Limitations of clinical platinum(II) therapeutics include systemic toxicity and inherent resistance.M odern approaches,t herefore,s eek new ways to deliver active platinum(II) to discrete nucleic acid targets.I nt he field of antigene therapy, triplex-forming oligonucleotides (TFOs) have attracted interest for their ability to specifically recognise extended duplex DNAtargets.Here,wereport aclickchemistry based approach that combines alkyne-modified TFOs with azide-bearing cis-platinum(II) complexes-based on cisplatin, oxaliplatin, and carboplatin motifs-to generate al ibrary of Pt II -TFO hybrids.T hese constructs can be assembled modularly and enable directed platinum(II) crosslinking to purine nucleobases on the target sequence under the guidance of the TFO.B yc ovalently incorporating modifications of thiazole orange-a knownD NA-intercalating fluorophore-into Pt II -TFOs constructs,e nhanced target binding and discrimination between target and off-target sequences was achieved.
Limitations of clinical platinum(II) therapeutics include systemic toxicity and inherent resistance.M odern approaches,t herefore,s eek new ways to deliver active platinum(II) to discrete nucleic acid targets.I nt he field of antigene therapy, triplex-forming oligonucleotides (TFOs) have attracted interest for their ability to specifically recognise extended duplex DNAtargets.Here,wereport aclickchemistry based approach that combines alkyne-modified TFOs with azide-bearing cis-platinum(II) complexes-based on cisplatin, oxaliplatin, and carboplatin motifs-to generate al ibrary of Pt II -TFO hybrids.T hese constructs can be assembled modularly and enable directed platinum(II) crosslinking to purine nucleobases on the target sequence under the guidance of the TFO.B yc ovalently incorporating modifications of thiazole orange-a knownD NA-intercalating fluorophore-into Pt II -TFOs constructs,e nhanced target binding and discrimination between target and off-target sequences was achieved.
Artificial metallo‐nucleases (AMNs) are promising DNA damaging drug candidates. Here, we demonstrate how the 1,2,3‐triazole linker produced by the Cu‐catalysed azide‐alkyne cycloaddition (CuAAC) reaction can be directed to build Cu‐binding AMN scaffolds. We selected biologically inert reaction partners tris(azidomethyl)mesitylene and ethynyl‐thiophene to develop TC‐Thio, a bioactive C3‐symmetric ligand in which three thiophene‐triazole moieties are positioned around a central mesitylene core. The ligand was characterised by X‐ray crystallography and forms multinuclear CuII and CuI complexes identified by mass spectrometry and rationalised by density functional theory (DFT). Upon Cu coordination, CuII‐TC‐Thio becomes a potent DNA binding and cleaving agent. Mechanistic studies reveal DNA recognition occurs exclusively at the minor groove with subsequent oxidative damage promoted through a superoxide‐ and peroxide‐dependent pathway. Single molecule imaging of DNA isolated from peripheral blood mononuclear cells shows that the complex has comparable activity to the clinical drug temozolomide, causing DNA damage that is recognised by a combination of base excision repair (BER) enzymes.
An ew chemistry ……g enerated artificial metallonuclease is reported in the Research Article by Andrew Kellett et al. (e202305759). Theo xidative DNAd amaging properties of ap olynuclear copper binding ligand called TC-Thio is demonstrated. Copper-TC-Thio binds in the minor groove of genomic DNAa nd promotes damage via as uperoxide linked mechanism. Theinset picture shows copper ions,bound to the TC-Thio ligand, melting into the DNAd uplex and filling the reaction chamber with molten liquid DNA.
An ew click chemistry ……g enerated artificial metallonuclease is reported in the Research Article by Andrew Kellett et al. (e202305759). Theo xidative DNAd amaging properties of ap olynuclear copper binding ligand called TC-Thio is demonstrated. Copper-TC-Thio binds in the minor groove of genomic DNAa nd promotes damage via as uperoxide linked mechanism. Theinset picture shows copper ions,bound to the TC-Thio ligand, melting into the DNAd uplex and filling the reaction chamber with molten liquid DNA.
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