RESUMO
Organometallic compounds which contain metals, such as ruthenium or gold, have been investigated as a replacement for platinum-derived anticancer drugs. They often show good antitumor effects, but the identification of their precise mode of action or their pharmacological optimization is still challenging. We have previously described a class of ruthenium(II) compounds with interesting anticancer properties. In comparison to cisplatin, these molecules have lower side effects, a reduced ability to interact with DNA, and they induce cell death in absence of p53 through CHOP/DDIT3. We have now optimized these molecules by improving their cytotoxicity and their water solubility. In this article, we demonstrate that by changing the ligands around the ruthenium we modify the ability of the compounds to interact with DNA. We show that these optimized molecules reduce tumor growth in different mouse models and retain their ability to induce CHOP/DDIT3. However, they are more potent inducers of cancer cell death and trigger the production of reactive oxygen species and the activation of caspase 8. More importantly, we show that blocking reactive oxygen species production or caspase 8 activity reduces significantly the activity of the compounds. Altogether our data suggest that water-soluble ruthenium(II)-derived compounds represent an interesting class of molecules that, depending on their structures, can target several pro-apoptotic signaling pathways leading to reactive oxygen species production and caspase 8 activation.
Assuntos
Antineoplásicos/farmacologia , Caspase 8/biossíntese , Espécies Reativas de Oxigênio/metabolismo , Compostos de Rutênio/farmacologia , Água/química , Animais , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Indução Enzimática , Transferência Ressonante de Energia de Fluorescência , Humanos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Reação em Cadeia da Polimerase em Tempo Real , Compostos de Rutênio/química , SolubilidadeRESUMO
A library of 32 organoruthenium compounds has been synthesised. Known and novel C-N cyclometalated compounds as well as N-C-N and N-N-C pincer derivatives of this metal have been used in this purpose. Most of the compounds have been tested for their in vitro antitumoral behaviours, good to excellent activities have thus been found. Several of the newly synthesized compounds pass the symbolic barrier of the nanomolar range for their IC(50) indicating a critical improvement. The level of activity is tentatively correlated to physicochemical properties of the compounds such as their Ru(III/II) redox potential and their lipophilicity (log P).
Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Compostos Organometálicos/química , Compostos Organometálicos/farmacologia , Rutênio/química , Rutênio/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Neoplasias do Colo/tratamento farmacológico , Ensaios de Seleção de Medicamentos Antitumorais , HumanosRESUMO
Human 17beta-hydroxysteroid dehydrogenase type 1 (17beta-HSD1) catalyzes the reduction of the weak estrogen estrone (E1) to the highly potent estradiol (E2). This reaction takes place in the target cell where the estrogenic effect is exerted via the estrogen receptor (ER). Estrogens, especially E2, are known to stimulate the proliferation of hormone-dependent diseases. 17beta-HSD1 is overexpressed in many breast tumors. Thus, it is an attractive target for the treatment of these diseases. Ligand- and structure-based drug design led to the discovery of novel, selective, and potent inhibitors of 17beta-HSD1. Phenyl-substituted bicyclic moieties were synthesized as mimics of the steroidal substrate. Computational methods were used to obtain insight into their interactions with the protein. Compound 5 turned out to be a highly potent inhibitor of 17beta-HSD1 showing good selectivity (17beta-HSD2, ERalpha and beta), medium cell permeation, reasonable metabolic stability (rat hepatic microsomes), and little inhibition of hepatic CYP enzymes.
Assuntos
17-Hidroxiesteroide Desidrogenases/antagonistas & inibidores , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Estrogênios/metabolismo , Naftalenos/síntese química , Naftalenos/farmacologia , Neoplasias Hormônio-Dependentes/tratamento farmacológico , Neoplasias Hormônio-Dependentes/enzimologia , Quinolinas/síntese química , Quinolinas/farmacologia , Animais , Hidrocarboneto de Aril Hidroxilases/antagonistas & inibidores , Sítios de Ligação , Células CACO-2 , Simulação por Computador , Desenho de Fármacos , Inibidores Enzimáticos/química , Humanos , Ligação de Hidrogênio , Fígado/enzimologia , Masculino , Microssomos Hepáticos/metabolismo , Modelos Moleculares , Estrutura Molecular , Naftalenos/química , Quinolinas/química , Ratos , Ratos Sprague-Dawley , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
We synthesized 3-O-methylviridicatin and several analogues of this fungal metabolite. We showed that replacement of the methoxy moiety by a thiomethyl enhanced dramatically its ability to inhibit TNF-alpha secretion. These results strongly suggest that 4-phenyl-3-methylthioquinolinone may provide the basis for the development of new anti-inflammatory agents.