title: Novel angular furo and thieno-quinolinones: synthesis and preliminary photobiological studies.
abstract: 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.
authors.affiliation: Dipartimento di Scienze Farmaceutiche, Universita' di Genova, Viale Benedetto XV 3, 16132 Genoa, Italy. fossap@unige.it
authors.forename: Paola
authors.initials: P
authors.lastname: Fossa
authors.forename: Luisa
authors.initials: L
authors.lastname: Mosti
authors.forename: Giulia
authors.initials: G
authors.lastname: Menozzi
authors.forename: Cristina
authors.initials: C
authors.lastname: Marzano
authors.forename: Franca
authors.initials: F
authors.lastname: Baccichetti
authors.forename: Franco
authors.initials: F
authors.lastname: Bordin
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000138:chemical synthesis / Q000494:pharmacology; D001435:Bacteriophages / Q000187:drug effects / Q000528:radiation effects; D004247:DNA / Q000096:biosynthesis / Q000187:drug effects / Q000528:radiation effects; D004890:Erythema / Q000139:chemically induced / Q000209:etiology; D004926:Escherichia coli / Q000187:drug effects / Q000235:genetics / Q000528:radiation effects; D011564:Furocoumarins / Q000009:adverse effects / Q000138:chemical synthesis / Q000494:pharmacology; D006168:Guinea Pigs; D006801:Humans; D011701:PUVA Therapy / Q000009:adverse effects / Q000379:methods; D017319:Photosensitizing Agents / Q000009:adverse effects / Q000138:chemical synthesis* / Q000494:pharmacology; D015363:Quinolones / Q000009:adverse effects / Q000138:chemical synthesis* / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000528:radiation effects; D014466:Ultraviolet Rays
chemical_list: D000970:Antineoplastic Agents; D011564:Furocoumarins; D017319:Photosensitizing Agents; D015363:Quinolones; D004247:DNA