Redox-active and DNA-binding coordination complexes of clotrimazole

Betanzos-Lara, Soledad; Chmel, Nikola Paul; Zimmerman, Matthew T.; Barrón-Sosa, Lidia R.; Garino, Claudio; Salassa, Luca; Rodger, Alison; Brumaghim, Julia L.; Gracia-Mora, Isabel; Barba-Behrens, Noráh

doi:10.1039/c4dt02883j

Cited by 26 publications

(13 citation statements)

References 60 publications

(118 reference statements)

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“…DNA damaging effects of phenolic compounds mediated by iron and copper have been reported, supporting the idea that DNA damage caused by FLC in vitro is also mediated by coordinated metals [59–61]. Previous studies have demonstrated DNA damage in vitro by imidazole-based compounds complexed with metals [39, 62]. Chemotherapeutic agents may cause direct DNA damage through agent-DNA binding and indirect damage through inhibition of DNA repair or accumulation of intracellular ROS [63].…”

Section: Discussionmentioning

confidence: 85%

Fluconazole induces ROS in Cryptococcus neoformans and contributes to DNA damage in vitro

et al. 2018

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Pathogenic basidiomycetous yeast, Cryptococcus neoformans, causes fatal meningitis in immunocompromised individuals. Fluconazole (FLC) is a fungistatic drug commonly administered to treat cryptococcosis. Unfortunately, FLC-resistant strains characterized by various degree of chromosomal instability were isolated from clinical patients. Importantly, the underlying mechanisms that lead to chromosomal instability in FLC-treated C. neoformans remain elusive. Previous studies in fungal and mammalian cells link chromosomal instability to the reactive oxygen species (ROS). This study provides the evidence that exposure of C. neoformans to FLC induces accumulation of intracellular ROS, which correlates with plasma membrane damage. FLC caused transcription changes of oxidative stress related genes encoding superoxide dismutase (SOD1), catalase (CAT3), and thioredoxin reductase (TRR1). Strikingly, FLC contributed to an increase of the DNA damage in vitro, when complexed with iron or copper in the presence of hydrogen peroxide. Strains with isogenic deletion of copper response protein metallothionein were more susceptible to FLC. Addition of ascorbic acid (AA), an anti-oxidant at 10 mM, reduced the inhibitory effects of FLC. Consistent with potential effects of FLC on DNA integrity and chromosomal segregation, FLC treatment led to elevated transcription of RAD54 and repression of cohesin-encoding gene SCC1. We propose that FLC forms complexes with metals and contributes to elevated ROS, which may lead to chromosomal instability in C. neoformans.

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Section: Discussionmentioning

confidence: 85%

Fluconazole induces ROS in Cryptococcus neoformans and contributes to DNA damage in vitro

et al. 2018

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“…30 This phenomenon results in a lower linearity of DNA, causing a decrease or even complete loss of the negative signal at 260 nm, indicative of a groove binder instead of an intercalator. 31 However, the discreet changes observed in the LD spectra compared with the spectrum in absence of complex (0 μM, black line) are inconclusive.…”

Section: Dna Interactionmentioning

confidence: 99%

Palladium(ii) complexes with thiosemicarbazones derived from pyrene as topoisomerase IB inhibitors

et al. 2019

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“…Therefore, many studies have been reported during the last 5 years, including those disclosing the 3D structure of the respective compounds [5,34,35]. Nevertheless, the mode of action of such metal complexes is still poorly understood; nucleic acids and proteins are likely targets [36][37][38][39]. For example, Cu(II), Co(II) and Zn(II) complexes featuring the quinolone antibacterial drug flumequine and N,N'-donor heterocyclic compounds as ligands have also been demonstrated to be able to interact with nucleic acids and serum albumin [40][41][42][43].…”

Section: Introductionmentioning

confidence: 99%

“…Author names and pages numbers of ref. 36 contains errors Indeed, we have now corrected this reference. Is ref.…”

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confidence: 99%

Transition-metal norharmane compounds as possible cytotoxic agents: New insights based on a coordination chemistry perspective

Khan

Almeida

Al-Farhan

et al. 2016

Journal of Inorganic Biochemistry

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New first-row transition-metal compounds with the ligand norharmane (9H-Pyrido[3,4-b]indole; Hnor) are reported. The compounds have the general formula [M(LL)(Hnor)(NO)](MeOH) (M=Co, Ni, Cu, Zn; LL=2,2'-bipyridyl (bpy), 1,10-phenanthroline (phen)) and have been characterized by physical and analytical methods. X-ray structural analysis revealed that the compound of formula [Cu(phen)(Hnor)(NO)], (1) has a distorted 6-coordinated octahedrally-based geometry, with a planar-based [CuNO] core, where Cu-L varies between 1.99 and 2.04Å and two weak axial CuO contacts (2.209 and 2.644Å) from two different nitrates. Based on spectroscopic similarities, the other compounds appear to have the same or very similar coordination geometries. The compounds showed clear cell growth inhibitory effects in two different cancer cell lines in vitro, with the copper and zinc complexes being the most toxic and in fact almost comparable to cisplatin. Flow-cytometry analysis confirmed induction of apoptosis in cancer cells treated with the compounds. Interestingly, co-incubation of the cells with metal complexes and CuCl induced an increase in the cytotoxic effects, most likely due to the conversion of the metal compounds in the corresponding, and most active, copper analogues.

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Redox-active and DNA-binding coordination complexes of clotrimazole

Cited by 26 publications

References 60 publications

Fluconazole induces ROS in Cryptococcus neoformans and contributes to DNA damage in vitro

Fluconazole induces ROS in Cryptococcus neoformans and contributes to DNA damage in vitro

Palladium(ii) complexes with thiosemicarbazones derived from pyrene as topoisomerase IB inhibitors

Transition-metal norharmane compounds as possible cytotoxic agents: New insights based on a coordination chemistry perspective

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