
Pyrazoles, categorized as nitrogen-containing heterocycles, are well known for their interminable participation in the field of perpetual research and development of therapeutical active agents. As a consequence pyrazoles became an inevitable core of numerous drugs having diverse activities. The broad spectrum of activities portrayed by the pyrazoles instigated the researchers to modify the pyrazole ring as 4,5-dihydro-1H-pyrazoles commonly known as 2-pyrazolines. This modification played a determining role in defining the biological activities of several compounds. The presence of aromatic/heterocyclic substituents on the pyrazoline ring only served to accentuate these activities. Literature survey also revealed that substitution such as amide group, acetyl groupetc.at N1 of the pyrazoline also played a decisive role in deciding the biological activity. The vast information obtained from literature survey stimulated us to synthesize compounds having 2-pyrazoline as the core moiety of which either the C3 or C5 was substituted with heterocyclic ring in addition to acetyl moiety at the N1 of the pyrazoline. The compounds were assessed for their anticancer potential against four cancer cell- MCF-7, H-460, T-47 D and A-549. MTT assay was carried out for testing the cell viability. The assay results revealed that certain compounds showed anticancer potential because these agents inhibited the proliferation of breast cancer cell lines but not against lung cancer cell line. Compounds showing good activity against the cancer cell lines were also evaluated for their antioxidant property especially against reactive oxygen species
In-vitro anti-mutagenic activity of Asparagus racemosus: An ayurvedic medicinal plant
(Academic Journals Inc., 2013) Singh, Ramit; Kaur, Rajbir; Arora, Saroj; Jaitak, Vikas
Asparagus racemosus is a plant traditionaly used in epilepsy, as a brain tonic, cardiac disorders, hypertension, habitual abortions, weakness of the uterus, excessive bleeding during menstruation. The current study evaluated the antimutagenic pottential of methanolic (RME) and aqueous methanolic extract (RAE) extracted from A. racemosus. Ames assay was used to acess the antimutagenic potential of RME and RAE (2.5x103, 1.0x103, 0.5x103, 0.25x103, 0.10x103 and 0.01x103 ?g 0.1 mL plate-1) that was added with mutagenic activation of TA98 and TA100 strain of Salmonella typhimurium. A. racemosus extract RME and RAE have been found to have effective in the inhibition of mutation induced by NPD and sodium azide. Among the two extracts, RAE showed maximum inhibition of 49.2% followed by RME having inhibition of 40.63% in Co-incubation mode. Current study indicated that A. racemosus can be used as a new source of anti-mutagenic. ? 2013 Academic Journals Inc.
Integrated in-vitro antioxidant and in-silico anti-apoptotic study of essential oil components of aconitum heterophyllum wall
(Central University of Punjab, 2013) Bhall, Yashika; Jaitak, Vikas
Aconitum heterophyllum Wall. is consumed for its promising medicinal properties in several parts of the world. Present study consists of hydrodistillation, antioxidant potential and in-silico antiapoptotic study of A. heterophyllum oil. Antioxidant activities were evaluated by in-vitro assays namely DPPH, Superoxide anion scavenging and CUPRAC. It was found that the anti-oxidative effect of A. heterophyllum oil was dose dependent up to 200 g/ml. For studying the apoptotic nature of the volatile constituents, in silico studies were carried out using BCL-2 anti-apoptotic receptors (BCL-2, BCL-XL, MCL-1). To understand the cascade of mechanisms leading to apoptosis, NF-?B was also considered. From the comparative study of the constituents with that of the standard inhibitor it has been observed that the constituents show favorable binding affinity for the receptors as in the case of BCL-2 receptor, ?--longipinene has a dock score of -4.26 kcal/mol as comparable to that of standard inhibitor ABT 263 (-4.67 kcal/mol); BCL-XL receptor, neryl acetate has a dock score of -4.05 kcal/mol as compared to ABT 737 (standard inhibitor) which was -9.47 kcal/mol. Best results were observed in the case of NF-?B with ?-fenchol, having the dock score of -4.36 kcal/ mol which shows higher binding affinity of the ?-fenchol molecule for the receptor site as compared to the selective inhibitors parthenolide whose dock score was -3.04 kcal/ mol. In summary, based on our in silico and in vitro results, it can be postulated that essential oil of A.heterophyllum could be used as functional antiapoptotic inhibitor and as natural antioxidant.
In-vitro guided fractionation of crude root extracts of potentilla atrosanguinea lodd and in-silico of polyphenolic compounds
(Central University of Punjab, 2013) Gupta, Vinay Kumar; Jaitak, Vikas
Modern therapeutic system is a kind of inspiration from traditional plant based medicine used for various diseases and ailments. Advancement in drug discovery technology including computational drug design and bioassay guided fractionation emboldens the interest of Medicinal Chemists? concerning to lead identification from medicinal plants for complicated diseases, in the last few years. There are so many traditional plants which are used in the treatment of various diseases in different parts of our country but scientific information is missing for the same. Potentilla atrosanguinea is a native to the western Himalaya region has been used traditionally for the treatment of wound-healing, diarrhea, influenza and bleeding but there is not even a single published evidence about its activity accept antioxidant activity of aerial part. In this context, the aim of the present study was to explore the roots of P.atrosanguinea in terms of its medicinal value for instances in-vitro photoprotective and antioxidant activity. The photoprotective activity was evaluated in the term of SPF (sun protection factor) by spectrophotometric method in the range of 290-320 nm (UVB region) whereas antioxidative activity was evaluated using a free radical scavenging assay (DPPH, superoxide anion scavenging and CUPRAC). Total phenolic contents of the extract/fractions were v determined by Folin Ciocalteu reagent. The ability of photo-protection of different fraction against UVB region followed the trend Pa-AcOEt > Pa- n-BuOH > Pa-H2O-MeOH > Pa-H2O. Ethyl acetate fraction of Potentilla atrosanguinea indicated the highest sun protection factor (SPF) (7.319 ' 0.353) at a concentration of 120 ?g/ml. IC50 values of aqueous methanolic (Pa-H2O-MeOH) and ethyl acetate fraction (Pa-AcOEt) for DPPH assay was comparable as that of rutin (80 ?g/ml). Superoxide anion scavenging activity of all fractions was found to be excellent than standard (IC50 150 ?g/ml). Calculated IC50 value for the aqueous-methanolic, ethyl acetate, n-butanol (Pa- n-BuOH) and aqueous fractions (Pa-H2O) were 60, 70, 90 and 140 ?g/ml respectively. In CUPRAC assay percentage reduction capacity of the aqueous methanolic crude extract was highest among all other fractions. Total phenol contents of aqueous methanol extract and ethyl acetate fraction were almost comparable and indicated high phenol content. Results indicated the importance of ethyl acetate extract of P. atrosanguinea as a photoprotective agent in sunscreen preparation in the pharmaceutical industry and natural antioxidants as well. Further isolation of molecules from ethyl acetate fraction was performed using column chromatography which led to the isolation of total seven molecules out of them two were characterized namely methyl pentatetraconta-30, 32, 34, 36, 38, 40, 42-heptaenoate (VVR-I) and pentadecyl butyrate (VVR-III). VVR-I is novel compound while VVR-II is already reported in literature. Moreover, in-silico study of already reported polyphenolic compounds which are considered to be anticancer agents were also carried out using Glide docking to investigate interaction pattern with MDR receptors (MRP1 and GSTP-1) involved in cancer chemotherapy. In-silico findings suggest that rutin may be used as dual modulator for MRP-1 and GSTP1-1 mediated multidrug resistance
Recent Advancements in Small Molecule Inhibitors of Insulin–like Growth Factor-1 Receptor (IGF-1R) Tyrosine Kinase as Anticancer agents
(Bentham Science, 2013) Negi, Arvind; Ramarao, P.; Kumar, Raj
Advancements in understanding of the genetics, genomics, biochemistry and the pharmacology of cancer in human, have driven the current cancer chemotherapy to intently focus on development of target-based approaches rather than conventional approaches. From among the various targets identified, validated and inhibited at different hallmarks of cancer, protein tyrosine kinases (PTKs) have been exploited the most. Insulin receptors (IRs), insulin like growth factor receptors (IGF-1R) and their hybrid receptors belong to tyrosine kinase receptor (TKR) family, constitute a structural homology among them and generate a growth promoting IGF system on binding with either insulin, IGF-1 or IGF-2. The system induces the mitogenic effects through a torrent of cell signals produced as a result of cross talk with other growth promoting peptides and steroidal hormones, ultimately resulting in hijacking apoptosis and increasing cell proliferation and cell survival in cancer cells. Various strategies such as anti-IGF-1R antibodies, IGF-1 mimetic peptides, antisense strategies, IGF-1R specific peptide aptamers, targeted degradation of IGF-1R and expression of dominant negative IGF- 1R mutants have been explored to inhibit the IGF-1R signaling. However, targeting IGF-1R with small molecules has gained considerable attention in last few years due to their ease of synthesis, ease of optimization of absorption, distribution, metabolism, excretion and toxicity (ADMET) parameters, oral route of administration, lesser side effects and cost effectiveness. The present review provides a broad overview and discusses the highlights on discoveries, SAR studies and binding interactions of small molecules with either IGF-1R active or allosteric sites reported till date.
Anticancer activity of essential oils: A review
(2013) Bhalla, Yashika; Gupta, Vinay Kumar; Jaitak, Vikas
Natural essential oil constituents play an important role in cancer prevention and treatment. Essential oil constituents from aromatic herbs and dietary plants include monoterpenes, sesquiterpenes, oxygenated monoterpenes, oxygenated sesquiterpenes and phenolics among others. Various mechanisms such antioxidant, antimutagenic and antiproliferative, enhancement of immune function and surveillance, enzyme induction and enhancing detoxification, modulation of multidrug resistance and synergistic mechanism of volatile constituents are responsible for their chemopreventive properties. This review covers the most recent literature to summarize structural categories and molecular anticancer mechanisms of constituents from aromatic herbs and dietary plants. ? 2013 Society of Chemical Industry.
Cystathionine β-Lyase-Like Protein with Pyridoxal Binding Domain Characterized in Leishmania major by Comparative Sequence Analysis and Homology Modelling
(Hindawi, 2013) Negi, Arvind; Bhushan, Satej; Gupta, Pawan; Garg, Prabha; Kumar, Raj
Cystathionine β-lyase-like protein (CBLP), one of the key enzymes involved in methionine biosynthesis utilising pyridoxal phosphate (PLP) as a cofactor, has recently been reported in Leishmania major. Its presence in the parasite and absence in humans warrant its full characterisation and fruition as a potent, selective, and inevitable druggable target. Due to the unavailability of X-ray 3D structure of CBLP, a homology model for this protein was developed for the first time. The model was evaluated for PLP binding site and various conserve domain residues of the protein recommended by comparative sequence analyses by different protein analysis tools. The model was validated and discovered to be robust and statistically significant. The final model was superimposed on template of Arabidopsis thaliana (PDB ID: 1IBJ) and RMSD was found to be 0.486. The PLP binding site residues of both the proteins were ensued to be highly conserved indicated by Gly71, Met72, Tyr95, Asp169, and Ser193 as well as formation of aldimine bond with Lys194. This was further verified through molecular simulation of PLP into the cofactor binding site of the modelled protein. The present study may therefore play a directing role in the designing of novel, potential, and selective antileishmanial agents.
Phytochemical investigation in vitro anti-mutagenic activity of potentilla fulgens lodd and silico study of flavonoids with CDK-2,CDK-6 receptors
(Central University of Punjab, 2013) Monga, Prakriti; Jaitak, Vikas
Plants have been used for thousand years in the treatment of various diseases. Plant secondary metabolites have proved to be an excellent source of new medicinal compounds. They offer protection against variety of chronic diseases including diabetes, cardiovascular diseases, obesity and cancer. Mutation is an important factor that is linked to carcinogenesis. It has been found that occurrence of cancer can be reduced by decreasing the incidence or rate of mutation. Plants are promising source of antimutagens agents which are present in them as secondary metabolites such as flavonoids, alkaloids, terpenoids, glycosides etc. Potentilla fulgens is an important medicinal plant of higher Himalayas that is known globally for its therapeutic importance. A number of antioxidant constituents have been reported from the plant which mainly consists of polyphenolic compounds. It has been observed that diet rich in polyphenolic compounds such as flavonoids can reduce the risk of cancer. P.fulgens reported to have polyphenolic compounds such as flavonoids which are potent bioactive molecules that possess anticarcinogenic effects as they can interfere with initiation, development and progression of cancer by the modulation of cell cycle, apoptosis, and angiogenesis. Anti-mutagenic activity on different fractions of P.fulgens was carried out, which indicates that n-butanol and water fractions of the plant are strongly anti-mutagenic. Inhibitory activity for n-butanol fraction was 60.4% and 35.4% in co-incubation and pre-incubation respectively in TA 98 tester strains while 55.6% and 62.0% inhibition was observed in TA100 tester strains respectively for co and pre-incubation. For water fraction 56.6% and 60.7% inhibitory activity in co-incubation and pre-incubation mode of treatment respectively against TA98 strain and 34.5% and 50.6% inhibition in TA100 strain for co-incubation and pre-incubation treatment respectively. Results specify the importance of P.fulgens as a new source of anti-mutagenic agents. Isolation of molecules from ethyl acetate and n-butanol v fractions led to the characterisation of one molecule namely catechin out of total six isolated molecules. In-silico study of various reported flavonoids were performed on CDK-2, CDK-6 as these receptors are linked to cell cycle and mutation in cell cycle may lead to cancer. In-silico study indicates that natural as well as synthetic flavonoid molecules can be considered as a treatment for cancer by inhibiting CDK-2 and CDK-6 receptors.
Medicinal attributes of pyrazolo[3,4-d]pyrimidines: A review
(2013) Chauhan, Monika; Kumar, Raj
Pyrazolopyrimidines are the fused heterocyclic ring systems which structurally resemble purines which prompted biological investigations to assess their potential therapeutic significance. They are known to play a crucial role in numerous disease conditions. The advent of their first bioactivity as adenosine antagonistic property divulged their medicinal potential. Radioactivity test on mice cells, morphometric and serological tests on rat hepatocytes, antitumor testing against L1210 and P388 leukemias in mice threw light on their biophysical aspects of significance. Biochemical properties were explored via xanthine oxidase assay, antioxidant enzyme assays, Western blot analysis, mRNA expression of apoptopic genes, receptor binding assays, and tryptan blue exclusion cytotoxicity evaluation. The collective results of biochemical and biophysical properties foregrounded their medicinal significance in central nervous system, cardiovascular system, cancer, inflammation etc. The present manuscript to the best of our knowledge is the first compilation on synthesis and medicinal aspects including structure-activity relationships of pyrazolo[3,4-d]pyrimidines reported to date. ? 2013 Elsevier Ltd. All rights reserved.
Phytochemical investigation and biological evaluation of secondary metabolites from asparagus racemosus l through in-vitro and in-silico approach
(Central University of Punjab, 2013) Singla, Ramit; Jaitak, Vikas
Nature has been a source of medicinal products for millennia, and with many useful drugs developed from different natural resources, with majority of drugs are from plant origin. Asparagus racemosus belonging to family liliaceae, is one such important medicinal plant. This plant species is used traditionally in India and other parts of the world in epilepsy, Vaat disorders, brain tonic, hypertension, hepatoprotection, immunostimulant and antiabortifacient. In this context, the aim of the present study was to explore the roots of A.racemosus in terms of its medicinal values for instances antimutagenic, and advanced glycation end-product inhibitor. Antimutagenic activity of different extracts were evaluated using Ames test. A. racemosus methanolic extract (RME) and aqueous extract (RAE) have been found to have effective in the inhibition mutation induced by NPD and sodium azide. Among the two extracts, RAE and RME showed maximum inhibition of 49.2%, and 40.63% in Co-incubation mode respectively. The inhibition of BSA-glucose for the determination of antiglycation activity showed that the inhibition varied significantly among different extracts of A. racemosus. The highest inhibition measured by BSA-glucose was observed for (Ethyl acetate extract) REE (IC50 37.56 ± 1.65 ?g/mL) followed by (methanolic extract) RME (IC50 51.32 ± 1.48 ?g/mL). Isolation of molecules from methanol extract led to the characterisation of one molecule v namely nyasol out of total seven isolated molecules. The molecular docking study of isolated molecule Nyasol displayed strong binding affinity with estrogen receptor ? and estrogen receptor ?, indicating that Nyasol is beneficial in hormone responsive breast cancer. Moreover, in-silico study of already reported phytoestrogens from A.racemosus was also carried out using Glide docking to investigate interaction pattern with Human placental estrone sulphatases (1P49), human 17?-hydroxysteroid-dehydrogenase type 1 (1FDS), human glucose 6-phosphate dehydrogenase (2BH9) and tubulin protein receptors. The top docking score was obtained for rutin (estrogen receptor ?), 3,6,4'-trimethoxy-7-O-?-D-glucopyranosyl [1?4]-O-?-D-xylopyranoside glucopyranpsyl (HSP90), 8-Methoxy-5,6,4-trihydroxyisoflavone-7-O-?-D-glucopyranoside (human placental estrone sulphatase), Shatavarin X (17?-hydroxydehydrogenase`), Racemoside A (Glucose-6-phosphate dehydrogenase), Immunoside (Colchicine binding site of tubulin). The results indicated that phytoestrogens are likely potential candidate for controlling tumor progression with a special emphasis in breast cancer progression.
Imidazole based compunds: Synethesis and in vitro anticancer screening
(Central University of Punjab, 2013) Negi, Arvind; Kumar, Raj
Imidazole is an important five-membered aromatic heterocycle widely present in natural products and synthetic molecules. The unique structural feature of imidazole ring with desirable electron rich characteristic is beneficial for imidazole derivatives to readily bind with a variety of enzymes and receptors in biological systems through diverse weak interactions, thereby exhibiting broad bioactivities. Numerous imidazole-based compounds are in being used extensively in the clinics to treat various types of diseases. We have synthesized, designed and evaluated imidazole-based compounds for anti-proliferative activity against A-549 and Hep-G2 human cancer cell lines. Further the free radical scavenging activity of the selected compounds was performed in order to observe their antioxidant potential (if any). The combined results have shown advent of their first in vitro bioactivity as anticancer and antioxidant compounds and revealed their medicinal potential. The synthetics offer the scope for generation of a library of compounds and their evaluation against a panel of cancer cell lines, studies on structure activity relationship, tracing their molecular mechanism(s) in addition to their development at preclinical level in future.
1-Acetyl-3,5-diaryl-4,5-dihydro(1H)pyrazoles: Exhibiting anticancer activity through intracellular ROS scavenging and the mitochondria-dependent death pathway
(Wiley-VCH Verlag, 2014) Alex, Jimi M.; Singh, Sandeep; Kumar, Raj
A series of 17 analogs of 1-acetyl-4,5-dihydro(1H)pyrazoles (JP-1 to JP-17) bearing two aromatic rings at positions 3 and 5, either of which ought to be heterocyclic, were synthesized and evaluated for their anti-proliferative potential against breast cancer (MCF-7 and T-47D) and lung cancer (H-460 and A-549) cell lines for the first time. JP-1-7, -10, -11, -14, and -15 were observed to exhibit significant anti-proliferative activity against MCF-7 cells. Some notions about structure-activity relationships are reported. The investigated compounds were found to lower the intracellular reactive oxygen species in the H2DCFDA assay and also caused mitochondria-dependent cell death in the MCF-7 cell line, indicating a plausible mechanism of their anticancer effect. Analogs of 1-acetyl-4,5-dihydro(1H)pyrazoles (JP-1-17) were synthesized and evaluated for their anti-proliferative activity in four cancer cell lines and for their intracellular ROS scavenging properties. An attempt was made to determine the mitochondrial membrane potential of MCF-7 cells treated with JP-1 and -14, aiming to elucidate the mechanism by which proliferation was curbed. ? 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.