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: 2020Subject: search.filters.subject.Cancer

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Now showing 1 - 9 of 9
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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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    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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    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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    Synthesis and In Silico Studies Of Quinazolinone Derivatives As PARP-1 INHIBITORS
    (Central University of Punjab, 2018) Verma, Sonia; Kumar,Pradeep
    Cancer is one of the leading diseases responsible for high mortality rates worldwide. It develops when normal cells begin to grow out of control in particular part of the body. Cancer is a leading cause of death worldwide, accounting for 8.8 million deaths in 2015. According to WHO, the most common causes of cancer death are cancers of Lung (1.69 million deaths), Liver (788 000 deaths), Colorectal (774 000 deaths), Stomach (754 000 deaths) and Breast (571 000 deaths). PARP-1 is a ubiquitous zincfinger DNA-binding enzyme that is activated by binding to DNA breaks and then catalyzes the synthesis of the branched polymer PAR using NAD+ as the building block. PARP-1 has a crucial role in cell proliferation, survival, and death, due to its properties on regulation of multiple biological processes. Quinazolinone and its derivatives possess a large class of biologically active compounds that exhibited broad spectrum of biological activities such as anti-HIV, anticancer, antifungal, antibacterial, anticonvulsant, anti-inflammatory, antidepressant, antimalarial, antioxidant, antileukemic, and antileishmanial activities and other activities. In this study, we have synthesized quinazolinone derivatives and studied the in silico properties as PARP-1 inhibitors which indicated that quinazolinone derivatives were having good affinity towards active site of PARP-1. Out of all synthesized compounds, SVA-11 was having maximum dock score (-10.421).
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    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.
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    Synthesis And Antiproliferative Activity Of Pyrazole-Based Heterocycles
    (Central University of Punjab, 2018) Pandey, Vishakha; Kumar, Raj
    Among the various heterocyclic compounds pyrazole and its derivatives have occupied wide range of biological and pharmacological activities. These were observed for their modes of function in the inhibition of topoisomerase and DNA repair. DNA topoisomerases usually modify DNA topology by their ability to break and reseals both its strands. Which were leads to DNA replication, transcription processes. It helps as a vital targets for numerous chemotherapeutic agents. The potency of topoisomerase inhibitors looks to be diminishing due to drug resistance and lack of efficacy. Thus, after long glimpsing the current scenario was made in order to develop topoisomerase inhibitors with completely new scaffold or alteration or modification in the existing scaffold. We herein report design and synthesis of pyrazole based compounds as topoisomerase inhibitors. The synthetics were evaluated for their in vitro anticancer activity against MDAMB 231 breast cancer cell line.
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    Synthesis, Characterization and Biological Evaluation of 5-(2- Nitrophenyl)-1H-Pyrazole Derivatives as Putative Antiproliferative Agents
    (Central University of Punjab, 2018) Saini, Geetika; Kumar, Raj
    Pyrazoles are known to exhibit various biological activities like antibacterial, antiprotozoal, anticonvulsant, analgesic, anti-inflammatory, antiviral and antiproliferative. An attempt has been made to synthesize substituted pyrazoles. Their antiproliferative activity was determined by performing MTT assay on MDA-MB 231 cell line (breast cancer). The compounds were further docked into topoisomerase 1 and 2
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    Imidazole based compunds: Synethesis and in vitro anticancer screening
    (Central University of Punjab, 2013) Negi, Arvind; Kumar, Raj
    Imidazole is an important five-membered aromatic heterocycle widely present in natural products and synthetic molecules. The unique structural feature of imidazole ring with desirable electron rich characteristic is beneficial for imidazole derivatives to readily bind with a variety of enzymes and receptors in biological systems through diverse weak interactions, thereby exhibiting broad bioactivities. Numerous imidazole-based compounds are in being used extensively in the clinics to treat various types of diseases. We have synthesized, designed and evaluated imidazole-based compounds for anti-proliferative activity against A-549 and Hep-G2 human cancer cell lines. Further the free radical scavenging activity of the selected compounds was performed in order to observe their antioxidant potential (if any). The combined results have shown advent of their first in vitro bioactivity as anticancer and antioxidant compounds and revealed their medicinal potential. The synthetics offer the scope for generation of a library of compounds and their evaluation against a panel of cancer cell lines, studies on structure activity relationship, tracing their molecular mechanism(s) in addition to their development at preclinical level in future.
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    Recent Advancements in Small Molecule Inhibitors of Insulin–like Growth Factor-1 Receptor (IGF-1R) Tyrosine Kinase as Anticancer agents
    (Bentham Science, 2013) Negi, Arvind; Ramarao, P.; Kumar, Raj
    Advancements in understanding of the genetics, genomics, biochemistry and the pharmacology of cancer in human, have driven the current cancer chemotherapy to intently focus on development of target-based approaches rather than conventional approaches. From among the various targets identified, validated and inhibited at different hallmarks of cancer, protein tyrosine kinases (PTKs) have been exploited the most. Insulin receptors (IRs), insulin like growth factor receptors (IGF-1R) and their hybrid receptors belong to tyrosine kinase receptor (TKR) family, constitute a structural homology among them and generate a growth promoting IGF system on binding with either insulin, IGF-1 or IGF-2. The system induces the mitogenic effects through a torrent of cell signals produced as a result of cross talk with other growth promoting peptides and steroidal hormones, ultimately resulting in hijacking apoptosis and increasing cell proliferation and cell survival in cancer cells. Various strategies such as anti-IGF-1R antibodies, IGF-1 mimetic peptides, antisense strategies, IGF-1R specific peptide aptamers, targeted degradation of IGF-1R and expression of dominant negative IGF- 1R mutants have been explored to inhibit the IGF-1R signaling. However, targeting IGF-1R with small molecules has gained considerable attention in last few years due to their ease of synthesis, ease of optimization of absorption, distribution, metabolism, excretion and toxicity (ADMET) parameters, oral route of administration, lesser side effects and cost effectiveness. The present review provides a broad overview and discusses the highlights on discoveries, SAR studies and binding interactions of small molecules with either IGF-1R active or allosteric sites reported till date.