RESUMO
A platinum (II) complex stabilized by a pyridine and an N-heterocyclic carbene ligand featuring an anthracenyl moiety was prepared. The compound was fully characterized and its molecular structure was determined by single-crystal X-ray diffraction. The compound demonstrated high in vitro antiproliferative activities against cancer cell lines with IC50 ranging from 10 to 80 nM. The presence of the anthracenyl moiety on the N-heterocyclic carbene (NHC) Pt complex was used as a luminescent tag to probe the metal interaction with the nucleobases of the DNA through a pyridine-nucleobase ligand exchange. Such interaction of the platinum complex with DNA was corroborated by optical tweezers techniques and liquid phase atomic force microscopy (AFM). The results revealed a two-state interaction between the platinum complex and the DNA strands. This two-state behavior was quantified from the different experiments due to contour length variations. At 24 h incubation, the stretching curves revealed multiple structural breakages, and AFM imaging revealed a highly compact and dense structure of platinum complexes bridging the DNA strands.
Assuntos
Antineoplásicos/química , DNA/química , Compostos Organoplatínicos/química , Antracenos/química , Antineoplásicos/farmacologia , Proliferação de Células/efeitos dos fármacos , DNA/metabolismo , Células HCT116 , Humanos , Células MCF-7 , Pinças Ópticas , Compostos Organoplatínicos/farmacologia , Células PC-3RESUMO
The current interest for platinum N-heterocyclic carbene complexes in cancer research stems from their impressive toxicity reported against a range of different human cancer cells. To date, the demonstration of their in vivo efficacy relative to that of established platinum-based drugs has not been specifically addressed. Here, we introduce an innovative approach to increase the NHC-Pt complex potency whereby multiple NHC-Pt(II) complexes are coordinated along a polyethylenimine polymer (PEI) chain. We show that such NHC-Pt(II)-PEI conjugates induce human cancer cell death in vitro and in vivo in a xenograft mouse model with no observable side effects in contrast to oxaliplatin. Additional studies indicate nucleus and mitochondria targeting and suggest various mechanisms of action compared to classical platinum-based anticancer drugs.
Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Compostos Organoplatínicos/química , Compostos Organoplatínicos/farmacologia , Polietilenoimina/química , Animais , Antineoplásicos/metabolismo , Transporte Biológico , Linhagem Celular Tumoral , Humanos , Camundongos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Compostos Organoplatínicos/metabolismo , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Expand and diversify your Ptfolio: N-Heterocyclic carbene-Pt-pyridine complexes have been used to generate an expanded and diversified set of trans NHC-Pt complexes with various amines, polyamines, hydroxylamines, or hydrazine as ligands. Attachment of a fluorophore moiety has also been successfully achieved.
Assuntos
Aminas/química , Complexos de Coordenação/síntese química , Corantes Fluorescentes/síntese química , Compostos Heterocíclicos/síntese química , Metano/análogos & derivados , Nitrogênio/química , Platina/química , Complexos de Coordenação/química , Corantes Fluorescentes/química , Compostos Heterocíclicos/química , Ligantes , Metano/química , Modelos Moleculares , Estrutura Molecular , Relação Estrutura-AtividadeRESUMO
The synthesis of alkyne-substituted N-heterocyclic carbene complexes of Pd(II) and Pt(II) is reported. Catalyzed 1,3-dipolar cycloaddition with azides has been applied as a modular way of functionalisation of group 10 transition metal NHC complexes to generate potentially new metallodrugs.