Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 5 de 5
Filtrar
Mais filtros

Base de dados
País/Região como assunto
Tipo de documento
País de afiliação
Intervalo de ano de publicação
1.
Angew Chem Int Ed Engl ; 63(13): e202318863, 2024 03 22.
Artigo em Inglês | MEDLINE | ID: mdl-38271265

RESUMO

The grooves of DNA provide recognition sites for many nucleic acid binding proteins and anticancer drugs such as the covalently binding cisplatin. Here we report a crystal structure showing, for the first time, groove selectivity by an intercalating ruthenium complex. The complex Λ-[Ru(phen)2 phi]2+ , where phi=9,10-phenanthrenediimine, is bound to the DNA decamer duplex d(CCGGTACCGG)2 . The structure shows that the metal complex is symmetrically bound in the major groove at the central TA/TA step, and asymmetrically bound in the minor groove at the adjacent GG/CC steps. A third type of binding links the strands, in which each terminal cytosine base stacks with one phen ligand. The overall binding stoichiometry is four Ru complexes per duplex. Complementary biophysical measurements confirm the binding preference for the Λ-enantiomer and show a high affinity for TA/TA steps and, more generally, TA-rich sequences. A striking enantiospecific elevation of melting temperatures is found for oligonucleotides which include the TATA box sequence.


Assuntos
Complexos de Coordenação , Compostos Organometálicos , Rutênio , Compostos Organometálicos/química , DNA/química , Oligonucleotídeos/química , Complexos de Coordenação/química , Temperatura , Rutênio/química
2.
Angew Chem Int Ed Engl ; 62(38): e202305759, 2023 09 18.
Artigo em Inglês | MEDLINE | ID: mdl-37338105

RESUMO

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.


Assuntos
Química Click , Cobre , Cobre/química , Leucócitos Mononucleares/metabolismo , Ligantes , DNA/química , Azidas/química
3.
Proc Natl Acad Sci U S A ; 116(49): 24676-24681, 2019 12 03.
Artigo em Inglês | MEDLINE | ID: mdl-31748272

RESUMO

Recreational fisheries are valued at $190B globally and constitute the predominant way in which people use wild fish stocks in developed countries, with inland systems contributing the main fraction of recreational fisheries. Although inland recreational fisheries are thought to be highly resilient and self-regulating, the rapid pace of environmental change is increasing the vulnerability of these fisheries to overharvest and collapse. Here we directly evaluate angler harvest relative to the biomass production of individual stocks for a major inland recreational fishery. Using an extensive 28-y dataset of the walleye (Sander vitreus) fisheries in northern Wisconsin, United States, we compare empirical biomass harvest (Y) and calculated production (P) and biomass (B) for 390 lake year combinations. Production overharvest occurs when harvest exceeds production in that year. Biomass and biomass turnover (P/B) declined by ∼30 and ∼20%, respectively, over time, while biomass harvest did not change, causing overharvest to increase. Our analysis revealed that ∼40% of populations were production-overharvested, a rate >10× higher than estimates based on population thresholds often used by fisheries managers. Our study highlights the need to adapt harvest to changes in production due to environmental change.


Assuntos
Conservação dos Recursos Naturais/métodos , Pesqueiros/organização & administração , Perciformes , Dinâmica Populacional/estatística & dados numéricos , Recreação/economia , Animais , Biomassa , Conservação dos Recursos Naturais/estatística & dados numéricos , Conjuntos de Dados como Assunto , Pesqueiros/economia , Pesqueiros/estatística & dados numéricos , Lagos , Wisconsin
4.
Angew Chem Int Ed Engl ; 61(3): e202110455, 2022 01 17.
Artigo em Inglês | MEDLINE | ID: mdl-34652881

RESUMO

Limitations of clinical platinum(II) therapeutics include systemic toxicity and inherent resistance. Modern approaches, therefore, seek new ways to deliver active platinum(II) to discrete nucleic acid targets. In the field of antigene therapy, triplex-forming oligonucleotides (TFOs) have attracted interest for their ability to specifically recognise extended duplex DNA targets. Here, we report a click chemistry based approach that combines alkyne-modified TFOs with azide-bearing cis-platinum(II) complexes-based on cisplatin, oxaliplatin, and carboplatin motifs-to generate a library of PtII -TFO hybrids. These constructs can be assembled modularly and enable directed platinum(II) crosslinking to purine nucleobases on the target sequence under the guidance of the TFO. By covalently incorporating modifications of thiazole orange-a known DNA-intercalating fluorophore-into PtII -TFOs constructs, enhanced target binding and discrimination between target and off-target sequences was achieved.


Assuntos
Complexos de Coordenação/química , DNA/química , Oligonucleotídeos/química , Platina/química , Alcinos/química , Química Click
5.
RSC Med Chem ; 15(2): 485-491, 2024 Feb 21.
Artigo em Inglês | MEDLINE | ID: mdl-38389892

RESUMO

We report a new class of carboplatin-TFO hybrid that incorporates a bifunctional alkyne-amine nucleobase monomer called AP-C3-dT that enables dual 'click' platinum(ii) drug conjugation and thiazole orange fluorophore coupling. Thiazole orange enhances the binding of Pt(ii)-TFO hybrids and provides an intrinsic method for monitoring triplex formation. These hybrid constructs possess increased stabilisation and crosslinking properties in comparison to earlier Pt(ii)-TFOs, and demonstrate sequence-specific binding at neutral pH.

SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA