Synthesis and topoisomerases inhibitory activity of heteroaromatic chalcones

Jeon, Kyung Hwa; Han, Yu; Kwak, Soo Yeon; Kwon, Young Joo; Na, Younghwa

doi:10.1016/j.bmc.2016.09.051

Cited by 28 publications

(11 citation statements)

References 19 publications

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“…Chalcones have attracted attention because of their promising therapeutic effects, as they are able to target multiple cellular molecules, such as MDM2/p53, tubulin, proteasome, NF-kappa B, TRIAL/death receptors and mitochondria mediated apoptotic pathways, cell cycle, Signal transducer and activator of transcription 3, Activator protein 1, nuclear erythroid 2-related factor 2, Peroxisome proliferator-activated receptor gamma [31], human topoisomerase IIα [32,33,34,35], and EGFR-TK. The hybrid of triazoloquinoxaline-chalcone derivatives showed dual EGFR-TKI and tubulin polymerization inhibition activities [36].…”

Section: Introductionmentioning

confidence: 99%

Biological Evaluation and Molecular Dynamics Simulation of Chalcone Derivatives as Epidermal Growth Factor-Tyrosine Kinase Inhibitors

et al. 2019

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Targeted cancer therapy has become a high potential cancer treatment. Epidermal growth factor receptor (EGFR), which plays an important role in cell signaling, enhanced cell survival and proliferation, has been suggested as molecular target for the development of novel cancer therapeutics. In this study, a series of chalcone derivatives was screened by in vitro cytotoxicity against the wild type (A431 and A549) and mutant EGFR (H1975 and H1650) cancer cell lines, and, subsequently, tested for EGFR-tyrosine kinase (TK) inhibition. From the experimental screening, all chalcones seemed to be more active against the A431 than the A549 cell line, with chalcones 1c, 2a, 3e, 4e, and 4t showing a more than 50% inhibitory activity against the EGFR-TK activity and a high cytotoxicity with IC50 values of < 10 µM against A431 cells. Moreover, these five chalcones showed more potent on H1975 (T790M/L858R mutation) than H1650 (exon 19 deletion E746-A750) cell lines. Only three chalcones (1c, 2a and 3e) had an inhibitory activity against EGFR-TK with a relative inhibition percentage that was close to the approved drug, erlotinib. Molecular dynamics studies on their complexes with EGFR-TK domain in aqueous solution affirmed that they were well-occupied within the ATP binding site and strongly interacted with seven hydrophobic residues, including the important hinge region residue M793. From the above information, as well as ADMET (absorption, distribution, metabolism, excretion, and toxicity) properties, all three chalcones could serve as lead compounds for the development of EGFR-TK inhibitors.

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Section: Introductionmentioning

confidence: 99%

Biological Evaluation and Molecular Dynamics Simulation of Chalcone Derivatives as Epidermal Growth Factor-Tyrosine Kinase Inhibitors

et al. 2019

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“…Среди хальконов интерес вызвали гетероароматические циклические эпоксид-или тиоэпоксидзамещённые производные, более активно ингибировавшие Тор1 и более активные, чем камптотецин. Некоторые агенты этого ряда ингибировали функцию Тор2 сильнее, чем этопозид, а более активные (авторский шифр 9 и 13) были равно цитотоксичны для чувствительной (T47D) и устойчивой (MDA-MB468) к этопозиду линий клеток рака молочной железы человека [42].…”

Section: результаты поиска новых ингибиторов топоизомеразunclassified

Prospects for Searching Multitarget Topoisomerase Inhibitors With Antitumor Properties

2019

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Purpose of research: to identify the prospects of search for new antitumor non-camptothecin inhibitors of topoisomerase I/II among the various chemical compounds based on the analysis of side effects.Material and Methods. The analysis included 65 relevant literature sources for 2002–2018 years, found in Systems such as Scopus, Web of Science, Pubmed, and eLIBRARY.Results. The antitumor and side effect characteristics of the agents, associated with the selective suppression of the activity of type I and/or II topoisomerase (Top1, Top2) in tumor cells were emphasized. Examples of the relationship between side effects of inhibitors and their structure and catalytic mechanisms were given. The following factors were highlighted as significant: 1) blocking of cells in G2 and S phases with a delay of entry into mitosis; 2) inhibition of the reaction of re-ligation with DNA breaks without re-linking; 3) launching of cytotoxic events with the inhibition of DNA replication and generation of double-strand breaks. Incurable cancers, such as gastric cancer, colorectal cancer, non-small cell lung cancer, hepatocellular carcinoma, glioblastoma, etc. were determined as more sensitive to inhibitors. Side effects of treatment and their connection with the mechanism of activity were described.Conclusion. Based on the comparative analysis of prognostically valuable data regarding the efficacy and safety of topoisomerase I/II inhibitors, multitargeted heterocyclic condensed nitrogen-containing compounds, in particular, anthrafurans, can be considered as new promising clinical candidates with higher selectivity of action.

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“…Finally, using the chalcone scaffold as starting material, interesting families of inhibitors can be achieved by simple preparation methods; for example, by incorporating heteroaromatic cyclopropane rings (Fig. 35) [84,85].…”

Section: Flavonoids and Chalconesmentioning

confidence: 99%

DNA Related Enzymes as Molecular Targets for Antiviral and Antitumoral Chemotherapy. A Natural Overview of the Current Perspectives

Garro¹,

Pungitore²

2018

CDT

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Synthesis and topoisomerases inhibitory activity of heteroaromatic chalcones

Cited by 28 publications

References 19 publications

Biological Evaluation and Molecular Dynamics Simulation of Chalcone Derivatives as Epidermal Growth Factor-Tyrosine Kinase Inhibitors

Biological Evaluation and Molecular Dynamics Simulation of Chalcone Derivatives as Epidermal Growth Factor-Tyrosine Kinase Inhibitors

Prospects for Searching Multitarget Topoisomerase Inhibitors With Antitumor Properties

DNA Related Enzymes as Molecular Targets for Antiviral and Antitumoral Chemotherapy. A Natural Overview of the Current Perspectives

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