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 carrying at position 5 or 8 of the furocoumarin moiety a methoxy, hydroxy, or dimethylaminopropoxy side chain is reported. The study of their photoantiproliferative activity and ability to induce erythema on guinea pig skin allows us to state that the derivatives carrying the dimethylaminopropoxy side chain exhibit a very interesting photobiological pattern. Indeed, if compared with the lead compounds 5-MOP and 8-MOP, they exert a higher cytotoxic activity devoid of significant skin phototoxicity. Between them, the more interesting appears to be 16, a nonphototoxic compound whose antiproliferative activity on HeLa cells is 2 orders of magnitude higher than that of the reference drug 8-MOP. Photoreaction experiments have revealed that, like classic furocoumarins, A-T is the preferred nucleic base pair in its photobinding. Moreover, the extent of covalent photoaddition to DNA correlates well with 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 probably the target accountable for this effect.
Dalla Via
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Department of Pharmaceutical Sciences, University of Padua, and "Centro di Studio sulla Chimica del Farmaco e dei Prodotti Biologicamente Attivi del CNR", Padova, Italy. dallavia@dsfarm.unipd.it
Gia
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Marciani Magno
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Santana
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Teijeira
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Uriarte
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D000078223:5-Methoxypsoralen; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D003374:Coumarins / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D004247:DNA / Q000737:chemistry* / Q000528:radiation effects; D004250:DNA Topoisomerases, Type II / Q000737:chemistry; D004354:Drug Screening Assays, Antitumor; D006168:Guinea Pigs; D006801:Humans; D008730:Methoxsalen / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010778:Photochemotherapy; D012867:Skin / Q000187:drug effects / Q000528:radiation effects; D014407:Tumor Cells, Cultured; D014466:Ultraviolet Rays
C400072:11-dimethylaminopropoxy-4-methylbenzofuro(3,2-g)coumarin; D000970:Antineoplastic Agents; D003374:Coumarins; D000078223:5-Methoxypsoralen; D004247:DNA; D004250:DNA Topoisomerases, Type II; D008730:Methoxsalen