SYNTHESIS AND PHOTOBIOLOGICAL PROPERTIES OF 4-HYDROXYMETHYL-4'-METHYLPSORALEN DERIVATIVES

The synthesis and the photobiological activity of two new hydroxymethy l derivatives of psoralen namely 4-hydroxymethyl-4'-methyl- and 4-hydr oxymethyl-4'-methyl-8-methoxypsoralen are described. Both compounds ex hibited efficient photobinding to DNA and RNA. The DNA-photobinding pr ocess 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 pr oduced relatively high levels of O-1(2). Most photobiological effects (DNA synthesis inhibition, T2 phage sensitization, inhibition of tumor transmitting capacity) showed a good correlation with the extent of c ovalent photoaddition. On the other hand, the new 4-hydroxymethylpsora lens were unable to induce skin erythema, in striking contrast with 8- MOP. Thus, neither cross-linking of the nucleic acid nor O-1(2) produc tion were coupled with skin phototoxicity in this class of compounds. The new derivatives appear to represent an important beginning to deve lopment of new active photochemotherapeutic agents devoid of undesired phototoxic side effects.