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首页> 外文期刊>Journal of Medicinal Chemistry >New tetracyclic analogues of photochemotherapeutic drugs 5-MOP and 8-MOP: synthesis, DNA interaction, and antiproliferative activity.
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New tetracyclic analogues of photochemotherapeutic drugs 5-MOP and 8-MOP: synthesis, DNA interaction, and antiproliferative activity.

机译：光化学治疗药物5-MOP和8-MOP的新四环类似物：合成，DNA相互作用和抗增殖活性。

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摘要

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.
机译：据报道，合成了在呋喃香豆素部分的5或8位带有甲氧基，羟基或二甲基氨基丙氧基侧链的新的四氢苯并-和苯并补骨脂素衍生物。对它们的光抗增殖活性和在豚鼠皮肤上诱导红斑的能力的研究使我们能够指出，携带二甲基氨基丙氧基侧链的衍生物表现出非常有趣的光生物学模式。实际上，如果与先导化合物5-MOP和8-MOP相比，它们发挥更高的细胞毒性活性，而没有明显的皮肤光毒性。在它们之间，更有趣的是16，这是一种非光毒性化合物，其对HeLa细胞的抗增殖活性比参考药物8-MOP高2个数量级。光反应实验表明，像经典的呋喃香豆素一样，A-T是其光结合中的首选核酸碱基对。此外，DNA共价光加成的程度与光生物学活性密切相关。对于这种化合物，在黑暗中也观察到一定的效果。对在人类拓扑异构酶II存在下诱导DNA裂解的能力的评估表明，该酶可能是造成这种效应的靶标。

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