Cytotoxic activity of copper(<scp>ii</scp>), nickel(<scp>ii</scp>) and platinum(<scp>ii</scp>) thiosemicarbazone derivatives: interaction with DNA and the H2A histone peptide

Bisceglie, Franco; Orsoni, Nicolò; Pioli, Marianna; Bonati, Beatrice; Tarasconi, Pieralberto; Rivetti, Claudio; Amidani, Davide; Montalbano, Serena; Buschini, Annamaria; Pelosi, Giorgio

doi:10.1039/c9mt00166b

Cited by 20 publications

(26 citation statements)

References 40 publications

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“…Taken together, the above results indicate that Ni(S-tcitr) 2 can induce chromatin condensation, likely by interfering with histone (de)acetylases and other chromatinremodeling components. These results seem to be in line with the identification of large interlaced DNA aggregates observed in the presence of Ni(S-tcitr) 2 , but not with the free metal ion, reported in our previous papers 31,33 .…”

Section: Ni(s-tcitr)supporting

confidence: 92%

“…A multi-target mode of action also seems to apply to TSC-metal complexes, which appear to be more potent and selective antineoplastic agents than their uncomplexed counterparts. In previous studies in which we compared a series of TSCs derived from different natural compounds and chemically modified analogues, we have shown a superior bioactivity of their TSC metal-complexes compared to the corresponding metal-free ligands and pointed to bis(Scitronellalthiosemicarbazonato)-copper(II) and nickel(II) complexes as the most effective ones 25,30,31 . Because of the non-redox nature and lower biological abundance of the nickel(II) ion, the latter complex, hereafter designated as Ni(S-tcitr) 2 , was subjected to a more detailed characterization 29,32,33 .…”

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confidence: 96%

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Mechanistic insights on the mode of action of an antiproliferative thiosemicarbazone-nickel complex revealed by an integrated chemogenomic profiling study

Baruffini

Ruotolo

Bisceglie

et al. 2020

Sci Rep

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thiosemicarbazones (tSc) and their metal complexes display diverse biological activities and are active against multiple pathological conditions ranging from microbial infections to abnormal cell proliferation. Ribonucleotide reductase (RNR) is considered one of the main targets of TSCs, yet, the existence of additional targets, differently responsible for the multifaceted activities of TSCs and their metal complexes has been proposed. to set the basis for a more comprehensive delineation of their mode of action, we chemogenomically profiled the cellular effects of bis(citronellalthiosemicar bazonato)nickel(ii) [ni(S-tcitr) 2 ] using the unicellular eukaryote Saccharomyces cerevisiae as a model organism. Two complementary genomic phenotyping screens led to the identification of 269 sensitive and 56 tolerant deletion mutant strains and of 14 genes that when overexpressed make yeast cells resistant to an otherwise lethal concentration of Ni(S-tcitr) 2. Chromatin remodeling, cytoskeleton organization, mitochondrial function and iron metabolism were identified as lead cellular processes responsible for ni(S-tcitr) 2 toxicity. The latter process, and particularly glutaredoxin-mediated iron loading of RNR, was found to be affected by Ni(S-tcitr) 2. Given the multiple pathways regulated by glutaredoxins, targeting of these proteins by Ni(S-tcitr) 2 can negatively affect various core cellular processes that may critically contribute to Ni(S-tcitr) 2 cytotoxicity. Originally discovered as antivirals active against smallpox and other viruses 1 , thiosemicarbazones (TSC) are still attracting significant interest as anticancer agents 2-4. The antiproliferative activity of TSCs has been initially ascribed to their metal (e.g., Fe 2+) sequestration capacity and to the inactivation of ribonucleotide reductase (RNR), the enzyme that converts ribonucleotides into deoxyribonucleotides and whose activity correlates with cell proliferation 5,6. However, additional targets have emerged from more recent studies, including topoisomerase II, the metalloenzymes xanthine oxidase and tyrosinase, and the mitochondria signalling pathway 7-11. One of the first TSC tested in phase I clinical trials was 5-hydroxy-2-formylpyridine thiosemicarbazone (5-HP) 12. However, these trials revealed severe side effects (mainly gastrointestinal toxicity) and fast inactivation via metabolic conversion (glucuronidation) of 5-HP 4. Further investigation has led to the development of 3-aminopyridine-2-carboxaldehyde thiosemicarbazone (3-AP, Triapine) 13 , whose efficacy is currently undergoing phase II clinical testing 14-17. This compound shows promising activity against hematologic disorders but not solid tumours 4. The reasons may be an inappropriate drug delivery due to a short plasma half-life, Triapine metabolic conversion, and/or rapid development of drug resistance 4. Recently, phase I clinical trials are being performed to test Triapine in combination therapy with other anticancer drugs 18. Since 2015 4,19,20 , phase I clinical trials were also starte...

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Section: Ni(s-tcitr)supporting

confidence: 92%

mentioning

confidence: 96%

Mechanistic insights on the mode of action of an antiproliferative thiosemicarbazone-nickel complex revealed by an integrated chemogenomic profiling study

Baruffini

Ruotolo

Bisceglie

et al. 2020

Sci Rep

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“…In recent years, derivatives of thiosemicarbazones have demonstrated a broad range of biological and pharmacological activities (viz. antifungal, anticancer, antimicrobial, and antiviral) [32][33][34][35][36][37][38][39][40][41]. In line with this, we found no research on the in silico ADMET and drug-likeness prediction, as well as the anticancer activity of the same compound presented in our study.…”

Section: Introductionsupporting

confidence: 38%

Synthesis, In Silico Study, and Anti-Cancer Activity of Thiosemicarbazone Derivatives

et al. 2021

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Thiosemicarbazones are known for their biological and pharmacological activities. In this study, we have synthesized and characterized 3-Methoxybenzaldehyde thiosemicarbazone (3-MBTSc) and 4-Nitrobenzaldehyde thiosemicarbazone (4-NBTSc) using IR, 1HNMR and 13C NMR. The compound’s in vitro anticancer activities against different cell lines were evaluated. Molecular docking, Insilco ADMET, and drug-likeness prediction were also done. The test compounds showed a comparative IC50 and growth inhibition with the standard drug Doxorubicin. The IC50 ranges from 2.82 µg/mL to 14.25 µg/mL in 3-MBTSc and 2.80 µg/mL to 7.59 µg/mL in 4-NBTSc treated cells. The MTT assay result revealed, 3-MBTSc inhibits 50.42 and 50.31 percent of cell growth in B16-F0 and EAC cell lines, respectively. The gene expression showed that tumor suppressor genes such as PTEN and BRCA1 are significantly upregulated in 7.42 and 5.33 folds, and oncogenes, PKC, and RAS are downregulated −7.96 and −7.64 folds, respectively in treated cells. The molecular docking performed on the four targeted proteins (PARP, VEGFR-1, TGF-β1, and BRAFV600E) indicated that both 4-NBTSc and 3-MBTSc potentially bind to TGF-β1 with the best binding energy of −42.34 Kcal/mol and −32.13 Kcal/mol, respectively. In addition, the test compound possesses desirable ADMET and drug-likeness properties. Overall, both 3-MBTSc and 4-NBTSc have the potential to be multitargeting drug candidates for further study. Moreover, 3-MBTSc showed better activity than 4-NBTSc.

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“…Since the ′60s, DNA has been referenced as the main molecular target for various copper(II) complexes in many studies [28]. In addition, various TSCs have been recently recognized as DNA binding compounds [116]. On this basis, we evaluated the ability of Cu(II) complexes 1-3 to interact with DNA.…”

Section: Biological Activitymentioning

confidence: 99%

Synthesis, Characterization and Biological Activity of Novel Cu(II) Complexes of 6-Methyl-2-Oxo-1,2-Dihydroquinoline-3-Carbaldehyde-4n-Substituted Thiosemicarbazones

et al. 2020

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Three new 6-methyl-2-oxo-1,2-dihydroquinoline-3-carbaldehyde-thiosemicarbazones-N-4-substituted pro-ligands and their Cu(II) complexes (1, -NH2; 2, -NHMe; 3, -NHEt) have been prepared and characterized. In both the X-ray structures of 1 and 3, two crystallographically independent complex molecules were found that differ either in the nature of weakly metal-binding species (water in 1a and nitrate in 1b) or in the co-ligand (water in 3a and methanol in 3b). Electron Paramagnetic Resonance (EPR) measurements carried out on complexes 1 and 3 confirmed the presence of such different species in the solution. The electrochemical behavior of the pro-ligands and of the complexes was investigated, as well as their biological activity. Complexes 2 and 3 exhibited a high cytotoxicity against human tumor cells and 3D spheroids derived from solid tumors, related to the high cellular uptake. Complexes 2 and 3 also showed a high selectivity towards cancerous cell lines with respect to non-cancerous cell lines and were able to circumvent cisplatin resistance. Via the Transmission Electron Microscopy (TEM) imaging technique, preliminary insights into the biological activity of copper complexes were obtained.

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Cytotoxic activity of copper(ii), nickel(ii) and platinum(ii) thiosemicarbazone derivatives: interaction with DNA and the H2A histone peptide

Abstract: Three analogous Cu, Ni, and Pt complexes interact with DNA and the “C-tail” region of histone H2A, having different biological effects.

Cited by 20 publications

References 40 publications

Mechanistic insights on the mode of action of an antiproliferative thiosemicarbazone-nickel complex revealed by an integrated chemogenomic profiling study

Mechanistic insights on the mode of action of an antiproliferative thiosemicarbazone-nickel complex revealed by an integrated chemogenomic profiling study

Synthesis, In Silico Study, and Anti-Cancer Activity of Thiosemicarbazone Derivatives

Synthesis, Characterization and Biological Activity of Novel Cu(II) Complexes of 6-Methyl-2-Oxo-1,2-Dihydroquinoline-3-Carbaldehyde-4n-Substituted Thiosemicarbazones

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