80 research outputs found

    Natural Products as Kinase Inhibitors: Total Synthesis, in Vitro Kinase Activity, in Vivo Toxicology in Zebrafish Embryos and in Silico Docking

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    Despite significant progress in developing small molecule kinase inhibitors, most human kinases still lack high-quality selective inhibitors that might be employed as chemical probes to study their biological function and pharmacology. Natural products (NPs) and their synthetic derivates might give avenues to overcome this frequently encountered challenge as they demonstrated to target a wide range of kinases, including all subfamilies of the known kinome. Nonetheless, isolating these NPs from their sources necessitates massive harvesting, which is fraught with difficulties and triggers enormous harm to the ecology. Moreover, the challenges encountered while extracting these NPs from their sources are constantly present and have few viable solutions. Considering these aspects, total synthesis and semisynthesis have been employed to replicate the most intriguing compounds of living nature in laboratories to obtain larger quantities for extended studies. The present work outlined the attempts to perform the first total syntheses and to evaluate the biological activity of naturally occurring potent anti-cancer compounds: Depsipeptide PM181110, Eudistomidin C, and Fusarithioamide A. Efforts to achieve the first total syntheses of these natural compounds have been based on highly convergent and unified approaches. Depsipeptide PM181110 is a bicyclic depsipeptide featuring four stereogenic centres whose attempts to perform its first total synthesis were undertaken by synthesizing its diastereomers 3R,9R,14R,17R, and 3R,9S,14R,17R. Similarly, for Eudistomidin C and Fusarithioamide A having known stereochemistry, the attempts to perform their syntheses were made starting from enantiomerically pure reagents. The synthesized compounds BSc5484, BSc5517 and the analogues were subjected to biological activity tests afterwards. Accordingly, a kinase inhibitory activity test was performed, followed by an in vivo toxicology assay in wild-type and gold-type zebrafish embryos Danio rerio. As a result, the assayed compounds displayed moderate to good inhibition of the kinases with an apparent selectivity profile and toxicity in zebrafish embryos illustrated by the observed phenotypes. Finally, an in silico experiment revealed that BSc5484 and BSc5485 might bind as type IV inhibitors, while BSc5517 demonstrated a better binding affinity to human Haspin kinase compared to the known b-carboline inhibitor Harmine across the panel of the tested kinases. This work thus provides the first directed tools about the potential of naturally derived compounds as inhibitors of disease-causing proteins that are key players in numerous forms of cancer and other illnesses. Consequently, establishing depsipeptide and b-carboline-based compounds as therapeutic leads is crucial and will provide a powerful tool to further elucidate their biological function through targeted structural variations

    Design, synthesis and characterisation of next-generation choline kinase inhibitors

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    Abnormal lipid metabolism is a common feature of cancers. In the clinic, elevated phosphocholine, an essential membrane lipid precursor, is revealed as a phenotype associated with malignant lipid metabolism. Overexpression of choline kinase alpha isoform (CHKA), is recognised as a predominant factor responsible for the phenotype, and, therefore, CHKA has become a novel therapeutic target for cancer. In the previous work by Trousil et al., a potent CHKA inhibitor ICL-CCIC-0019 was reported, which displayed high cellular activity but undesirable pharmacological properties to be ameliorated. In this thesis, CK146, an active analogous scaffold of ICL-CCIC-0019, bearing a reactive piperazine handle, is presented. This novel scaffold opens the further possibilities for structural elaboration of the classic pharmacophore by innovatively exploiting two advanced drug development strategies. In the first strategy, selective CHKA inhibition was attempted to be achieved by prodrug CK145, via the incorporation of an ε-(Ac)Lys motif into CK146. In the second strategy, a peptide ligand targeting prostate-specific membrane antigen (PSMA) receptor was embodied in CK146 to afford CK147, aimed to realise the targeted delivery to the malignant cells with high expression of PSMA receptors on cell surface. As expected, the precursor scaffold CK146 displayed high CHKA activity in kinase screening (CHKA activity as part of a 15 human lipid kinase screen: CK146: 69%, ICL-CCIC-0019: 53%) and good antiproliferative activity against four selected cancer cell lines (overall GI50 against HCT-116, A549, HepG2 and Caco-2: CK146: 2.5 ± 0.3 μM, ICL-CCIC-0019: 0.5 ± 0.02 μM). Proposed prodrug CHKA inhibitor (CK145) and PSMA-targeted CHKA inhibitor (CK147) were successfully synthesised. The pharmacological activity and pharmacokinetic profiles of the obtained compounds were evaluated in vitro. Although attempts to improve the pharmacological profiles of ICL-CCIC-0019 were not effective by these two modification strategies, important and informative structure-activity relationships were concluded and have been reported.Open Acces

    Studying the Conformational Changes of Protein Kinases Using In Silico Structural Approaches

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    Protein kinases were brought to the scientific community's attention with the remarkable approval of imatinib more than 20 years ago. Since then, enormous efforts have been made to identify, characterise, and investigate the dynamic and function of this broad protein family. Nowadays, protein kinases are associated with numerous human diseases, including the origin of cancer and beyond.Extensive research of protein kinases led not only to the steady development and approval of new inhibitors and therapeutics but also to the awareness that there are still plenty of questions to be answered about these dynamic proteins. Hence, the In Silico methods come in hand to study their highly dynamic nature. Offering a wide range of novel computational techniques, they provide a possibility to lift the veil of secrecy and glance into the minor details of kinase behaviour. The presentation will cover the introduction to the main research focus – protein kinases, and the central methodology – computer-aided drug design. Firstly, the classification, function, drug discovery trends and a detailed review of the kinase domain’s structural features will be presented. Next, the In Silico drug discovery methods, encompassing the sample workflows and analyses with the main emphasis on the theory and application of molecular dynamics will be discussed. The application of the computational chemistry approaches in kinase drug research will be illustrated in two scientific publications. The first is dedicated to the application of long-scale molecular dynamics in understanding the impact of phosphorylation and mutation on the autoinhibition and dimerization of mitogen- activated protein kinase kinase 4 (MKK4). The second publication focuses on the investigation of the statistical trends and patterns related to protein kinase regulatory hydrophobic spine (R-spine), emphasizing the alfa- helical hydrophobic spine residue three (RS3). The aforementioned publications demonstrate the successful application of In Silico approaches, particularly molecular dynamics in the field of drug discovery, and furthermore offer a framework modification for the investigation of geometrical motions within the protein structures during molecular dynamics simulation

    Marine Compounds and Cancer 2020

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    The very first marine-derived anticancer drug, Cytarabine (aka Ara-C, Cytosar-U®), was approved by the FDA in 1969 for the treatment of leukemia. At the beginning of 2021, the list of approved marine-derived anticancer drugs consists of nine substances, five of which received approval within the last two years, demonstrating the rapid evolution of the field. The current book is a collection of scientific articles related to the exponentially growing field of anticancer marine compounds. These articles cover the whole field, from agents with cancer-preventive activity, to novel and previously characterized compounds with anticancer activity, both in vitro and in vivo, as well as the latest status of compounds under clinical development

    Research on Melanoma

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    The book Research on Melanoma: A Glimpse into Current Directions and Future Trends, is divided into sections to represent the most cutting-edge topics in melanoma from around the world. The emerging epigenetics of disease, novel therapeutics under development and the molecular signaling aberrations are explained in detail. Since there are a number of areas in which unknowns exist surrounding the complex development of melanoma and its response to therapy, this book illuminates and comprehensively discusses such aspects. It is relevant for teaching the novice researcher who wants to initiate projects in melanoma and the more senior researcher seeking to polish their existing knowledge in this area. Many chapters include visuals and illustrations designed to easily guide the reader through the ideas presented

    Translational Research in Cancer

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    Translational research in oncology benefits from an abundance of knowledge resulting from genome-scale studies concerning the molecular pathways involved in tumorigenesis. Translational oncology represents a bridge between basic research and clinical practice in cancer medicine. The vast majority of cancer cases are due to environmental risk factors. Many of these environmental factors are controllable lifestyle choices. Experimental cancer treatments are studied in clinical trials to compare the proposed treatment to the best existing treatment through translational research. The key features of the book include: 1) New screening for the development of radioprotectors: radioprotection and anti-cancer effect of β-Glucan (Enterococcus faecalis) 2) Translational perspective on hepatocellular carcinoma 3) Brachytherapy for endometrial cancer 4) Discovery of small molecule inhibitors for histone methyltransferases in cance
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