Browsing by Author "Kumar, Raj"

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1-Acetyl-3, 5?diaryl-4, 5?dihydro (1H) pyrazoles: Exhibiting Anticancer Activity through Intracellular ROS Scavenging and the Mitochondria-Dependent Death Pathway
(Wiley, 2014) Alex, JM; Singh, S; 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.
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.
2-(2-Arylphenyl) benzoxazole As a Novel Anti-Inflammatory Scaffold: Synthesis and Biological Evaluation
(ACS publications, 2014) Seth, Kapileswar; Garg, Sanjeev K.; Kumar, Raj; Purohit, Priyank; Meena, Vachan S.; Goyal, Rohit; Banerjee, Uttam C.; Chakraborti, Asit K.
The 2-(2-arylphenyl)benzoxazole moiety has been found to be a new and selective ligand for the enzyme cyclooxygenase-2 (COX-2). The 2-(2-arylphenyl)benzoxazoles 3a−m have been synthesized by Suzuki reaction of 2-(2-bromophenyl)benzoxazole. Further synthetic manipulation of 3f and 3i led to 3o and 3n, respectively. The compounds 3g, 3n, and 3o selectively inhibited COX-2 with selectivity index of 3n much better than that of the COX-2 selective NSAID celecoxib. The in vivo anti-inflammatory potency of 3g and 3n is comparable to that of celecoxib and the nonselective NSAID diclofenac at two different doses, and 3o showed better potency compared to these clinically used NSAIDs.
4,5-Dihydro-1H-pyrazole: An indispensable scaffold
(Informa Healthcare, 2014) Alex, Jimi Marin; 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. The present review is a concerted effort to retrace compounds covered from 2009-till date which owe diverse biological activities to the 2-pyrazoline scaffold and also condenses the retro-synthetic approaches employed for their synthesis. This endeavor culminated in revelation that inhibitory potential varied when the substituents in particular N-substituents of 2-pyrazolines were altered. ? 2014 Informa UK Ltd.
ALK and ERBB2 Protein Inhibition is Involved in the Prevention of Lung Cancer Development by Vincamine
(Bentham Science Publishers, 2023-04-13T00:00:00) Verma, Aarti; Yadav, Poonam; Rajput, Sonu; Verma, Saloni; Arora, Sahil; Kumar, Raj; Bhatti, Jasvinder Singh; Khurana, Amit; Navik, Umashanker
Background: According to the WHO report of 2022, 2.21 million new cases and 1.80 million deaths were reported for lung cancer in the year 2020. Therefore, there is an urgent need to explore novel, safe, and effective therapeutic interventions for lung cancer. Objective: To find the potential targets of vincamine using a network pharmacology approach and docking studies and to evaluate the anti-cancer effect of vincamine on A549 cell line. Methods: Hence, in the present study, we explored the anti-cancer potential of vincamine by using network pharma-cology, molecular docking, and in vitro approaches. Network pharmacology demonstrated that the most common targets of vincamine are G-protein coupled receptors, cytosolic proteins, and enzymes. Among these targets, two targets, ALK and ERBB2 protein, were common between vincamine and non-small cell lung cancer. Results: We discovered a link between these two targets and their companion proteins, as well as cancer-related pathways. In addition, a docking investigation between the ligand for vincamine and two targeted genes revealed a strong affinity toward these targeted proteins. Further, the in vitro study demonstrated that vincamine treatment for 72 h led to dose-dependent (0-500 ?M) cytotoxicity on the A549 lung cancer cell line with an IC50 value of 291.7 ??. The wound-healing assay showed that vincamine treatment (150 and 300 ?M) significantly inhibited cell migration and invasion. Interestingly, acridine orange/ethidium bromide dual staining demonstrated that vincamine treatment induces apoptosis in A549 cells. Additionally, the dichloro-dihydro-fluorescein diacetate (DCFH-DA) assay showed an increased level of reactive oxygen species (ROS) after the vincamine treatment, indicating ROS-mediated apoptosis in A549 cells. Conclusion: Altogether, based on our findings, we hypothesize that vincamine-induced apoptosis of lung cancer cells via ALK and ERBB2 protein modulation may be an attractive futuristic strategy for managing lung cancer in combination with chemotherapeutic agents to obtain synergistic effects with reduced side effects. � 2023 Bentham Science Publishers.
Anticancer activity of dihydropyrazolo[1,5-c]quinazolines against rat C6 glioma cells via inhibition of topoisomerase II
(Wiley-VCH Verlag, 2018) Kaur, G.; Cholia, R.P.; Joshi, G.; Amrutkar, S.M.; Kalra, S.; Mantha, Anil K.; Banerjee, U.C.; Kumar, Raj
The design and synthesis of dihydropyrazolo[1,5-c]quinazolines (1a?h) as human topoisomerase II (TopoII) catalytic inhibitors are reported. The compounds were investigated for their antiproliferative activity against the C6 rat glial cell line. Two compounds, 1b and 1h, were found to be potent cytotoxic agents against glioma cells and exerted selective TopoII inhibitory activity. Furthermore, the compounds induced alterations in reactive oxygen species levels as measured by DCFDA assay and were found to induce cell cycle arrest at the G1 phase at lower concentrations and profound apoptosis at higher concentrations. The interaction of selected investigational molecules with TopoII was further corroborated by molecular modeling. ? 2018 Deutsche Pharmazeutische Gesellschaft
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
Antiproliferative Activity of Chloroform and Methanol Extracts of Piper attenuatum (Buch-Ham)
(Central University of Punjab, 2018) Pathak, Neha; Kumar, Raj
Indian traditional medicinal plant Piper attenuatum (Buch-Ham) has been investigated for its antiproliferative activity. Dried powder of fruits of Piper attenuatum (Buch-Ham) was subjected to maceration to prepare various extracts using different solvents in the order of increasing polarity. In vitro antiproliferative activity of all the extract was carried out using MTT assay against MDA-MB-231(Breast cancer) cell line. The Chloroform and Methanol extracts were found to be the most active fractions. The results from MTT assay of isolated compounds from Chloroform extract, NP7C was found to be the most potent antiproliferative agent with IC50 value of 3.83 ?M which is comparable to etoposide 2.37 ?M. Compound NP7L also exhibit significant antiproliferative activity (IC50 of 6.44 ?M) which was comparable to colchicine (IC50 = 6.3 ?M). Thus, the present study indicated that isolated compounds of Piper attenuatum (Buch-Ham) possess great potential to be developed as anticancer agent in future.
Association of CYP2C19*2 and ALDH1A1*1/*2 variants with disease outcome in breast cancer patients: results of a global screening array
(Springer Verlag, 2018) Kalra, Sourav; Kaur, Raman Preet; Ludhiadch, Abhilash; Shafi, Gowhar; Vashista, Rajesh; Kumar, Raj; Munshi, Anjana
Purpose: Cyclophosphamide and doxorubicin (adjuvant chemotherapy) are commonly used to treat breast cancer patients. Variation in the genes involved in pharmacodynamics and pharmacokinetics of these drugs plays an important role in prediction of drug response and survival. The present study was carried out with an aim to evaluate the variation in all the genes involved in pharmacokinetic and pharmacodynamics pathways of cyclophosphamide and doxorubicin, and correlate specific variants with disease outcome in breast cancer patients from the Malwa region of Punjab. Methods: A total of 250 confirmed breast cancer patients were involved in the study. Genotyping was performed on an Illumina Infinium HD assay platform using a Global Screening Array (GSA) microchip. GenomeStudio (Illumina, Inc.) was used for data preprocessing and a p value less than or equal to 5 ? 10?8 was considered statistically significant. To rule out the influence of confounding risk factors, a step-wise multivariate regression analysis was carried out to evaluate the association of genotype with overall clinical outcome. Results: Two gene variants, CYP2C19 (G681A) and ALDH1A1*2 (17 bp deletion), were found to be significantly associated with the disease outcome, including overall survival, recurrence and metastasis, in breast cancer patients on adjuvant therapy. Both these genes are involved in the pharmacokinetics of cyclophosphamide. However, none of the variants in the genes involved in pharmacokinetics and pharmacodynamics of doxorubicin were found to have any significant impact on disease outcome in the studied group. Conclusion: CYP2C19 (G681A) variant and ALDH1A1*2 emerged as two important biomarkers associated with bad outcome in breast cancer patients on adjuvant therapy. ? 2018 Springer-Verlag GmbH Germany, part of Springer Nature
Association of CYP2C19*2 and ALDH1A1*1/*2 variants with disease outcome in breast cancer patients: results of a global screening array.
(Springer, 2018) Kalra, Sourav; Ludhiadch Abhilash; Shafi, Gowhar; Vashista, Rajesh; Kumar, Raj; Munshi, Anjana
Cyclophosphamide and doxorubicin (adjuvant chemotherapy) are commonly used to treat breast cancer patients. Variation in the genes involved in pharmacodynamics and pharmacokinetics of these drugs plays an important role in prediction of drug response and survival. The present study was carried out with an aim to evaluate the variation in all the genes involved in pharmacokinetic and pharmacodynamics pathways of cyclophosphamide and doxorubicin, and correlate specific variants with disease outcome in breast cancer patients from the Malwa region of Punjab.
Biodegradable nanoparticulate co-delivery of flavonoid and doxorubicin: Mechanistic exploration and evaluation of anticancer effect in vitro and in vivo
(Elsevier Ltd, 2021-07-30T00:00:00) Khan, Iliyas; Sarkar, Bibekananda; Joshi, Gaurav; Nakhate, Kartik T.; Ajazuddin; Mantha, Anil K.; Kumar, Raj; Kaul, Ankur; Chaturvedi, Shubhra; Mishra, Anil K.; Gupta, Umesh
The proposed study involves delivering drug/bioactive using a single nanoplatform based on poly lactic-co-glycolic acid (PLGA) for better efficacy, synergistic effect, and reduced toxicity. PLGA was conjugated to doxorubicin (D1), and this conjugate was used for encapsulation of naringenin (D2) to develop naringenin loaded PLGA-doxorubicin nanoparticles (PDNG). The PDNG NPs were 165.4 � 4.27 nm in size, having 0.112 � 0.035 PDI, with -10.1 � 2.74 zeta potential. The surface morphology was confirmed through transmission electron microscopy (TEM) and atomic force microscopy (AFM). The in vitro studies revealed that PDNG NPs exhibited selective anticancer potential in breast cancer cells, and induced apoptosis with S-phase inhibition via an increase in intrinsic reactive oxygen species (ROS) and altering the mitochondrial potential. The results also signified the efficient uptake of nanoparticles encapsulated drugs by cells besides elevating the caspase level suggesting programmed cell death induction upon treatment. In vivo studies results revealed better half-life (27.35 � 1.58 and 11.98 � 1.21 h for doxorubicin and naringenin) with higher plasma drug concentration. In vivo biodistribution study was also in accordance with the in vitro studies and in line with the in vivo pharmacokinetic. In vivo tumor regression assay portrayed that the formulation PDNG halts the tumor growth and lessen the tumor volume with the stable bodyweight of the mice. Conclusively, the dual delivery approach was beneficial and highly effective against tumor-induced mice. � 2021 The Author(s)
C-N and N-N bond formation via reductive cyclization: Progress in cadogan/cadogan-sundberg reaction
(Wiley-Blackwell, 2018) Kaur, M.; Kumar, Raj
Cadogan/Cadogan-Sundberg cyclization reaction has been reported as one of the most efficient routes for the synthesis of a wide variety of N-heterocycles from the easily accessible starting materials such as o-nitrobiaryls or o-nitroarenes, onitrostyrenes by treating with tetravalent phosphorus compounds (trialkyl or triaryl phosphines or trialkyl phosphites). The reaction has been successfully employed in Carbon-Carbon as well as Carbon-Nitrogen bond formation for the scaffolds like carbazole, indoles, coumarins, and indazoles. To the best of authors'knowledge, the present review is the first compilation of the literature from almost two decades (2000 to present) on Cadogan/Cadogan-Sundberg cyclization reaction, its scope, mechanistic aspects, and limitations.
A comprehensive review on bioactive fused heterocycles as purine-utilizing enzymes inhibitors
(Birkhauser Boston, 2015) Chauhan, Monika; Kumar, Raj
Purine-utilizing enzymes (PUEs) are involved in the control of biological actions of nitrogen-containing bases, purines and pyrimidines, by participating in their catabolism, and this has made them a topic of considerate interest. The heterocyclics, as purine-utilizing enzyme inhibitors (PUEIs), play a vital role in a number of diseases, e.g., malaria, cancer, rheumatoid arthritis, inflammation, tissue rejection, and autoimmune disorders. The present review is first of its kind covering the literature up to 2014 on the advances in broad-spectrum medicinal activities exhibited by heterocycles as PUEIs. The drug designing of the purine and pyrimidine antimetabolites is based on the structural mimicking of the existing compounds. The basic consideration during the designing of this class is the introduction of small structural changes without the alteration of basic skeleton of pharmacophore. The balance between the existing empirical approach and rational approach is yet to be maintained during the design and synthesis of new PUEIs by combining in vivo, in vitro, and in silico methods. The data compiled in the present manuscript on SARs, IC50s, Kis, Km, in silico studies, and their reported X-ray co-crystal structures with PUEs will offer the researchers the rational approaches for the design and development of selective and specific PUEIs devoid of adverse effects. ? 2014 Springer Science+Business Media.
Current insights and molecular docking studies of HIV-1 reverse transcriptase inhibitors
(John Wiley and Sons Inc, 2023-10-12T00:00:00) Singh, Ankit Kumar; Kumar, Adarsh; Arora, Sahil; Kumar, Raj; Verma, Amita; Khalilullah, Habibullah; Jaremko, Mariusz; Emwas, Abdul-Hamid; Kumar, Pradeep
Human immunodeficiency virus (HIV) causes acquired immunodeficiency syndrome (AIDS), a lethal disease that is prevalent worldwide. According to the Joint United Nations Programme on HIV/AIDS (UNAIDS) data, 38.4 million people worldwide were living with HIV in 2021. Viral reverse transcriptase (RT) is an excellent target for drug intervention. Nucleoside reverse transcriptase inhibitors (NRTIs) were the first class of approved antiretroviral drugs. Later, a new type of non-nucleoside reverse transcriptase inhibitors (NNRTIs) were approved as anti-HIV drugs. Zidovudine, didanosine, and stavudine are FDA-approved NRTIs, while nevirapine, efavirenz, and delavirdine are FDA-approved NNRTIs. Several agents are in clinical trials, including apricitabine, racivir, elvucitabine, doravirine, dapivirine, and elsulfavirine. This review addresses HIV-1 structure, replication cycle, reverse transcription, and HIV drug targets. This study focuses on NRTIs and NNRTIs, their binding sites, mechanisms of action, FDA-approved drugs and drugs in clinical trials, their resistance and adverse effects, their molecular docking studies, and highly active antiretroviral therapy (HAART). � 2023 John Wiley & Sons Ltd.
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.
Design and synethesis of APE1 inhibitors as putative anticancer agents
(Central University of Punjab, 2014) Kaur, Gagandeep; Kumar, Raj
Success in chemotherapy has not been attained completely yet and has remained a worried issue from years. Various reasons drive this failure, but the much talked about is failure due to emergence of resistance to chemotherapeutic drugs due to various factors. One of the major reasons here we have targeted is the resistance developed against DNA damaging chemotherapy due to over activation of APE1 enzyme evolved in BER pathway, which is the major repair pathway responsible for 95% of the DNA repair. Design and synthesis of APE1 inhibitors using rational approach fulfilling the pharmacophoric requirements has been carried out in this research work. Molecular modelling studies were performed to confirm that designed compounds fit well into the repair active cavity. 14 compounds have been designed and synthesized having pyrazolo-quinazolines core structure. The anticancer potential of the 8 representative compounds was evaluated against rat C-6 glial cell line at different concentrations. All synthesized compounds showed good anticancer activity against rat C-6 glial cell lines. The inhibitory potential of the compounds obtained from the MTT assay results helped us to formulate the SAR studies. Further ROS measurement was also carried out using DCFDA assay. Compounds showing good MTT results were also found to be potential antioxidants which conclude their mechanism of anticancer activity through APE1 inhibition. The active compounds may be taken further for lead optimisation and mechanistic interventions for their in vitro binding studies on APE1 in future.
Design and synthesis of non-covalent imidazo[1,2-a]quinoxaline-based inhibitors of EGFR and their anti-cancer assessment
(MDPI AG, 2021-03-09T00:00:00) Kumar, Manvendra; Joshi, Gaurav; Arora, Sahil; Singh, Tashvinder; Biswas, Sajal; Sharma, Nisha; Bhat, Zahid Rafiq; Tikoo, Kulbhushan; Singh, Sandeep; Kumar, Raj
A series of 30 non-covalent imidazo[1,2-a]quinoxaline-based inhibitors of epidermal growth factor receptor (EGFR) were designed and synthesized. EGFR inhibitory assessment (against wild type) data of compounds revealed 6b, 7h, 7j, 9a and 9c as potent EGFRWT inhibitors with IC50 values of 211.22, 222.21, 193.18, 223.32 and 221.53 nM, respectively, which were comparable to erlotinib (221.03 nM), a positive control. Furthermore, compounds exhibited excellent antiproliferative activity when tested against cancer cell lines harboring EGFRWT; A549, a non-small cell lung cancer (NSCLC), HCT-116 (colon), MDA-MB-231 (breast) and gefitinib-resistant NSCLC cell line H1975 harboring EGFRL858R/T790M. In particular, compound 6b demonstrated significant inhibitory potential against gefitinib-resistant H1975 cells (IC50 = 3.65 �M) as compared to gefitinib (IC50 > 20 �M). Moreover, molecular docking disclosed the binding mode of the 6b to the domain of EGFR (wild type and mutant type), indicating the basis of inhibition. Furthermore, its effects on redox modulation, mitochondrial membrane potential, cell cycle analysis and cell death mode in A549 lung cancer cells were also reported. Copyright: � 2021 by the authors. Licensee MDPI, Basel, Switzerland.
Design, microwave-mediated synthesis and biological evaluation of novel 4 aryl(alkyl)amino-3-nitroquinoline and 2,4-diaryl(dialkyl) amino-3-nitroquinolines as anticancer agents
(Elsevier, 2015) Chauhan, Monika; Rana, Anil; Alex, Jimi Marin; Negi, Arvind; Singh, Sandeep; Kumar, Raj
Design, microwave-assisted synthesis of novel 4-aryl (alkyl)amino-3-nitroquinoline (1a–1l) and 2,4-diaryl (dialkyl)amino-3-nitroquinolines (2a–2k and 3a) via regioselective and complete nucleophilic substitution of 2,4-dichloro-3-nitroquinoline, respectively in water are presented. The newly synthesized compounds were evaluated for the first time for antiproliferative activity against EGFR overexpressing human lung (A-549 and H-460) and colon (HCT-116-wild type and HCT-116-p53 null) cancer cell lines. Some notions about structure–activity relationships (SAR) are presented. Compounds 2e, 2f, 2j and 3a overall exhibited excellent anticancer activity comparable to erlotinib which was used as a positive control. Molecular modeling studies disclosed the recognition pattern of the compounds and also supported the observed SAR.
Design, synthesis and anticancer activity of 2-arylimidazo[1,2-a]pyridinyl-3-amines
(Academic Press Inc., 2021-11-01T00:00:00) Yadav, Umesh Prasad; Ansari, Arshad J.; Arora, Sahil; Joshi, Gaurav; Singh, Tashvinder; Kaur, Harsimrat; Dogra, Nilambra; Kumar, Raj; Kumar, Santosh; Sawant, Devesh M.; Singh, Sandeep
A series of imido-heterocycle compounds were designed, synthesized, characterized, and evaluated for the anticancer potential using breast (MCF-7 and MDA-MB-231), pancreatic (PANC-1), and colon (HCT-116 and HT-29) cancer cell lines and normal cells, while normal cells showed no toxicity. Among the screened compounds, 4h exhibited the best anticancer potential with IC50 values ranging from 1 to 5.5 ?M. Compound 4h caused G2/M phase arrest and apoptosis in all the cell lines except MDA-MB-231 mammosphere formation was inhibited. In-vitro enzyme assay showed selective topoisomerase II? inhibition by compound 4h, leading to DNA damage as observed by fluorescent staining. Cell signalling studies showed decreased expression of cell cycle promoting related proteins while apoptotic proteins were upregulated. Interestingly MDA-MB-231 cells showed only cytostatic effects upon treatment with compound 4h due to defective p53 status. Toxicity study using overexpression of dominant-negative mutant p53 in MCF-7 cells (which have wild type functional p53) showed that anticancer potential of compound 4h is positively correlated with p53 expression. � 2021 Elsevier Inc.
Design, Synthesis and Biological Evaluation of New 5-(2-Nitrophenyl)-1-aryl-1H-pyrazoles as Topoisomerase Inhibitors
(John Wiley and Sons Inc, 2021-07-09T00:00:00) Kaur, Manpreet; Mehta, Vikrant; Arora, Sahil; Munshi, Anjana; Singh, Sandeep; Kumar, Raj
5-(2-Nitrophenyl)-1-aryl-1H-pyrazoles are designed as topoisomerase (Topo) inhibitors, synthesised and assessed for their anticancer properties against breast (MDA-MB-231 and MCF7), lung (A549), and colorectal (HCT116) cancer cell lines. All the compounds induced significant cytotoxicity at low micromolar concentration. The compound 5e exerted potential anticancer effects on breast cancer cell lines at a low micromolar level (IC50<2 ?M), and showed negligible toxicity towards normal cells. Compound 5 e reduced reactive oxygen species (ROS) level in breast cancer cells, altered mitochondrial membrane potential and induced the cell cycle arrest at the G2/M phase. This was accompanied by downregulation of oncogenic p-Akt and upregulation of p-PTEN along with modulation of apoptotic markers suggesting multiple mechanisms to reduce cancer cell viability. Finally, the topoisomerase inhibition assay revealed the inhibitory activity of 5 e against Topo I and Topo II. � 2021 Wiley-VCH GmbH.