Multiply Intercalator-Substituted Cu(II) Cyclen Complexes as DNA Condensers and DNA/RNA Synthesis Inhibitors

Hormann, Jan; Malina, Jaroslav; Lemke, Oliver; Hülsey, Max J.; Wedepohl, Stefanie; Potthoff, Jan; Schmidt, Claudia; Ott, Ingo; Keller, Bettina; Brabec, Viktor; Kulak, Nora

doi:10.1021/acs.inorgchem.8b00027

Cited by 19 publications

(17 citation statements)

References 64 publications

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“…Interestingly, increasing the incubation time from 0.5 to 2 h had no significant effect on the results (Supplementary Figures S7 and S8), which suggests that the complete disappearance of DNA is caused by a binding event rather than multiple cleavage events. These data collectively suggest that the Co(III) complexes of ligands 1 – 6 possess significant hydrolytic DNase activity at micromolar concentrations but that the ligand–metal sequestering procedure used successfully for the Cu(II) complexes (see experimental procedures and Supplementary Figure S2) was unable to remove the Co(III) complexes from the DNA; presumably this in-turn (i) causes the DNA to be charge neutralized and consequently not to run on the gel or (ii) prevents the ethidium bromide from binding to the DNA. , …”

Section: Resultsmentioning

confidence: 95%

“…These data collectively suggest that the Co(III) complexes of ligands 1−6 possess significant hydrolytic DNase activity at micromolar concentrations but that the ligand−metal sequestering procedure used successfully for the Cu(II) complexes (see experimental procedures and Supplementary Figure S2) was unable to remove the Co(III) complexes from the DNA; presumably this in-turn (i) causes the DNA to be charge neutralized and consequently not to run on the gel or (ii) prevents the ethidium bromide from binding to the DNA. 43,44 Indeed, Schneider 27 et al notes that cleavage experiments with Co(III)-cyclen derivatives required cyanide treatment to sequester the cobalt prior to electrophoresis. Nonetheless, these data do demonstrate very clearly that the Co(III) complexes of the compounds 1−6 bind very strongly to DNA and therefore would not be able to generate a catalytic turnover.…”

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confidence: 99%

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Toward Catalytic Antibiotics: Redesign of Fluoroquinolones to Catalytically Fragment Chromosomal DNA

et al. 2021

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A library of ciprofloxacin−nuclease conjugates was designed and synthesized to investigate their potential as catalytic antibiotics. The Cu(II) complexes of the new designer compounds (i) showed excellent in vitro hydrolytic and oxidative DNase activity, (ii) showed good antibacterial activity against both Gramnegative and Gram-positive bacteria, and (iii) proved to be highly potent bacterial DNA gyrase inhibitors via a mechanism that involves stabilization of the fluoroquinolone−topoisomerase− DNA ternary complex. Furthermore, the Cu(II) complexes of two of the new designer compounds were shown to fragment supercoiled plasmid DNA into linear DNA in the presence of DNA gyrase, demonstrating a "proof of concept" in vitro. These ciprofloxacin−nuclease conjugates can therefore serve as models with which to develop next-generation, in vivo functioning catalytic antimicrobials.

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Section: Resultsmentioning

confidence: 95%

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confidence: 99%

Toward Catalytic Antibiotics: Redesign of Fluoroquinolones to Catalytically Fragment Chromosomal DNA

et al. 2021

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“…The condensation or aggregation phenomena plays a critical role in many antitumor drugs. DNA condensation has become a dynamic useful technique as it can be used to transfer DNA containing genes of therapeutic interest from solution to target cells involving gene therapy [45,46]. Since DNA possess negative charge density due to nucleobases present in the major and minor grooves, positively charged metal ions can easily intercalate within these nucleobases, thus showing molecular recognition and in vivo modification of DNA in the condensed state.…”

Section: Morphological Studiesmentioning

confidence: 99%

Copper (II)-based halogen-substituted chromone antitumor drug entities: Studying biomolecular interactions with ct-DNA mediated by sigma hole formation and cytotoxicity activity

Arjmand¹,

Khursheed²,

Roisnel³

et al. 2020

Bioorganic Chemistry

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Copper-based antitumor drug entities 1-3 derived from substituted (F -, Br -, -CH 3 ) 3formylchromone pharmacophore were synthesized and thoroughly characterized by spectroscopic and single X-ray crystallographic studies. These complexes show structural novelty due to presence of the X-bonds in chromone scaffold which could facilitate higher propensity for nucleic acids via sigma σ-hole interactions. Therefore, structure-activity relationship of 1-3 was studied by performing ct-DNA binding, pBR322 cleavage and cytotoxicity activity to validate their potential to act as chemotherapeutic drug entities. The binding studies of 1-3 with ct-DNA were carried out employing many biophysical techniques and the corroborative results of these experiments showed intercalation mode of binding and the order of binding was found to be 2 > 1 >3. The structure of drug entities could facilitated strong halogen bonding interaction(in case of 1 &2) and stability of X bond was rationalized by sigma hole region of positive electrostatic potential on the surface of C-X covalent bond, as determined by gas phase B3LYP computational DFT studies. Interestingly, 2 exhibited most avid binding affinity due to presence of Brelectron withdrawing and polarizable group. Further, cleavage studies of 1-3 with pBR322 plasmid DNA were performed which demonstrated significant cleavage activity , the supercoiled form (Form I) of plasmid DNA was converted to nicked form (Form II) with the appearance of linearized form(Form III) in between two, implicating lethal double strand breaks of DNA. 2 showed predominantly higher cleavage activity following the similar trend as observed for binding studies.The cytotoxicity of the complexes 1-3 was evaluated by MTT assay against the human liver carcinoma (Huh-7) and prostate cancer (DU-145) cell lines; complex 2 exhibited specific and selective cytotoxicity for the DU-145 cancer cell line with LC 50 value of 1.6μM. Highlights Substituted chromone Copper (II) complexes were synthesized and characterized.  DFT computational studies were also performed.  Electrophoretic studies revealed an oxidative cleavage pathway.  Cytotoxicity was evaluated against the human liver carcinoma (Huh-7) and prostate cancer (DU-145) cell lines.  Copper (II) complex 2 exhibited selective cytotoxicity against DU-145 cell line at GI 50 =1.6μM.

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“…The cytotoxicity evaluation in cancer cell lines showed an enhanced cytotoxicity compared with the Schiff base ligand; thus, a positive synergetic effect may be occurring [98]. Horman et al developed functionalized Cu(II) cyclen complexes with three (2-anthraquinonyl)methyl substituents that efficiently inhibited DNA and RNA syntheses resulting in high cytotoxicity accompanied by DNA condensation/aggregation phenomena [99]. Sigman et al reported the first set of copper complexes with phen ligand with good cytotoxic activities [100].…”

Section: Coppermentioning

confidence: 99%

Inorganic Coordination Chemistry: Where We Stand in Cancer Treatment?

Pedrosa¹,

Carvalho²,

Baptista³

et al. 2018

Basic Concepts Viewed From Frontier in Inorganic Coordination Chemistry

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Metals have unique characteristics such as variable coordination modes, redox activity, and reactivity being indispensable for several biochemical processes in cells. Due to their reactivity, their concentration is tightly regulated inside the cells, and abnormal concentrations are associated with many disorders, such as cancer. As such metal complexes turned out to be very attractive as potential anticancer agents. The discovery of cisplatin was a crucial moment, which prompted the interest in Pt(II) and other metal complexes as potential anticancer agents. This chapter highlights the state of the art on metal complexes in cancer therapy, highlighting their uptake mechanisms, biological targets, toxicity, and drug resistance. Finally, based on the importance of selective target of cancer cells, drug delivery systems will also be discussed.

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Multiply Intercalator-Substituted Cu(II) Cyclen Complexes as DNA Condensers and DNA/RNA Synthesis Inhibitors

Cited by 19 publications

References 64 publications

Toward Catalytic Antibiotics: Redesign of Fluoroquinolones to Catalytically Fragment Chromosomal DNA

Toward Catalytic Antibiotics: Redesign of Fluoroquinolones to Catalytically Fragment Chromosomal DNA

Copper (II)-based halogen-substituted chromone antitumor drug entities: Studying biomolecular interactions with ct-DNA mediated by sigma hole formation and cytotoxicity activity

Inorganic Coordination Chemistry: Where We Stand in Cancer Treatment?

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