Department Of Pharmaceutical Sciences and Natural Products

Permanent URI for this communityhttps://kr.cup.edu.in/handle/32116/52

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End date: 2020Has files: No

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    Synthesis and Biological Evaluation of Inhibitors of Topoisomerases and Histone Deacetylase for In Vitro Anticancer Activity
    (Central University of Punjab, 2019) Joshi, Gaurav; Kumar, Raj & Singh, Sandeep
    Topoisomerases (Topos) and histone deacetylases (HDACs) are validated oncotherapeutic targets due to their involvement in most of the cellular events such as initiation, proliferation, and survival of cancer cells. Widespread research has undergone to design and discover small molecule inhibitors of each protein which has led to the development of several drugs that are making their presence felt in clinic. Considering the issues of stability, toxicity, reported crosstalk(s) and resitance of existing pharmacophores, we herein report the discovery of target-based molecules pertaining to pyrazolo[1,5-c]quinazolines, 2-aryl quinolines and imidazo[1,2- a]quinoxaline scaffolds as inhibitors of TopoI or dual TopoI and II designed rationally via in silico tools. The chemical space of scaffolds was further exploited to design and synthesise dual/multi inhibitors of Topo-HDAC by connecting pharmacophoric features of HDAC inhibitors via a linker. Detailed biological evaluation of synthetics was performed using multiple cancer cell lines as well as normal cells/cell lines. Utilizing MTT, dye exclusion, redox potential, cell cycle and annexin V vs PI assays in 2D as well as 3D cultures, we established their preferential cytotoxic potential. Signaling responsible for anticancer mechanism was delineated using western immunoblotting and qPCR assays. Further, in vitro assays v for topoisomerases (DNA relaxation and catenation), and/or HDAC1 revealed target specificity of synthetics. In addition, we also demonstrated a novel bioreductive methodology, specific to cancer cells, exploiting cancer microenvironment leading to delivery of molecularly targeted agents as topo(s) inhibitors.
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    Design, Synthesis and Evaluation of Indole Based Compounds as Putative Anticancer Agents
    (Central University of Punjab, 2018) Singla, Ramit; Jaitak, Vikas
    In the course of efforts to develop new chemotherapeutic agent for targeting breast cancer, indole-benzimidazole, indole-xanthendione, indole-chromene carbonitrile and indole-dihydropyridine derivatives were computationally designed and synthesized. All the compounds were first analyzed for antiproliferative activity using ER-α responsive T47D breast cancer cells line and cytotoxicity using hPBMC. Further, all the synthesized compounds were also evaluated for ER-α binding affinity. Lead compounds 5f and 8f of series 1 and 2; 10e and 10f of series 3, 11c and 12d of series 4 and 5 were found to be most active at both cellular and receptor level hence were biologically evaluated for gene expression studies for targeting ER-α. Cell imaging experiment clearly suggest that compounds were able to cross cell membrane and accumulate thus causing cytotoxicity. Semiquantitative RT-PCR and Western blotting experiments further supported that lead compounds altered the expression of mRNA and protein of ER-α, thereby preventing the further transactivation and signaling pathway in T47D cells line. Structural investigation from induced fit simulation study suggest that lead compounds binds in a conformation similar to bazedoxifene by extensive hydrogen bonding and Van der Waals forces. All these results indicate that compounds 5f, 8f, 10e, 10f, 11c and 12d represents new putative anticancer agents and can be proved promising in the discovery of antiestrogens for the management of breast cancer.
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    SYNTHESIS AND ANTICANCER EVALUATION OF NOVEL HETEROCYCLICS DERIVED FROM IMIDAZOLE AND QUINOLINE SCAFFOLDS
    (Central University of Punjab, 2018) Chauhan, Monika; Kumar, Raj
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    Targeting cancer stem cells pathways for the effective treatment of cancer
    (Bentham Science Publishers, 2020) Dwivedi, A.R; Thakur, A; Kumar, V; Skvortsova, I; Kumar, V.
    Resistance to chemotherapy and relapse are major hurdles for the effective treatment of cancer. Major reason for this is a small sub population of cancer stem cells (CSCs) and its microenvironment. CSCs are critical driving force for several types of cancer, such as gastric, colon, breast and many more. Hence, for the complete eradication of cancer, it is necessary to develop therapeutic approaches that can specifically target CSCs. Chemical agents that target different proteins involved in CSC signaling pathways, either as single agent or simultaneously targeting two or more proteins have generated promising pre-clinical and clinical results. In the current review article, we have discussed various targets and cellular pathways that can be explored for the effective and complete eradication of CSCs. Some latest developments in the field of design, synthesis and screening of ligands to target cancer stem cells have been summarized in the current review article. � 2020 Bentham Science Publishers.
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    Epidermal growth factor receptor and its trafficking regulation by acetylation: Implication in resistance and exploring the newer therapeutic avenues in cancer
    (Bentham Science Publishers, 2020) Kumar, M; Joshi, G; Chatterjee, J; Kumar, R.
    Background: The EGFR is overexpressed in numerous cancers. So, it becomes one of the most favorable drug targets. Single-acting EGFR inhibitors on prolong use induce resistance and side effects. Inhibition of EGFR and/or its interacting proteins by dual/combined/multitargeted therapies can deliver more efficacious drugs with less or no resistance. Objective: The review delves deeper to cover the aspects of EGFR mediated endocytosis, leading to its trafficking, internalization, and crosstalk(s) with HDACs. Methods and Results: This review is put forth to congregate relevant literature evidenced on EGFR, its impact on cancer prognosis, inhibitors, and its trafficking regulation by acetylation along with the current strategies involved in targeting these proteins (EGFR and HDACs) successfully by involving dual/hybrid/combination chemotherapy. Conclusion: The current information on cross-talk of EGFR and HDACs would likely assist researchers in designing and developing dual or multitargeted inhibitors through combining the required pharmacophores. � 2020 Bentham Science Publishers.
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    A review on quinoline derivatives as anti-methicillin resistant Staphylococcus aureus (MRSA) agents
    (BioMed Central Ltd., 2020) Kumar, P.
    Methicillin Resistant Staphylococcus aureus (MRSA) consists of strains of S. aureus which are resistant to methicillin. The resistance is due to the acquisition of mecA gene which encodes PBP2a unlike of any PBPs normally produced by S. aureus. PBP2a shows unusually low ?-Lactam affinity and remains active to allow cell wall synthesis at normally lethal ?-Lactam concentrations. MRSA can cause different types of infections like Healthcare associated MRSA, Community associated MRSA and Livestock associated MRSA infections. It causes skin lesions, osteomyelitis, endocarditis and furunculosis. To treat MRSA infections, only a few options are available like vancomycin, clindamycin, co-trimoxazole, fluoroquinolones or minocycline and there is a dire need of discovering new antibacterial agents that can effectively treat MRSA infections. In the current review, an attempt has been made to compile the data of quinoline derivatives possessing anti-MRSA potential reported to date.[Figure not available: see fulltext.] � 2020 The Author(s).
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    E-pharmacophore guided discovery of pyrazolo[1,5-c]quinazolines as dual inhibitors of topoisomerase-I and histone deacetylase
    (Academic Press Inc., 2020) Joshi G.; Kalra S.; Yadav U.P.; Sharma P.; Singh P.K.; Amrutkar S.; Ansari A.J.; Kumar S.; Sharon A.; Sharma S.; Sawant D.M.; Banerjee U.C.; Singh S.; Kumar R.
    In the quest to ameliorate the camptothecin (CPT) downsides, we expedite to search for stable non-CPT analogues among 11 motifs of pyrazoloquinazolines reported. E-pharmacophore drug design approach helped filtering out pyrazolo[1,5-c]quinazolines as Topoisomerase I (TopoI) 'interfacial' inhibitors. Three compounds, 3c, 3e, and 3l were shown to be potent non-intercalating inhibitors of TopoI specifically and showed cancer cell-specific cytotoxicity in lung, breast and colon cancer cell lines. The compounds induced cell cycle arrest at S-phase, mitochondrial cell death pathway and modulated oxidative stress in cancer cells. Furthermore, a preliminary study was conducted to explore the feasibility of these compounds to be developed as dual TopoI-HDAC1 (histone deacetylase 1) inhibitors (4a) to combat resistance. Compound 4a was found to possess dual inhibitory capabilities in-vitro. Cytotoxic potential of 4a was found to be significantly higher than parent compound in 2D as well as 3D cancer cell models. Probable binding modes of 4a with TopoI and HDAC1 active sites were examined by molecular modelling.
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    Steering the antitumor drug discovery campaign towards structurally diverse indolines
    (Academic Press Inc., 2020) Thakur A.; Singh A.; Kaur N.; Ojha R.; Nepali K.
    Indoline framework is often perpended as a privileged heterocycle present in medicinally valuable compounds of natural and synthetic origin. This review article presents the rational approaches/strategies employed for the design of anticancer indolines along with the structure activity relationship and mechanistic insights revealed in the in-vitro and in-vivo assays. The chemist has always been fascinated towards the indoline ring for the construction of antitumor scaffolds owing to its versatility as evidenced by its existence in scaffolds inducing antiproliferative effects via diverse mechanisms. To the delight of medicinal chemist, the applicability of indoline has also been expanded towards the design of dual inhibitors (multitargeting anticancer agents) as well as PROTACS. Overall, it can be concluded that indoline moiety is a magic bullet and the scaffolds containing this ring are foraying towards detailed preclinical and clinical stage investigations by leaps and bounds.
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    A panoramic review of IL-6: Structure, pathophysiological roles and inhibitors
    (Elsevier Ltd, 2020) Kaur S.; Bansal Y.; Kumar R.; Bansal G.
    Interleukin-6 (IL-6) is a pleiotropic pro-inflammatory cytokine. Its deregulation is associated with chronic inflammation, and multifactorial auto-immune disorders. It mediates its biological roles through a hexameric complex composed of IL-6 itself, its receptor IL-6R, and glycoprotein 130 (IL-6/IL-6R/gp130). This complex, in turn, activates different signaling mechanisms (classical and trans-signaling) to execute various biochemical functions. The trans-signaling mechanism activates various pathological routes, like JAK/STAT3, Ras/MAPK, PI3K–PKB/Akt, and regulation of CD4+ T cells and VEGF levels, which cause cancer, multiple sclerosis, rheumatoid arthritis, anemia, inflammatory bowel disease, Crohn's disease, and Alzheimer's disease. Involvement of IL-6 in pathophysiology of these complex diseases makes it an important target for the treatment of these diseases. Though some anti-IL-6 monoclonal antibodies are being used clinically, but their high cost, only parenteral administration, and possibility of immunogenicity have limited their use, and warranted the development of novel small non-peptide molecules as IL-6 inhibitors. In the present report, all molecules reported in literature as IL-6 inhibitors have been classified as IL-6 production, IL-6R, and IL-6 signaling inhibitors. Reports available till date are critically studied to identify important and salient structural features common in these molecules. These analyses would assist medicinal chemists to design novel and potent IL-6 production and signaling inhibitors, through knowledge- and/or computer-based approaches, for the treatment of complex multifactorial diseases.
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    P53-mediated anticancer activity of Citrullus colocynthis extracts
    (Bentham Science Publishers, 2019) Joshi G.; Kaur J.; Sharma P.; Kaur G.; Bhandari Y.; Kumar R.; Singh S.
    Background: Current anticancer therapeutics comes with significant side effects and thus focus is shifting towards minimizing the side effects or to avoid the disease altogether. Thus, various natural products are being investigated for their potential therapeutic values which can be easily included in daily diet of a person. Citrullus colocynthis (L.) fruit is commonly used in traditional medicines and is known to have antioxidant effects, thus may possess potent anticancer activity as well. Objectives: To establish the anticancer potential of fruit belonging to Citrullus colocynthis (L.) and delineate the potential targets. Results: In the present study it was found that seed and pulp extracts of the fruit are effective against various cancer cell lines while the normal cells, with lower rate of division, remain largely unaffected. The current study for the first time shows that these extracts function via regulation of p53 pathways and the mode of apoptosis is mostly via mitochondrial (intrinsic) pathway. The biological profiling of the extracts was also validated using molecular modelling studies utilizing the two major polyphenols constituents from colocynths i.e., Isoorientin and Isovitexin. Conclusion: The study suggested that the constituent has a multiple target approach for the inhibition of cancer cell proliferation and inhibition of ROS production via the major apoptotic proteins. All of these outcomes suggest and establish a critical role of ROS accumulation and mitochondrial function in the p53-dependent cell.