Synthesis and photobiological properties of 4-hydroxymethyl-4'-methylpsoralen derivatives.
The synthesis and the photobiological activity of two new hydroxymethyl derivatives of psoralen namely 4-hydroxymethyl-4'-methyl- and 4-hydroxymethyl-4'-methyl-8-methoxypsoralen are described. Both compounds exhibited efficient photobinding to DNA and RNA. The DNA-photobinding process was investigated using different nucleic acid structures such as double-helical DNA, ribosomal RNA, bacterial DNA and DNA organized in the nucleosomal arrangement. The test derivatives were able to induce cross-links to a similar extent as 8-methoxypsoralen (8-MOP), used as a reference photochemotherapeutic drug. In contrast to 8-MOP, they produced relatively high levels of 1O2. Most photobiological effects (DNA synthesis inhibition, T2 phage sensitization, inhibition of tumor transmitting capacity) showed a good correlation with the extent of covalent photoaddition. On the other hand, the new 4-hydroxymethylpsoralens were unable to induce skin erythema, in striking contrast with 8-MOP. Thus, neither cross-linking of the nucleic acid nor 1O2 production were coupled with skin phototoxicity in this class of compounds. The new derivatives appear to represent an important beginning to development of new active photochemotherapeutic agents devoid of undesired phototoxic side effects.
Zagotto
G
G
Department of Pharmaceutical Sciences of Padua University, Padova, Italy.
Gia
O
O
Baccichetti
F
F
Uriarte
E
E
Palumbo
M
M
D000818:Animals; D004247:DNA / Q000737:chemistry / Q000528:radiation effects*; D004307:Dose-Response Relationship, Radiation; D004890:Erythema / Q000139:chemically induced; D011564:Furocoumarins / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity; D006168:Guinea Pigs; D008730:Methoxsalen; D017319:Photosensitizing Agents / Q000737:chemistry*; D012313:RNA / Q000737:chemistry / Q000528:radiation effects*; D012867:Skin / Q000187:drug effects / Q000473:pathology; D014466:Ultraviolet Rays
D011564:Furocoumarins; D017319:Photosensitizing Agents; D012313:RNA; D004247:DNA; D008730:Methoxsalen