Dalla Via Lisa, Mammi Stefano, Uriarte Eugenio, Santana Lourdes, Lampronti Ilaria, Gambari Roberto, Gia Ornella
Department of Pharmaceutical Sciences, University of Padova, Via Marzolo 5, 35131 Padova, Italy.
J Med Chem. 2006 Jul 13;49(14):4317-26. doi: 10.1021/jm058032q.
Novel tetracyclic allopsoralen derivatives characterized by the condensation of a fourth cyclohexenylic (5-7) or benzenic (8-10) ring at the furan side and a methoxy (5 and 8), a hydroxy (6 and 9), or a dimethylaminopropoxy (7 and 10) side chain in the 10 position of the chromophore were prepared. Compounds 7 and 10 showed a strong photoantiproliferative activity, up to 3 orders of magnitude higher than that of the photochemotherapeutic drug 8-methoxypsoralen (8-MOP). The investigation into the mechanism of action demonstrated for 10 the capacity to intercalate between DNA base pairs in the ground state, to give rise to a covalent photoaddition upon UVA irradiation, and to inhibit polymerase chain reaction (PCR) in a sequence-specific manner. Conversely, compound 7 showed a limited capacity to form an intercalative complex and the lack of ability to photoadd to the macromolecule, thus revealing a novel and unusual behavior for an allopsoralen derivative.
制备了新型四环补骨脂素衍生物，其特征在于在呋喃侧稠合了第四个环己烯基（5-7）或苯环（8-10），并且在发色团的10位带有甲氧基（5和8）、羟基（6和9）或二甲基氨基丙氧基（7和10）侧链。化合物7和10表现出很强的光抗增殖活性，比光化学治疗药物8-甲氧基补骨脂素（8-MOP）高3个数量级。对作用机制的研究表明，化合物10能够在基态下插入DNA碱基对之间，在UVA照射下产生共价光加成，并以序列特异性方式抑制聚合酶链反应（PCR）。相反，化合物7形成插入复合物的能力有限，且缺乏与大分子进行光加成的能力，从而揭示了补骨脂素衍生物一种新颖且不寻常的行为。
