School Of Basic And Applied Sciences
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Item 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, UmeshThe 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)Item 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, PradeepHuman 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.Item PROTAC�ing oncoproteins: targeted protein degradation for cancer therapy(BioMed Central Ltd, 2023-03-30T00:00:00) Kelm, Jeremy M.; Pandey, Deepti S.; Malin, Evan; Kansou, Hussein; Arora, Sahil; Kumar, Raj; Gavande, Navnath S.Molecularly targeted cancer therapies substantially improve patient outcomes, although the durability of their effectiveness can be limited. Resistance to these therapies is often related to adaptive changes in the target oncoprotein which reduce binding affinity. The arsenal of targeted cancer therapies, moreover, lacks coverage of several notorious oncoproteins with challenging features for inhibitor development. Degraders are a relatively new therapeutic modality which deplete the target protein by hijacking the cellular protein destruction machinery. Degraders offer several advantages for cancer therapy including resiliency to acquired mutations in the target protein, enhanced selectivity, lower dosing requirements, and the potential to abrogate oncogenic transcription factors and scaffolding proteins. Herein, we review the development of proteolysis targeting chimeras (PROTACs) for selected cancer therapy targets and their reported biological activities. The medicinal chemistry of PROTAC design has been a challenging area of active research, but the recent advances in the field will usher in an era of rational degrader design. � 2023, This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.Item Targeting the Epidermal Growth Factor Receptor with Molecular Degraders: State-of-the-Art and Future Opportunities(American Chemical Society, 2023-02-22T00:00:00) Maity, Pritam; Chatterjee, Joydeep; Patil, Kiran T.; Arora, Sahil; Katiyar, Madhurendra K.; Kumar, Manvendra; Samarbakhsh, Amirreza; Joshi, Gaurav; Bhutani, Priyadeep; Chugh, Manoj; Gavande, Navnath S.; Kumar, RajEpidermal growth factor receptor (EGFR) is an oncogenic drug target and plays a critical role in several cellular functions including cancer cell growth, survival, proliferation, differentiation, and motility. Several small-molecule tyrosine kinase inhibitors (TKIs) and monoclonal antibodies (mAbs) have been approved for targeting intracellular and extracellular domains of EGFR, respectively. However, cancer heterogeneity, mutations in the catalytic domain of EGFR, and persistent drug resistance limited their use. Different novel modalities are gaining a position in the limelight of anti-EGFR therapeutics to overcome such limitations. The current perspective reflects upon newer modalities, importantly the molecular degraders such as PROTACs, LYTACs, AUTECs, and ATTECs, etc., beginning with a snapshot of traditional and existing anti-EGFR therapies including small molecule inhibitors, mAbs, and antibody drug conjugates (ADCs). Further, a special emphasis has been made on the design, synthesis, successful applications, state-of-the-art, and emerging future opportunities of each discussed modality. � 2023 American Chemical Society.Item Fused Pyrimidine-Based Drug Discovery(Elsevier, 2022-10-14T00:00:00) Kumar, RajFused Pyrimidine-Based Drug Discovery covers all categories of fused-pyrimidines along with pharmacological and in silico studies. It covers the chemistry and biological activities, as well as the design of novel fused-pyrimidine scaffolds. N-Heterocyclic scaffolds are found in most known drug candidates, and are of interest to medicinal and organic chemists to design, synthesize and evaluate their biological properties. A variety of fused-pyrimidine molecules have been synthesized and extracted from natural resources, and are found to exhibit various biological activities such as antifolates, anticancer agents, analgesics, antimetabolites, CNS active agents and many more. Some of these scaffolds like purines are also known to have involvement in biological processes and are part of the framework of genetic material. This book focuses on the classification, structural chemistry, and chemical and physical properties along with various approaches for their synthesis. This book is ideal for researchers in organic chemistry both in academic and industrial settings, postgraduates in chemistry and medicinal chemistry. � 2023 Elsevier Ltd. All rights reserved.Item FDA approved five-membered ring fused pyrimidine-based derivatives and their biological properties(Elsevier, 2022-10-14T00:00:00) Kumar, Manvendra; Chatterjee, Joydeep; Rani, Dimpy; Kumar, RajPyrimidines-based drugs are one of the most important drugs for novel and recurring viruses, including the coronavirus. This chapter deals with 41 FDA-approved five-membered ring fused pyrimidine-based drugs, their synthetic strategies, and pharmacological activities. � 2023 Elsevier Ltd. All rights reserved.Item Introduction(Elsevier, 2022-10-14T00:00:00) Kumar, Pradeep; Kumar, Rakesh; Kumar, RajAn overview of 11 chapters in the book is presented. � 2023 Elsevier Ltd. All rights reserved.Item FDA approved six-membered ring fused pyrimidine-based derivatives(Elsevier, 2022-10-14T00:00:00) Arora, Sahil; Kumar, RajPyrimidine-based derivatives play a vital role in the development of drugs due to their indispensable role in various biological processes. To date, ring fused pyrimidine-based derivatives have been reported to exhibit numerous biological activities including anticancer, antiviral, antianginal, anti-HIV, antifungal, antibacterial, anti-inflammatory, antitubercular and many others. There are numerous synthetic approaches available for the synthesis of fused pyrimidine-based derivatives which provides ample scope in the development of new drugs. Considering these medicinal attributes of fused pyrimidine-based derivatives, we have put forth this book chapter mainly focusing on the FDA approved six-membered ring fused pyrimidine-based derivatives. The present chapter deals with improved synthetic schemes, their biological importance and the adverse effects of FDA approved six-membered ring fused pyrimidine-based drugs. Covering all these aspects may lighten the researchers with the updated literature exploring the best synthetic routes and can think of alternative synthetic routes with less time consuming and non-toxic solvents. � 2023 Elsevier Ltd. All rights reserved.Item Seven-membered ring fused pyrimidine-based derivatives and their biological properties(Elsevier, 2022-10-14T00:00:00) Kaur, Manpreet; Kumar, RajIn the chapter, the synthesis along-with the biological importance of seven-membered ring fused pyrimidine-based derivatives has been discussed, where the seven-membered rings may consist of heteroatoms such as sulfur, oxygen, and nitrogen, which are supposed to provide important binding interactions within the binding pocket of certain receptors/enzymes like Epidermal growth factor receptor, HER, etc. � 2023 Elsevier Ltd. All rights reserved.Item Naturally occurring fused pyrimidine derivatives and their medicinal attributes(Elsevier, 2022-10-14T00:00:00) Maity, Pritam; Katiyar, Madhurendra K.; Kumar, RajA wide variety of fused pyrimidine derivatives, mainly occurring as alkaloids, are obtained from different natural sources worldwide. These have been documented to exert some important biological activities including anticancer, antimicrobial, anti-inflammatory, etc. Based on the natural source, these fused pyrimidine derivatives are categorized and discussed further in the subsequent sections highlighting their medicinal attributes. � 2023 Elsevier Ltd. All rights reserved.