Design, synthesis and photobiological properties of 3,4-cyclopentenepsoralens.
The QSAR directed synthesis of tetracyclic psoralen derivatives (3-5) characterised by the condensation of a cyclopentane ring at the level of the 3,4 double bond of the tricyclic psoralen moiety is reported. The new compounds present a methoxy (3), a hydroxy (4) or a dimethylaminopropoxy (5) side chain inserted in position 8 of the lead chromophore. The evaluation of photoantiproliferative activity on human tumour cell lines reveals for 5 an ability to inhibit cell growth significantly higher with respect to that of the reference drug, 8-MOP. Interestingly, the enhancement in antiproliferative activity is accompanied by the disappearance of skin phototoxicity. On the other hand, no significant photobiological activity was scored for 3 and 4. The ability to photoreact with DNA, evaluated by isolating the 4',5' monoadduct and by estimating the ability to form interstrand cross-links, appeared to be significant for 5, practically negligible for 3 and 4. Furthermore, a back-projection of the more active compound identifies structural features suitable for further synthetic modifications.
Gia
Ornella
O
Department of Pharmaceutical Sciences, University of Padova, via Marzolo, 5, 35131 Padova, Italy.
Marciani Magno
Sebastiano
S
Gonzalez-Diaz
Humberto
H
Quezada
Elias
E
Santana
Lourdes
L
Uriarte
Eugenio
E
Dalla Via
Lisa
L
D000818:Animals; D002455:Cell Division / Q000187:drug effects; D004247:DNA / Q000378:metabolism; D015195:Drug Design; D011564:Furocoumarins / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D006168:Guinea Pigs; D006367:HeLa Cells; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D010777:Photochemistry; D021281:Quantitative Structure-Activity Relationship; D012867:Skin / Q000187:drug effects / Q000528:radiation effects
D011564:Furocoumarins; D004247:DNA