Department Of Pharmaceutical Sciences and Natural Products

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Author: search.filters.author.Joshi G.Has files: No

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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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    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.