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1.
J Am Chem Soc ; 143(48): 20309-20319, 2021 12 08.
Artigo em Inglês | MEDLINE | ID: mdl-34826219

RESUMO

Deoxyribonucleic acid (DNA) has been hypothesized to act as a molecular wire due to the presence of an extended π-stack between base pairs, but the factors that are detrimental in the mechanism of charge transport (CT) across tunnel junctions with DNA are still unclear. Here we systematically investigate CT across dense DNA monolayers in large-area biomolecular tunnel junctions to determine when intrachain or interchain CT dominates and under which conditions the mechanism of CT becomes thermally activated. In our junctions, double-stranded DNA (dsDNA) is 30-fold more conductive than single-stranded DNA (ssDNA). The main reason for this large change in conductivity is that dsDNA forms ordered monolayers where intrachain tunneling dominates, resulting in high CT rates. By varying the temperature T and the length of the DNA fragments in the junctions, which determines the tunneling distance, we reveal a complex interplay between T, the length of DNA, and structural order on the mechanism of charge transport. Both the increase in the tunneling distance and the decrease in structural order result in a change in the mechanism of CT from coherent tunneling to incoherent tunneling (hopping). Our results highlight the importance of the interplay between structural order, tunneling distance, and temperature on the CT mechanism across DNA in molecular junctions.


Assuntos
DNA de Cadeia Simples/química , Condutividade Elétrica , Conformação de Ácido Nucleico , Temperatura
2.
Chembiochem ; 21(17): 2487-2494, 2020 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-32255248

RESUMO

Four new bis-substituted ferrocene derivatives containing either a hydroxyalkyl or methoxyalkyl group and either a thyminyl or methylthyminyl group have been synthesised and characterised by a range of spectroscopic and analytical techniques. They were included in a structure-activity-relationship (SAR) study probing anticancer activities in osteosarcoma (bone cancer) cell lines and were compared with a known lead compound, 1-(S,Rp ), a nucleoside analogue that is highly toxic to cancer cells. Biological studies using the MTT assay revealed that a regioisomer of ferronucleoside 1-(S,Rp ), which only differs from the lead compound in being substituted on two cyclopentadienyl rings rather than one, was over 20 times less cytotoxic. On the other hand, methylated derivatives of 1-(S,Rp ) showed comparable cytotoxicities to the lead compound. Overall these studies indicate that a mechanism of action for 1-(S,Rp ) cannot proceed through alcohol phosphorylation and that its geometry and size, rather than any particular functional group, are crucial factors in explaining its high anticancer activity.


Assuntos
Antineoplásicos/farmacologia , Neoplasias Ósseas/tratamento farmacológico , Compostos Ferrosos/farmacologia , Metalocenos/farmacologia , Nucleosídeos/farmacologia , Compostos Organometálicos/farmacologia , Osteossarcoma/tratamento farmacológico , Antineoplásicos/síntese química , Antineoplásicos/química , Neoplasias Ósseas/patologia , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Compostos Ferrosos/química , Humanos , Metalocenos/química , Metilação , Modelos Moleculares , Estrutura Molecular , Nucleosídeos/química , Compostos Organometálicos/síntese química , Compostos Organometálicos/química , Osteossarcoma/patologia , Relação Estrutura-Atividade , Células Tumorais Cultivadas
3.
Dalton Trans ; 49(4): 1181-1190, 2020 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-31897458

RESUMO

A new chiral organometallic nucleoside analogue containing ruthenocene is reported, in which alkylthymine and alkylhydroxyl groups are attached in adjacent positions on one cyclopentadienyl ring. The synthetic procedures for this metallocene derivative and two control compounds are described, along with their characterisation by cyclic voltammetry and X-ray crystallography. Their biological activities in a human pancreatic cancer cell line (MIA-Pa-Ca-2) were significantly lower than those of three previously reported analogous ferrocene compounds, indicating that the choice of metallocene metal atom (Fe or Ru) plays a pivotal role in determining the anticancer properties of these nucleoside analogues, which in turn suggests a different mode of action from that of a conventional nucleoside analogue.


Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Metalocenos/química , Metalocenos/farmacologia , Nucleosídeos/química , Linhagem Celular Tumoral , Eletroquímica , Humanos , Concentração Inibidora 50 , Modelos Moleculares , Conformação Molecular
4.
Sci Rep ; 8(1): 14358, 2018 09 25.
Artigo em Inglês | MEDLINE | ID: mdl-30254296

RESUMO

Gliomas are highly malignant brain tumours characterised by extensive areas of poor perfusion which subsequently leads to hypoxia and reduced survival. Therapies that address the hypoxic microenvironment are likely to significantly improve patient outcomes. Verteporfin, a benzoporphyrin-like drug, has been suggested to target the Yes-associated protein (YAP). Increased YAP expression and transcriptional activity has been proposed in other tumour types to promote malignant cell survival and thus YAP-inhibitor, verteporfin, may be predicted to impact glioma cell growth and viability. Due to the extensive hypoxic nature of gliomas, we investigated the effect of hypoxia on YAP expression and found that YAP transcription is increased under these conditions. Treatment of both primary and immortalised glioblastoma cell lines with verteporfin resulted in a significant decrease in viability but strikingly only under hypoxic conditions (1% O2). We discovered that cell death occurs through a YAP-independent mechanism, predominately involving binding of free iron and likely through redox cycling, contributes to production of reactive oxygen species. This results in disruption of normal cellular processes and death in cells already under oxidative stress - such as those in hypoxia. We suggest that through repurposing verteporfin, it represents a novel means of treating highly therapy-resistant, hypoxic cells in glioma.


Assuntos
Glioma/patologia , Ferro/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Hipóxia Tumoral/efeitos dos fármacos , Verteporfina/farmacologia , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Dano ao DNA , Humanos , Estresse Oxidativo/efeitos dos fármacos
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