Psoralenamines. 3. Synthesis, pharmacological behavior, and DNA binding of 5-(aminomethyl)-8-methoxy-, 5-[[(3-aminopropyl)oxy]methyl]- and 8-[(3-aminopropyl)oxy]psoralen derivatives

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Abstract
A series of derivatives of 5-(aminomethyl)-8-methoxypsoralens, 8-[(3-aminopropyl)oxy]psoralens, and 5-[[[3-(trimethylammonio)propyl]oxy]methyl]-8-methoxypsoralen were synthesized and their potential as PUVA [psoralen-UVA] reagents examined. While the DNA association constants of selected psoralens were 105-106 l/mol, corresponding to efficient binding, flow linear dichroism studies indicated that only the 8 substituted psoralens bind to DNA by intercalation. The ability of photoinduce interstrand cross-links in calf thymus DNA, in vitro, was as efficient as that of 8-methoxypsoralen for the 8-substituted psoralens, which were up to 25 times as efficient as the 5-substituted psoralens. Four of the psoralens studied were radiolabeled and used to study photobinding to DNA. Analogously to the cross-binding results, the 8-substituted psoralens were more efficiently photobound than the 5-substituted, while only slight differences were found in the photobinding-cross linking ratio. The photoreactivity of the aminopsoralens toward cyclohexene and 2''-deoxythymidine was enhanced compared to that of 8-methoxypsoralen, the effect being most pronounced when the amino group is close to the furocoumarin ring system. Most of the new compounds were less photocytotoxic than 8-methoxypsoralen to NHIK 3025 cells, in vitro, and they caused less light-induced DNA interstrand cross-linking, in situ, in these cells. A clear correlation between the photocytotoxicity and the DNA cross-linking ability of the psoralens was observed. Several of the derivatives showed more pronounced effects in the light-dependent skin thickening (inflammatory) test on mice than 8-methoxypsoralen. No correlation between DNA cross-linking capacity, in vitro, and skin phototoxicity was found for this series of psoralens.

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