N- and S-donor leaving groups in triazole-based ruthena(ii)cycles: potent anticancer activity, selective activation, and mode of action studies

The functionalization of cycloruthenated triazole arene complexes with N- or S-donors affords pH or redox-activatable complexes with high cytotoxic activities.

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Naphthoquinone-based hydrazone hybrids: synthesis and potent activity against cancer cell lines

Medicinal Chemistry ◽

10.2174/1573406416666200817164308 ◽

2020 ◽

Vol 16 ◽

Author(s):

Délis Galvão Guimarães ◽

Arlan de Assis Gonsalves ◽

Larissa Araújo Rolim ◽

Edigênia Cavalcante Araújo ◽

Victória Laysna dos Anjos Santos ◽

...

Keyword(s):

Anticancer Activity ◽

Cell Lines ◽

Cancer Cell ◽

Biological Activities ◽

Supporting Electrolyte ◽

Cancer Cell Lines ◽

Molecular Structures ◽

Cytotoxic Activities ◽

Electrochemical Studies ◽

Ic50 Values

Background: Natural naphthoquinones have shown diversified biological activities including antibacterial, antifungal, antimalarial, and cytotoxic activities. However, they are also compounds with acute cytotoxicity, immunotoxicity, carcinogenesis, and cardio- and hepatotoxicity, then the modification at their redox center is an interesting strategy to overcome such harmful activity. Objective: In this study, four novel semisynthetic hydrazones, derived from the isomers α- and β-lapachones (α and β, respectively) and coupled with the drugs hydralazine (HDZ) and isoniazid (ACIL), were prepared, evaluated by electrochemical methods and assayed for anticancer activity. Method: The semisynthetic hydrazones were obtained and had their molecular structures established by NMR, IR, and MS. Anticancer activity was evaluated by cell viability determined by reduction of 3-(4,5-dimethyl-2-thiazol)-2,5-diphenyl-2H-tetrazolium bromide (MTT). The electrochemical studies, mainly cyclic voltammetry, were performed, in aprotic and protic media. Result: The study showed that the compounds 2, 3, and 4 were active against at least one of the cancer cell lines evaluated, being compounds 3 and 4 the most cytotoxic. Toward HL-60 cells, compound 3 was 20x more active than β-lapachone, and 3x more cytotoxic than doxorubicin. Furthermore, 3 showed an SI value of 39.62 for HL-60 cells. Compound 4 was active against all cancer cells tested, with IC50 values in the range 2.90–12.40 μM. Electrochemical studies revealed a profile typical of self-protonation and reductive cleavage, dependent on the supporting electrolyte. Conclusion: These results therefore indicate that compounds 3 and 4 are strong candidates as prototypes of new antineoplastic drugs.

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Copper(II) complexes with tridentate halogen‐substituted Schiff base ligands: synthesis, crystal structures and investigating the effect of halogenation, leaving group and ligand flexibility on antiproliferative activities

Dalton Transactions ◽

10.1039/d0dt03962d ◽

2021 ◽

Author(s):

Nazanin Kordestani ◽

Hadi Amiri Rudbari ◽

Alexandra R Fernandes ◽

Luís R Raposo ◽

André Luz ◽

...

Keyword(s):

Schiff Base ◽

Anticancer Activity ◽

Crystal Structures ◽

Copper Complexes ◽

Schiff Base Ligands ◽

Leaving Group ◽

Leaving Groups ◽

Tridentate Schiff Base ◽

Antiproliferative Activities

To investigate the effect of different halogen substituents, leaving groups and the flexibility of ligand on the anticancer activity of copper complexes, sixteen copper(II) complexes with eight different tridentate Schiff-base...

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Triazol: a privileged scaffold for proteolysis targeting chimeras

Future Medicinal Chemistry ◽

10.4155/fmc-2019-0159 ◽

2019 ◽

Vol 11 (22) ◽

pp. 2919-2973 ◽

Cited By ~ 4

Author(s):

Li-Wen Xia ◽

Meng-Yu Ba ◽

Wei Liu ◽

Weyland Cheng ◽

Chao-Ping Hu ◽

...

Keyword(s):

Drug Discovery ◽

Anticancer Activity ◽

Mode Of Action ◽

Critical Analysis ◽

Enzyme Inhibitors ◽

Structure Activity Relationship ◽

Target Protein ◽

Activity Relationship ◽

Structure Activity ◽

Privileged Scaffold

Current traditional drugs such as enzyme inhibitors and receptor agonists/antagonists present inherent limitations due to occupancy-driven pharmacology as the mode of action. Proteolysis targeting chimeras (PROTACs) are composed of an E3 ligand, a connecting linker and a target protein ligand, and are an attractive approach to specifically knockdown-targeted proteins utilizing an event-driven mode of action. The length, hydrophilicity and rigidity of connecting linkers play important role in creating a successful PROTAC. Some PROTACs with a triazole linker have displayed promising anticancer activity. This review provides an overview of PROTACs with a triazole scaffold and discusses its structure–activity relationship. Important milestones in the development of PROTACs are addressed and a critical analysis of this drug discovery strategy is also presented.

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Reactive Oxygen Species-Mediated Apoptosis and Cytotoxicity of Newly Synthesized Pyridazin-3-Ones In P815 (Murin Mastocytoma) Cell Line

Drug Research ◽

10.1055/a-0762-3775 ◽

2019 ◽

Vol 69 (10) ◽

pp. 528-536

Author(s):

Najat Bouchmaa ◽

Reda Ben Mrid ◽

Youness Boukharsa ◽

Youssef Bouargalne ◽

Mohamed Nhiri ◽

...

Keyword(s):

Reactive Oxygen Species ◽

Anticancer Activity ◽

Cell Line ◽

Cytotoxic Effect ◽

Redox Homeostasis ◽

Reactive Oxygen ◽

Cytotoxic Activities ◽

Oxygen Species ◽

P815 Cell

Abstract Background In cancer cells, the intracellular antioxidant capacity and the redox homeostasis are mainly maintained by the glutathione- and thioredoxin-dependent systems which are considered as promising targets for anticancer drugs. Pyridazinones constitute an interesting source of heterocyclic compounds for drug discovery. The present investigation focused on studying the in-vitro antitumor activity of newly synthesized Pyridazin-3(2h)-ones derivatives against P815 (Murin mastocytoma) cell line. Methods The in-vitro cytotoxic activities were investigated toward the P815 cell line using tetrazolium-based MTT assay. Lipid peroxidation and the specific activities of antioxidant enzymes were also determined. Results The newly compounds had a selective dose-dependent cytotoxic effect without affecting normal cells (PBMCs). Apoptosis was further confirmed through the characteristic apoptotic morphological changes and DNA fragmentation. Two compounds (6f and 7h) were highly cytotoxic and were submitted to extend biological testing to determine the likely mechanisms of their cytotoxicity. Results showed that these molecules may induce cytotoxicity via disturbing the redox homeostasis. Importantly, the anticancer activity of 6f and 7h could be due to the intracellular reactive oxygen species hypergeneration through significant loss of glutathione reductase and thioredoxin reductase activities. This eventually leads to oxidative stress-mediated P815 cell apoptosis. Furthermore, the co-administration of 6f or 7h with Methotrexate exhibited a synergistic cytotoxic effect. Conclusions considering their significant anticancer activity and chemosensitivity, 6f and 7h may improve the therapeutic efficacy of the current treatment for cancer.

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Tunable anticancer activity of furoylthiourea‐based Ru(II)‐arene complexes and their mechanism of action

Chemistry - A European Journal ◽

10.1002/chem.202004954 ◽

2021 ◽

Author(s):

Srividya Swaminathan ◽

Jebiti Haribabu ◽

Kalagatur Naveen Kumar ◽

Nikhil Maroli ◽

Nithya Balakrishnan ◽

...

Keyword(s):

Anticancer Activity ◽

Mechanism Of Action ◽

Arene Complexes

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Anticancer Activity and Catalytic Potential of Ruthenium(II)–Arene Complexes with N,O-Donor Ligands

Inorganic Chemistry ◽

10.1021/acs.inorgchem.8b00346 ◽

2018 ◽

Vol 57 (13) ◽

pp. 7558-7567 ◽

Cited By ~ 23

Author(s):

Mohammad Mehdi Haghdoost ◽

Juliette Guard ◽

Golara Golbaghi ◽

Annie Castonguay

Keyword(s):

Anticancer Activity ◽

Donor Ligands ◽

Arene Complexes ◽

Catalytic Potential

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Yeast Chemogenetic Screening as a Tool to Unravel the Antifungal Mode of Action of Two Selected Selenocyanates

Applied Sciences ◽

10.3390/app9183728 ◽

2019 ◽

Vol 9 (18) ◽

pp. 3728 ◽

Cited By ~ 1

Author(s):

Sarfraz ◽

Nasim ◽

Jacob ◽

Gruhlke

Keyword(s):

Anticancer Agents ◽

Protein Function ◽

Mode Of Action ◽

Biological Activities ◽

Resistance Mechanisms ◽

Yeast Cells ◽

Cytotoxic Activities ◽

Organoselenium Compounds ◽

Arabidopsis Mutants ◽

Wide Range

During recent decades, selenium-containing compounds, as with the chemically similar sulfur-containing compounds, have gained considerable interest as cytotoxic and anticancer agents. Selenocyanates represent a well-established class of organic selenium compounds. These agents exhibit a wide range of biological activities. Classically, selenocyanates may cause an increase in the intracellular levels of reactive oxygen species (ROS) and exert cytotoxic activities, thus, acting as pro-oxidants. In this study, chemogenetic profiling was carried out to decipher the resistance mechanisms as central part of the antifungal mode of action against two selected selenocyanates. If a mutant line is less resistant against a compound compared to the wildtype, the gene deleted in that strain seems to be correlated with the resistance. Yeast mutants carrying gene deletions for specific redox-related protein function were employed in the chemogenetic screening. The results of screening reveal the hypersensitivity of mutants carrying deletions for glutathione pool and metabolism. To confirm the results, Arabidopsis mutants deficient in glutathione were subjected to various concentrations of selenocyanates to observe their effects on mutants and the wildtype. A significant dose dependent inhibition in Arabidopsis mutants compared to the wildtype confirmed the findings of the chemogenetic screening. The data suggest that the two representatives of organoselenium compounds cause oxidative stress in yeast cells and glutathione participates towards the development of resistance against the chemicals.

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Synthesis, Characterization, and Anticancer Activity of a Series of Ketone-N4-Substituted Thiosemicarbazones and Their Ruthenium(II) Arene Complexes

Inorganic Chemistry ◽

10.1021/ic401362s ◽

2013 ◽

Vol 52 (21) ◽

pp. 12440-12449 ◽

Cited By ~ 51

Author(s):

Wei Su ◽

Quanquan Qian ◽

Peiyuan Li ◽

Xiaolin Lei ◽

Qi Xiao ◽

...

Keyword(s):

Anticancer Activity ◽

Arene Complexes

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Redox Properties of 8-Quinolinol and Implications for its Mode of Action

Natural Product Communications ◽

10.1177/1934578x1100600505 ◽

2011 ◽

Vol 6 (5) ◽

pp. 1934578X1100600 ◽

Cited By ~ 3

Author(s):

Vladimir Chobot ◽

Sigrid Drage ◽

Franz Hadacek

Keyword(s):

Antioxidant Activity ◽

Cyclic Voltammetry ◽

Complex Formation ◽

Mode Of Action ◽

Reactive Oxygen Species Generation ◽

Reducing Power ◽

Free Form ◽

Cytotoxic Activities ◽

Major Mode ◽

Deoxyribose Degradation

8-Quinolinol (oxine, 8-hydroxyquinoline) is a simple aromatic alkaloid with allelopathic, antibacterial, antifungal, and cytotoxic activities. Generally, it is assumed that 8-quinolinol toxicity depends on transition metal chelation that negatively affects their availability for metalloenzymes in the cell or reactive oxygen species generation (ROS), which are formed following reduction of molecular oxygen by autoxidation of the redox active metal central atom of the 8-quinolinol complex. On the contrary, beneficial effects of 8-quinolinol and its derivatives in the medication of certain degenerative diseases are known. In this context, the activity of 8-quinolinol derivatives is attributed to their antioxidant activity following iron complex formation. To address this controversial issue, we explore the possible anti- or pro-oxidant effects of 8-quinolinol and its iron complexes in the deoxyribose degradation assay, by cyclic voltammetry and in a biological assay. The antibacterial effects of 8-quinolinol and its complex with iron were evaluated on Curtobacterium flaccumfacies and Paenibacillus amylolyticus. 8-Quinolinol showed strong antioxidant activity in the deoxyribose degradation assay. This activity may not depend exclusively on iron chelation, but probably more on the notable reducing properties of 8-quinolinol; it proved to be a more efficient antioxidant than the flavonoids catechin and quercetin. By contrast, 8-quinolinol showed no pro-oxidative effects in the deoxyribose degradation assay, both in free form and in complex with iron, as it may occur with redox cyclers. Cyclic voltammetry confirmed this too. 8-Quinolinol significantly inhibited bacterial growth and respiration. Idiosyncratically, its 50:1 mixture with iron(III) ions was less active compared with free 8-quinolinol; it even caused a U-shaped nonlinear hormetic effect on growth and failed to inhibit respiration as totally as the pure mixture; the respiration was even accelerated compared with the control as a result of lower stress. Our results support the notion that complex formation with either iron or other transition metals affects the reducing power of 8-quinolinol, but, in contrast to general assumptions, this study finds no support that complex formation with iron represents the major mode of action.

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