RESUMEN
1,4,8-Trimethylfuro[2,3-h]quinolin-2(1H)-one (compound 5a) is the most interesting derivative among some new furoquinolinones prepared with the aim of moderating the strong toxic effects of 1,4,6,8-tetramethyl derivative (FQ), a powerful potential drug for photomedicine. Compound 5a showed a photobiological activity lower than FQ, but considerable higher than 8-MOP, the furocoumarin used in clinical photomedicine; contrary to classic furocoumarins, 5a induced a strong inhibition of protein synthesis in mammalian cells. Genotoxicity and skin erythema induction, the main side effects of both FQ and 8-MOP photosensitization, are virtually absent with 5a. This behavior seems to be connected to its particular reaction mechanism: differently from furocoumarin derivatives, 5a induced low levels of DNA-protein and no inter-strands cross-links, but formed covalent RNA-protein linkages, lesions not observed with known furocoumarins. Moreover, compound 5a generated reactive oxygen species to a considerable extent. For these features, compound 5a appears to be a new photosensitizing agent whose special activity deserves to be deeply investigated.
Asunto(s)
Furanos/farmacología , Furanos/toxicidad , Furocumarinas/farmacología , Furocumarinas/toxicidad , Fármacos Fotosensibilizantes/farmacología , Fármacos Fotosensibilizantes/toxicidad , Quinolonas/farmacología , Quinolonas/toxicidad , Animales , División Celular/efectos de los fármacos , Línea Celular Tumoral , Cricetinae , ADN/efectos de los fármacos , ADN/metabolismo , Replicación del ADN/efectos de los fármacos , Relación Dosis-Respuesta en la Radiación , Evaluación Preclínica de Medicamentos , Furanos/síntesis química , Furocumarinas/síntesis química , Células HeLa/efectos de los fármacos , Humanos , Ratones , Estructura Molecular , Fotobiología , Fármacos Fotosensibilizantes/síntesis química , Proteínas/efectos de los fármacos , Proteínas/metabolismo , Quinolonas/síntesis química , ARN/efectos de los fármacos , ARN/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Piel/efectos de los fármacos , Piel/efectos de la radiación , Rayos Ultravioleta/efectos adversosRESUMEN
A number of new furo and thienoquinolinones carrying an electron-withdrawing function or unsubstituted at the position 3 were synthesized in order to obtain new potential photochemotherapeutic agents with increased antiproliferative activity and decreased toxic side effects. Our interest in studying the SAR of these derivatives also prompted us to investigate the influence of N-methylation on biological activity, by preparing N-methyl derivatives. The antiproliferative activity of all the newly synthesized compounds was evaluated and compared to 8-methoxypsoralen (8-MOP), the drug widely used in PUVA-therapy. The 3-unsubstituted thienoquinolinones were generally the most potent derivatives, followed by the furo-analogues. In particular, the unsubstituted thieno[2,3-h]quinoline-2(1H)one showed the highest activity in T2 bacteriophage, HeLa cells and Ehrlich cells tests. All the compounds, assayed on Escherichia coli WP2 TM9, showed a similar mutagenic activity, very close to that of 8-MOP. Except for 2-oxo-1,2-dihydrothieno[2,3-h]quinoline-3-carboxylic acid, which appeared to be very effective, all compounds generated singlet oxygen to slightly larger amounts when compared to 8-MOP. The N-methyl analogues only induced moderate skin erythemas on albino guinea pigs, while all other derivatives appeared to be entirely inactive. On the basis of these results, the unsubstituted thieno[2,3h]quinoline 2(1H)one seems to be the most interesting potential drug for PUVA photochemotherapy and photopheresis.