1,4,8-trimethylfuro[2,3-H]quinolin-2(1H)-one, a new furocoumarin bioisoster.
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.
Marzano
Cristina
C
Department of Pharmaceutical Sciences of Padova University, Via Marzolo 5, 35131, Padova, Italy.
Chilin
Adriana
A
Baccichetti
Francarosa
F
Bettio
Frazia
F
Guiotto
Adriano
A
Miolo
Giorgia
G
Bordin
Franco
F
D000818:Animals; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D006224:Cricetinae; D004247:DNA / Q000187:drug effects / Q000378:metabolism; D004261:DNA Replication / Q000187:drug effects; D004307:Dose-Response Relationship, Radiation; D004353:Drug Evaluation, Preclinical; D005663:Furans / Q000138:chemical synthesis / Q000494:pharmacology* / Q000633:toxicity*; D011564:Furocoumarins / Q000138:chemical synthesis / Q000494:pharmacology* / Q000633:toxicity*; D006367:HeLa Cells / Q000187:drug effects; D006801:Humans; D051379:Mice; D015394:Molecular Structure; D018462:Photobiology; D017319:Photosensitizing Agents / Q000138:chemical synthesis / Q000494:pharmacology* / Q000633:toxicity*; D011506:Proteins / Q000187:drug effects / Q000378:metabolism; D015363:Quinolones / Q000138:chemical synthesis / Q000494:pharmacology* / Q000633:toxicity*; D012313:RNA / Q000187:drug effects / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D012867:Skin / Q000187:drug effects / Q000528:radiation effects; D014466:Ultraviolet Rays / Q000009:adverse effects
C494223:1,4,8-trimethylfuro(2,3-H)quinolin-2(1H)-one; D005663:Furans; D011564:Furocoumarins; D017319:Photosensitizing Agents; D011506:Proteins; D015363:Quinolones; D017382:Reactive Oxygen Species; D012313:RNA; D004247:DNA