Discovery and Mechanistic Study of Tailor-Made Quinoline Derivatives as Topoisomerase 1 Poison with Potent Anticancer Activity

Kundu, Biswajit; Das, Subhendu; Chowdhuri, Srijita Paul; Pal, Sourav; Sarkar, Dipayan; Ghosh, Arijit; Mukherjee, Ayan; Bhattacharya, Debomita; Das, Benu Brata; Talukdar, Arindam

doi:10.1021/acs.jmedchem.8b01938

Cited by 59 publications

(41 citation statements)

References 56 publications

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“…[17] To investigate whether Ru1-7 are topo poisons,t he formation of topoisomerase-induced DNAstrand breaks was measured. As shown in Figure S13A [11][12][13][14][15][16][17], suggesting that the Ru II complexes act as tep upstream of CPT.S imilar results were observed for topoisomerase II ( Figure S13B). Thepoison VP-16 selectively affects topo II-mediated DNAr e-ligation, which leads to the presence of al inear DNAb and.…”

Section: Resultsmentioning

confidence: 61%

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Necroptosis Induced by Ruthenium(II) Complexes as Dual Catalytic Inhibitors of Topoisomerase I/II

et al. 2020

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Inducing necroptosis in cancer cells is an effective approach to circumvent drug‐resistance. Metal‐based triggers have, however, rarely been reported. Ruthenium(II) complexes containing 1,1‐(pyrazin‐2‐yl)pyreno[4,5‐e][1,2,4]triazine were developed with a series of different ancillary ligands (Ru1‐7). The combination of the main ligand with bipyridyl and phenylpyridyl ligands endows Ru7 with superior nucleus‐targeting properties. As a rare dual catalytic inhibitor, Ru7 effectively inhibits the endogenous activities of topoisomerase (topo) I and II and kills cancer cells by necroptosis. The cell signaling pathway from topo inhibition to necroptosis was elucidated. Furthermore, Ru7 displays significant antitumor activity against drug‐resistant cancer cells in vivo. To the best of our knowledge, Ru7 is the first Ru‐based necroptosis‐inducing chemotherapeutic agent.

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Section: Resultsmentioning

confidence: 61%

“…Them ajority of topo inhibitors are topo poisons and reports on topo I/II dual catalysis inhibitors are rare. [16] This may be due to the structural differences between the two enzymes,r esulting in design difficulties. [17] To investigate whether Ru1-7 are topo poisons,t he formation of topoisomerase-induced DNAstrand breaks was measured.…”

Section: Resultsmentioning

confidence: 99%

Necroptosis Induced by Ruthenium(II) Complexes as Dual Catalytic Inhibitors of Topoisomerase I/II

et al. 2020

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“…Live-cell imaging was carried out as described previously ( 12 , 27 , 63 , 64 ). Briefly, indicated cells were grown on confocal dishes (Genetix Biotech Asia Pvt.…”

Section: Methodsmentioning

confidence: 99%

“…Immunofluorescence staining and confocal microscopy were performed as described previously ( 12 , 27 , 28 , 63 , 64 ). Briefly, cells were fixed with 4% paraformaldehyde for 20 min at room temperature.…”

Section: Methodsmentioning

confidence: 99%

SCAN1-TDP1 trapping on mitochondrial DNA promotes mitochondrial dysfunction and mitophagy

et al. 2019

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A homozygous mutation of human tyrosyl-DNA phosphodiesterase 1 (TDP1) causes the neurodegenerative syndrome, spinocerebellar ataxia with axonal neuropathy (SCAN1). TDP1 hydrolyzes the phosphodiester bond between DNA 3′-end and a tyrosyl moiety within trapped topoisomerase I (Top1)-DNA covalent complexes (Top1cc). TDP1 is critical for mitochondrial DNA (mtDNA) repair; however, the role of mitochondria remains largely unknown for the etiology of SCAN1. We demonstrate that mitochondria in cells expressing SCAN1-TDP1 (TDP1H493R) are selectively trapped on mtDNA in the regulatory non-coding region and promoter sequences. Trapped TDP1H493R-mtDNA complexes were markedly increased in the presence of the Top1 poison (mito-SN38) when targeted selectively into mitochondria in nanoparticles. TDP1H493R-trapping accumulates mtDNA damage and triggers Drp1-mediated mitochondrial fission, which blocks mitobiogenesis. TDP1H493R prompts PTEN-induced kinase 1–dependent mitophagy to eliminate dysfunctional mitochondria. SCAN1-TDP1 in mitochondria creates a pathological state that allows neurons to turn on mitophagy to rescue fit mitochondria as a mechanism of survival.

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“…Mechanistically, it was found to be a strong mTOR inhibitor by inducing apoptosis via mitochondrial dependent pathway [43]. In addition, Kundu et al, have shown the validation of a new class of quinoline-based topoisomerase 1 (Top1) inhibitor which possesses the highest human Top1 inhibition activity [44]. Topoisomerase I (PDB ID: 1T8I) is complex with the standard pre-bonded top I poison camptothecin as a co-crystal in a planar geometry with the important residues Arg-364, Asp-533 and Thr-718 in active site of 1T8I.…”

Section: Discussionmentioning

confidence: 99%

Antiproliferative potential, quantitative structure-activity relationship, cheminformatic and molecular docking analysis of quinoline and benzofuran derivatives

et al. 2020

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Quinoline and benzofuran moieties are commonly used for the synthesis of therapeutically beneficial molecules and drugs since they possess a wide range of pharmacological activities including potent anticancer activity as compared to other heterocyclic compounds. Many of well-known antimalarial, antimicrobial, anti-helminthic, analgesic, anti-inflammatory, antiprotozoal, and antitumor compounds contain quinoline/benzofuran skeleton. The aim of this study was to analyze ten new quinoline and eighteen benzofuran derivatives for carcinoma cell line growth inhibition and to predict possible interactions with the target. The anticancer activity of these compounds against colon cancer (HCT-116) and triple-negative breast cancer (MDA-MB-468) cell lines was determined and performed molecular docking to predict the possible interactions. Among ten quinoline derivatives, Q1, Q4, Q6, Q9, and Q10 were found to be the most potent against HCT-116 and MDA-MB-468 with IC50 values ranging from 6.2-99.6 and 2.7-23.6 μM, respectively. Using the IC50 values, a model equation with quantitative structure activity relationship (QSAR) was generated with their descriptors such as HBA1, HBA2, kappa (1, 2 and 3), Balaban index, Wiener index, number of rotatable bonds, log S, log P and total polar surface area (TPSA). The effect of benzofuran derivatives was moderate in cytotoxicity tests and hence only quinolines were considered for further analysis. The molecular docking indicated the mammalian / mechanistic target of rapamycin (mTOR), Topoisomerase I and II as possible targets for these molecules. The predicted results obtained from QSAR and molecular docking analysis of quinoline derivatives showed high correlation in comparison to the results of the cytotoxic assay. Overall, this study indicated that quinolines are more potent as anticancer agents compared to benzofurans. Further, compound Q9 has emerged as a lead molecule which could be the base for further development of more potent anticancer agents.

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Discovery and Mechanistic Study of Tailor-Made Quinoline Derivatives as Topoisomerase 1 Poison with Potent Anticancer Activity

Cited by 59 publications

References 56 publications

Necroptosis Induced by Ruthenium(II) Complexes as Dual Catalytic Inhibitors of Topoisomerase I/II

Necroptosis Induced by Ruthenium(II) Complexes as Dual Catalytic Inhibitors of Topoisomerase I/II

SCAN1-TDP1 trapping on mitochondrial DNA promotes mitochondrial dysfunction and mitophagy

Antiproliferative potential, quantitative structure-activity relationship, cheminformatic and molecular docking analysis of quinoline and benzofuran derivatives

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