Pharmaceutical Sciences and Natural Products - Research Publications

Permanent URI for this collectionhttps://kr.cup.edu.in/handle/32116/56

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Author: search.filters.author.Singla, Ramit

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    Synthesis, in vitro, and docking analysis of c-3 substituted coumarin analogues as anticancer agents
    (Bentham Science Publishers, 2020-01-28T00:00:00) Thakur, Anuradha; Kaur, Kamalpreet; Sharma, Praveen; Singla, Ramit; Singh, Sandeep; Jaitak, Vikas
    Background: Breast cancer (BC) is a leading cause of cancer-related deaths in women next to skin cancer. Estrogen receptors (ERs) play an important role in the progression of BC. Current anticancer agents have several drawbacks such as serious side effects and the emergence of resistance to chemotherapeutic drugs. As coumarins possess minimum side effects along with multidrug reversal activity, it has a tremendous ability to regulate a diverse range of cellular pathways that can be explored for selective anticancer activity. Objectives: Synthesis and evaluation of new coumarin analogues for anti-proliferative activity on human breast cancer cell line MCF-7 along with exploration of binding interaction of the compounds for ER-? target protein by molecular docking. Methods: In this study, the anti-proliferative activity of C-3 substituted coumarins analogues (1-17) has been evaluated against estrogen receptor-positive MCF-7 breast cancer cell lines. Molecular interactions and ADME study of the compounds were analyzed by using Schrodinger software. Results: Among the synthesized analogues, 12 and 13 show good antiproliferative activity with IC50 values 1 and 1.3 ?M, respectively. Molecular docking suggests a remarkable binding pose of all the seventeen compounds. Compounds 12 and 13 were found to exhibit a docking score of -4.10 kcal/mol and -4.38 kcal/mol, respectively. Conclusion: Compounds 12 and 13 showed the highest activity followed by 1 and 5. ADME properties of all compounds were in the acceptable range. The active compounds can be taken for lead optimization and mechanistic interventions for their in vivo study in the future. � 2021 Bentham Science Publishers.
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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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    Recent Advances in Plant Metabolites Analysis, Isolation, and Characterization
    (Springer, 2018) Singla, Ramit; Jaitak, Vikas
    Metabolites from natural sources either from terrestrial or marine sources serve as unmatched resources for new drug leads or diverse chemical identity. Due to ever-rising requirement for new pharmacophore in high-throughput screening and discovery for therapeutic drugs from metabolites, there has been motivated interest particularly in edible plants around the globe. Bioactive compounds are indispensable component present in different forms of botanicals, nutraceuticals, and herbal preparations used for the various medicinal applications. The prime focus in present chapter is to enlighten and discus diverse analytical methodologies which have been applied during extraction, isolation, and characterization of active constituents in botanicals, nutraceutical, and herbal preparations.
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    Coumarin Derivatives as Anticancer Agents for Lung Cancer Therapy: A Review.
    (Bentham Science, 2018) Kumar, Manvendra; Singla, Ramit; Jandriyal, Jyoti; Jaitak, Vikas
    Background: The prevalence of lung cancer is 14% among the newly diagnosed cancer cases worldwide. Currently, the number of drugs that are in clinical practice is having a high prevalence of side effect and multidrug resistance. Researchers have made an attempt to expand a suitable anticancer drug that has no MDR and side effect. Objective: Extensive exploration of Coumarin derivatives as a potent inhibitor of variety of proteins including EGFR, tyrosine kinase, ERK1/2, PI3K, HSP 90, Bax, STAT proteins, NF-κB and telomerase which have been associated with lung cancer. Method: The recent literature was surveyed utilizing the online resources and databases including scifinder, pubchem, EMBL, scopus and google scholar. Results: Upon analyzing the structure-activity relationship, it was found that N-aryl carboxamide, phenyl substitution at the C-3 position and 1,2,3- triazolyl, trihydroxystilbene, amino substitution at the C-4 position of the coumarin nucleus were the most effective in targeting lung cancer. Conclusion: This review is a collaborative and extensive compilation of synthetic strategies, mechanism of action, and the structure-activity relationship thereof for the management of lung carcinoma.
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    Multitargeted molecular docking study of natural-derived alkaloids on breast cancer pathway components
    (Bentham Science Publishers B.V., 2017) Singla, Ramit; Jaitak, Vikas
    Background: Targeting of multiple sites is a pharmacologically, pharmacokinetic and dynamically more acceptable approach for complex diseases such as BC. It is recommended that the women who are at high risk of developing BC might be given foods enhanced by indole alkaloids from vegetables like cabbage and broccoli. Administration of indole-3-carbinol is associated with decreased incidence of hormone-responsive BC (HRBC) which is implicated due to the induction of cytochrome P450 and glutathione-S-transferase which metabolizes chemical mutagens and by altering estrogen metabolism. Objective: To determine the molecular mechanism behind the anticancer activity of natural indole alkaloids present in various food and nutraceuticals products by utilizing Induced-fit docking (IFD) approach. Methods: Indole alkaloids were obtained from the database maintained by ChEBI (The database and ontology of Chemical Entities of Biological Interest) with ChEBI id 38958. The 3-dimentional and X-ray structure coordinates of Estrogen receptor- ? (ER-?), Estrogen receptor- ? (ER-?), and aromatase were obtained from protein data bank with PDB id codes 3ERT, 3OLS, and 3S7S (www.rcsb.org). The Induced fit molecular docking and ADME properties were calculated using Maestro 9.6. Results: IFD analysis showed that bromocriptine exhibits maximum binding affinity towards ER-? and fellutanine B towards ER-? and aromatase. Conclusion: Present research provided in-depth analysis of molecular mechanism and helped in the future design of new pharmacophores based on natural indole alkaloids targeting BC. ? 2017 Bentham Science Publishers.
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    In silico study of flavonoids as DPP-4 and α-glucosidase inhibitors
    (Bentham Science Publishers B.V., 2018) Kaur, J.; Singla, Ramit; Jaitak, Vikas
    Background: Diabetes being among the most prevalent disease is being studied widely to achieve most potent drug with lesser side-effects. Numerous targets have been explored and several drugs have been developed to combat type-2 diabetes. Worldwide scenario depicts an increase in the number of diabetics at an alarming rate. Due to this critical need in the current scenario, the focus has been shifted to natural products. Amongst which flavonoids have been extensively studied for their anti-diabetic potential. Among various targets inhibition of DPP-4, ?-glucosidase arose as an advantageous methodology for the management of type-2 diabetes. DPP-4 inhibitor helps to maintain the insulin levels in the body and ?-glucosidase inhibitor aids in the control of the postprandial glycemia. Methods: In the present study, the molecular modeling of 155 flavonoids has been performed using GLIDE against Dipeptidyl Peptidase-4 (DPP-4) (PDB ID:2ONC) and ?-glucosidase (PDB ID: 2QMJ) so as to achieve lead compounds that can be further used to develop a new drug. Results: Rutin and Theaflavin-3,3'-di-O-gallate were observed to possess the best docking score for ?-glucosidase and DPP-4 respectively. Conclusions: The top scoring flavonoids show promising results, but further studies are required to be carried out including the pharmacophore mapping, SAR and QSAR studies. The results illustrated that the hydrogen bonding plays a crucial role in the binding and positioning of the molecules into the active site. Further, the rescoring of the docking values mentioned as MMGB/SA also reconfirmed that these compounds show favorable results. ? 2018 Bentham Science Publishers.
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    Identification of novel indole based heterocycles as selective estrogen receptor modulator
    (Academic Press Inc., 2018) Singla, Ramit; Prakash, Kunal; Bihari Gupta, Kunj; Upadhyay, Shishir; Dhiman, Monisha; Jaitak, Vikas
    In the present study, we have designed and synthesized indole derivatives by coalescing the indole nucleus with chromene carbonitrile and dihydropyridine nucleus. Two compounds 5c and 6d were selected from series I and II after sequential combinatorial library generation, docking, absorption, distribution, metabolism and excretion (ADME) filtering, anti-proliferative activity, cytotoxicity, and ER-? competitor assay kit by utilizing estrogen receptor-? (ER-?) dominant T47D BC cells line and PBMCs (Peripheral Blood Mononuclear Cells). Cell imaging experiment suggested that both the compounds successfully cross cellular biomembrane and accumulate in nuclear, cytoplasmic and plasma membrane region. Semiquantitative RT-PCR and Western blotting experiments further supported that both compounds reduced the expression of mRNA and receptor protein of ER-? thereby preventing downstream transactivation and signaling pathway in T47D cells line. Current findings imply that 5c and 6d represent novel ER-? antagonists and may be used in the development of chemotherapy for the management of BC. ? 2018 Elsevier Inc.
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    An in-silico approach on essential oil molecules as apoptosis inducer in cancer chemotherapy
    (Innovations in Pharmaceuticals and Pharmacotherapy, 2017) Bhalla, Yashika; Singla, Ramit; Jaitak, Vikas; Sapra, Sameer
    Essential oils (EOs) are very engrossing natural plant products and apart from this they possess various biological properties. It has been reported that these essential oil molecules are able to inhibit tumor cell proliferation and induce tumor cell death by inhibiting multiple cancer-specific targets including the suppression of anti-apoptotic pathways i.e., BCL-2, BCL-XL, MCL-1, and NFκb. This study was conducted with the objective of exploring the anticancer activity of herbs and spices, with special reference to its potential to inhibit anti-apoptotic pathways by studying their interaction pattern with the selective inhibitors of the particular receptors. Hence a comparative in-silico study was done in which the essential oil molecules were docked with specific anti-apoptotic receptors with respect to the particular known inhibitor of that receptor therefore the binding affinity of the essential oil molecule with that of the receptor site was analyzed. It has been observed that the phytochemicals like capsaicin have an impressive binding affinity for NFκb receptor, BCL-2 as compared to its standard inhibitors, which shows that the phytochemical has stronger binding affinity for receptor. These docking results hereby apparently tells us that the binding affinity of the essential oil molecules are either comparable or more than that of the specific inhibitors of the receptors hence in future drug molecules can be synthesized keeping in view the strong binding affinity of these molecules with the receptors.
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    Synthesis of rebaudioside A from stevioside and their interaction model with hTAS2R4 bitter taste receptor
    (Elsevier Ltd, 2016) Singla, Ramit; Jaitak, Vikas
    Steviol glycosides (SG's) from Stevia rebaudiana (Bertoni) have been used as a natural low-calorie sweeteners. Its aftertaste bitterness restricts its use for human consumption and limits its application in food and pharmaceutical products. In present study, we have performed computational analysis in order to investigate the interaction of two major constituents of SG's against homology model of the hTAS2R4 receptor. Molecular simulation study was performed using stevioside and rebaudioside A revealed that, sugar moiety at the C-3?? position in rebaudioside A causes restriction of its entry into the receptor site thereby unable to trigger the bitter reception signaling cascade. Encouraged by the current finding, we have also developed a greener route using ?-1,3-glucanase from Irpex lacteus for the synthesis of de-bittered rebaudioside A from stevioside. The rebaudioside A obtained was of high quality with percent conversion of 62.5%. The results here reported could be used for the synthesis of rebaudioside A which have large application in food and pharmaceutical industry. ? 2016 Elsevier Ltd. All rights reserved.
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    Photoprotective, antioxidant screening and new ester from dry root extracts of Potentilla atrosanguinea (Himalayan cinquefoil)
    (Elsevier, 2016) Kaur, Rajbir; Singla, Ramit; Jaitak, Vikas; Gupta, Vinay Kumar
    In vitro photoprotective and antioxidant activities of dried aqueous-methanolic (H2O/MeOH) crude extract and ethyl acetate (EtOAc), n-butanol (n-BuOH) as well as aqueous (H2O) fractions of roots of western Himalayan plant Potentilla atrosanguinea (Himalayan cinquefoil) were evaluated. The ability of protection against UVB region followed the trend EtOAc>n-BuOH>H2O/MeOH>H2O. Total phenol content of crude H2O/MeOH extract was found to be 429.808mg GAE/g. The H2O/MeOH crude extract showed highest antioxidant of DPPH radical scavenging, superoxide anion radical scavenging and cupric ion reducing of 90.04, 78.86 and 88.64% respectively at 200?g/mL. One new compound methyl pentatetraconta-30,32,34,36,38,40,42-heptaenoate (PA-1) along with a known pentadecylbutyrate (PA-2) was isolated by column chromatography. Results indicated the importance of root extracts as photoprotective agents in sunscreen preparation in the pharmaceutical industry and considered as a natural source of antioxidants. ? 2015 South African Association of Botanists.