RESUMO
Novel azole compounds were prepared which demonstrated potent hCB2 binding activities with antioxidant activity for a selected compound. These compounds show good selectivity over the hCB1 receptor and are full agonists at the hCB2 receptor.
Assuntos
Azóis/química , Azóis/metabolismo , Agonistas de Receptores de Canabinoides/química , Agonistas de Receptores de Canabinoides/metabolismo , Receptor CB2 de Canabinoide/agonistas , Receptor CB2 de Canabinoide/metabolismo , Animais , Células CHO , Canabinoides/química , Canabinoides/metabolismo , Cricetinae , Cricetulus , HumanosRESUMO
Epstein-Barr virus (EBV)-associated nasopharyngeal carcinomas (NPC) are much more sensitive to chemotherapy than other head and neck carcinomas. Spectacular regressions are frequently observed after induction chemotherapy. However, these favorable responses are difficult to predict and often of short duration. So far there have been only few experiments to investigate the mechanisms which underline the cytotoxic effects of anti-neoplastic drugs against NPC cells. In addition, these studies were performed almost entirely on EBV-negative cell lines therefore not truly representative of NPC cells. For the first time, we have used two EBV-positive NPC tumor lines derived from a North African (C15) and a Chinese (C666-1) patient as in vitro targets for a panel of anti-neoplastic agents. Doxorubicin, taxol and in a lesser extent cis-platinum efficiently inhibited NPC cell proliferation at clinically relevant concentrations, but all three agents failed to induce apoptosis. However, massive apoptosis of C15 cells was achieved when doxorubicin (1 microM) was combined with a farnesyl-transferase inhibitor, BIM 2001 (5 microM). Moreover, this apoptotic process was associated with a caspase-dependent early cleavage of the TNF-receptor associated factor 1 (TRAF-1) molecule, a signaling adaptor which is specifically expressed in latently EBV-infected cells. TRAF-1 cleavage might become a useful indicator of chemo-induced apoptosis in EBV-associated NPCs.
Assuntos
Apoptose , Doxorrubicina/farmacologia , Inibidores Enzimáticos/farmacologia , Compostos Heterocíclicos com 3 Anéis/farmacologia , Neoplasias Nasofaríngeas/patologia , Nitrilas/farmacologia , Proteínas/metabolismo , Alquil e Aril Transferases/antagonistas & inibidores , Divisão Celular/efeitos dos fármacos , Combinação de Medicamentos , Farnesiltranstransferase , Feminino , Herpesvirus Humano 4/isolamento & purificação , Humanos , Neoplasias Nasofaríngeas/metabolismo , Neoplasias Nasofaríngeas/virologia , Fator 1 Associado a Receptor de TNF , Células Tumorais CultivadasRESUMO
A series of hybrid compounds possessing an nNOS pharmacophore linked to an antioxidant fragment has been synthesized. Among them, compound 8d, a propofol derivative, displayed the greatest dual potencies against nNOS (IC(50)=0.12 microM) and lipid peroxidation (IC(50)=0.4 microM) accompanied with e/nNOS selectivity (67.5). This shows that nNOS was able to accommodate very bulky groups such as di-tert-butyl or di-iso-propyl phenol in its active site.
Assuntos
Antioxidantes/síntese química , Antioxidantes/farmacologia , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Óxido Nítrico Sintase/antagonistas & inibidores , Peroxidação de Lipídeos/efeitos dos fármacos , Inibidores de Lipoxigenase/síntese química , Inibidores de Lipoxigenase/farmacologia , Óxido Nítrico Sintase Tipo I , Óxido Nítrico Sintase Tipo III , Propofol/análogos & derivados , Propofol/síntese química , Propofol/farmacologia , Especificidade por SubstratoRESUMO
The synthesis and biological activity of novel lipoic acid analogues are reported. Lipoic acid and structural homologues coupled to arylthiophene amidine via carboxamide linkers are metabolic antioxidants capable of protecting neuronal cells against glutamate cytotoxicity, preventing loss of intracellular glutathione, and inhibit nitric oxide synthase.