New tetracyclic analogues of photochemotherapeutic drugs 5-MOP and 8-MOP: Synthesis, DNA interaction, and antiproliferative activity

The synthesis of new tetrahydrobenzo- and benzopsoralen derivatives carryin g at position 5 or 8 of the furocoumarin moiety a methoxy, hydroxy, or dime thylaminopropoxy side chain is reported. The study of their photoantiprolif erative activity and ability to induce erythema on guinea pig skin allows u s to state that the derivatives carrying the dimethylaminopropoxy side. cha in exhibit a very interesting photobiological pattern. Indeed, if compared with the lead compounds 5-MOP and 8-MOP, they exert a higher cytotoxic acti vity devoid of significant skin phototoxicity. Between them, the more inter esting appears to be 16, a nonphototoxic compound whose antiproliferative a ctivity on HeLa cells is 2 orders of magnitude higher than that of the refe rence drug 8-MOP. Photoreaction experiments have revealed that, like classi c furocoumarins, A-T is the preferred nucleic base pair in its photobinding . Moreover, the extent of covalent photoaddition to DNA correlates well wit h the photobiological activity. For this compound a certain effect was also observed in the dark. Evaluation of the ability to induce DNA cleavage in the presence of human topoisomerase II has suggested that this enzyme is pr obably the target accountable for this effect.