Abstract
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 furocoumarin moiety. The photoantiproliferative activity of all compounds, tested on two human tumor cell lines (HeLa and HL-60), appeared from 8 to 22 times higher than that of the well-known photochemotherapeutic drug 8-methoxypsoralen (8-MOP) in HeLa, slightly higher in HL-60. 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.
Highlights
Inside the wide field of photochemotherapy the psoralens play a significant role
The synthesized cyclopentenepsoralen bearing the cyclopentane ring fused to the 4',5' double bond appears to show a slight improvement in photobiological properties, i.e. increased photoantiproliferative activity on human tumor cell line and diminished skin photosensitization, with respect to the drug 8-MOP.16
Comparing the above results with the chemical molecular structure of the tetracyclic methyl derivatives, it is evident that the extension of the tricyclic psoralen moiety, due to the condensation of a fourth ring, appears to be always relevant to increase the photoantiproliferative activity
Summary
Inside the wide field of photochemotherapy the psoralens play a significant role. In particular, skin diseases characterized by hyperproliferation, such as psoriasis, are effectively treated by means of PUVA therapy (psoralen plus UVA light).1-3 psoralens are successfully employed for the treatment of cutaneous T-cell lymphoma, a T-cell mediated disorder, by an extracorporeal photochemotherapy called photopheresis.4,5 the existence of some undesired side-effects limits the therapeutic use of psoralens. As regards the tetrahydrobenzopsoralen moiety, the most interesting derivatives showed a cytotoxic activity higher with respect to that exerted by the reference drug along with a significant decrease of skin phototoxicity.14,15 The condensation of a cyclopentane ring to the tricyclic psoralen nucleus was reported.16 In detail, the synthesized cyclopentenepsoralen bearing the cyclopentane ring fused to the 4',5' double bond appears to show a slight improvement in photobiological properties, i.e. increased photoantiproliferative activity on human tumor cell line and diminished skin photosensitization, with respect to the drug 8-MOP.16
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