Novel pyrone side tetracyclic psoralen derivatives: synthesis and photobiological evaluation.
This study reports the synthesis of tetrahydrobenzo- (4-6) and benzopsoralen (7-9) derivatives obtained by condensing the fourth ring to the pyrone side of the tricyclic psoralen moiety. The new compounds are characterized by having a methoxy, a hydroxy, or a dimethylaminopropoxy side chain inserted at position 8 of the psoralen chromophore. The evaluation of the photoantiproliferative activity on human tumor cell lines along with skin phototoxicity on guinea pigs revealed an interesting photobiological pattern for the dimethylaminopropoxy derivatives 6 and 9: they are in fact able to exert an antiproliferative effect up to 1 order of magnitude higher than that of the well-known drug 8-MOP, but they are devoid of skin phototoxicity. The ability of both 6 and 9 to photoadd to DNA is demonstrated by the isolation and characterization of the 4',5'-monoadducts. AM1 calculations were also performed to gain further insight into the molecular basis of their photobiological behavior.
Dalla Via
Lisa
L
Department of Pharmaceutical Sciences, University of Padova, Via Marzolo 5, 35131 Padova, Italy. lisa.dallavia@unipd.it
Uriarte
Eugenio
E
Quezada
Elias
E
Dolmella
Alessandro
A
Ferlin
Maria Grazia
MG
Gia
Ornella
O
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002942:Circular Dichroism; D003374:Coumarins / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D003432:Cross-Linking Reagents / Q000138:chemical synthesis / Q000737:chemistry; D003510:Cyclohexanes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D053138:Cyclohexenes; D018736:DNA Adducts / Q000138:chemical synthesis; D004354:Drug Screening Assays, Antitumor; D005663:Furans / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011564:Furocoumarins / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006168:Guinea Pigs; D006801:Humans; D007364:Intercalating Agents / Q000138:chemical synthesis / Q000737:chemistry; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D008958:Models, Molecular; D011701:PUVA Therapy; D011753:Pyrones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D012867:Skin / Q000187:drug effects / Q000528:radiation effects; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured; D014466:Ultraviolet Rays
C477190:3,4-cyclohexene-8-(3-dimethylaminopropoxy)-4'-methylfuro(3,2-g)coumarin; C477189:3,4-cyclohexene-8-hydroxy-4'-methylfuro(3,2-g)coumarin; D000970:Antineoplastic Agents; D003374:Coumarins; D003432:Cross-Linking Reagents; D003510:Cyclohexanes; D053138:Cyclohexenes; D018736:DNA Adducts; D005663:Furans; D011564:Furocoumarins; D007364:Intercalating Agents; D011753:Pyrones