Methyl derivatives of tetracyclic psoralen analogues: antiproliferative activity and interaction with DNA

A number of new tetracyclic psoralen derivatives were studied. The fourth ring is constituted by cyclopentane (4, 7 and 9), cyclohexane (11, 15 and 18) or benzene (12, 16 and 20) fused to either 4',5' or 3,4 photoreactive double bond of tricyclic furopcoumarin moiety. The photoantiproliferative activity of all compounds, tested on two human tumor cell lines (HeLa and HL60), appeared from 8 to 22 times higher than that of the well-known photochemotherapeutic drug 8-methoxypsoralen (8-MOP) in HeLa, slightly higher in HL60. Interestingly, the evaluation of skin phototoxicity on guinea pigs evidenced a decrease in erythema induction for all compounds with respect to the drug. As regards the molecular mechanism of action, the ability to photoadd to DNA is demonstrated by isolation and characterization of the photoadducts and by the ability to give rise to interstrand cross-links for the difunctional derivatives.