New furan side tetracyclic allopsoralen derivatives: synthesis and photobiological evaluation.
Novel tetracyclic allopsoralen derivatives characterized by the condensation of a fourth cyclohexenylic (5-7) or benzenic (8-10) ring at the furan side and a methoxy (5 and 8), a hydroxy (6 and 9), or a dimethylaminopropoxy (7 and 10) side chain in the 10 position of the chromophore were prepared. Compounds 7 and 10 showed a strong photoantiproliferative activity, up to 3 orders of magnitude higher than that of the photochemotherapeutic drug 8-methoxypsoralen (8-MOP). The investigation into the mechanism of action demonstrated for 10 the capacity to intercalate between DNA base pairs in the ground state, to give rise to a covalent photoaddition upon UVA irradiation, and to inhibit polymerase chain reaction (PCR) in a sequence-specific manner. Conversely, compound 7 showed a limited capacity to form an intercalative complex and the lack of ability to photoadd to the macromolecule, thus revealing a novel and unusual behavior for an allopsoralen derivative.
Dalla Via
Lisa
L
Department of Pharmaceutical Sciences, University of Padova, Via Marzolo 5, 35131 Padova, Italy. lisa.dallavia@unipd.it
Mammi
Stefano
S
Uriarte
Eugenio
E
Santana
Lourdes
L
Lampronti
Ilaria
I
Gambari
Roberto
R
Gia
Ornella
O
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology / Q000633:toxicity; D045744:Cell Line, Tumor; D018736:DNA Adducts / Q000138:chemical synthesis; D004250:DNA Topoisomerases, Type II / Q000737:chemistry; D003624:Darkness; D004354:Drug Screening Assays, Antitumor; D005663:Furans / Q000138:chemical synthesis* / Q000494:pharmacology / Q000633:toxicity; D011564:Furocoumarins / Q000138:chemical synthesis* / Q000494:pharmacology / Q000633:toxicity; D006168:Guinea Pigs; D006576:Heterocyclic Compounds, 4 or More Rings / Q000138:chemical synthesis* / Q000494:pharmacology / Q000633:toxicity; D006801:Humans; D007364:Intercalating Agents / Q000138:chemical synthesis* / Q000494:pharmacology / Q000633:toxicity; D011701:PUVA Therapy; D016133:Polymerase Chain Reaction; D012867:Skin / Q000187:drug effects; D013329:Structure-Activity Relationship; D013941:Thymine / Q000737:chemistry; D018675:Toxicity Tests; D014466:Ultraviolet Rays
D000970:Antineoplastic Agents; D018736:DNA Adducts; D005663:Furans; D011564:Furocoumarins; D006576:Heterocyclic Compounds, 4 or More Rings; D007364:Intercalating Agents; D004250:DNA Topoisomerases, Type II; D013941:Thymine