Marzano C, Severin E, Falcomer S, Chilin A, Bordin F
Department of Pharmaceutical Sciences of Padua University, Centro di Studio sulla Chimica del Farmaco e dei Prodotti Biologicamente Attivi del CNR, (associated to the National Institute for the Chemistry of Biological Systems), Padua, Italy.
Mutat Res. 1999 Jan 13;438(2):133-43. doi: 10.1016/s1383-5718(98)00165-x.
The mechanism of action of two tetrahydrobenzopsoralenquinones: 4-methyl-tetrahydrobenzopsoralenquinone (compound 3) and 4-hydroxymethyltetrahydrobenzopsoralenquinone (compound 4) was studied in mammalian cells. These agents differ structurally from earlier benzo and tetrahydrobenzopsoralen derivatives 4-hydroxymethylbenzopsoralen (compound 1) and 4-hydroxymethyltetrahydrobenzopsoralen (compound 2) by the replacement of the benzopyranone with a quinonepyranone. In this study, we evaluated the antiproliferative activity of such derivatives in normal human lymphocytes and CHO cells cultivated in vitro. Compound 4 showed a noticeable antiproliferative activity. Studying the induction of chromosomal aberrations and of SCEs, we demonstrated that compound 4 has a clastogenic effect on mammalian cells. By means of DNA filter elution and protein precipitation techniques we evaluated the DNA damage produced by the tested compounds. Some experiments performed in presence of a DNA synthesis inhibitor showed that ongoing DNA synthesis is involved in cell killing by derivative 4. All data obtained suggest that compound 4 can interfere with the activity of topoisomerase II. Catalytic studies carried out with purified topoisomerase II and bacteriophage DNA confirmed this hypothesis.
4-甲基-四氢苯并补骨脂醌（化合物3）和4-羟甲基四氢苯并补骨脂醌（化合物4）在哺乳动物细胞中的作用机制。这些试剂在结构上与早期的苯并和四氢苯并补骨脂衍生物4-羟甲基苯并补骨脂醌（化合物1）和4-羟甲基四氢苯并补骨脂醌（化合物2）不同，它们用醌并吡喃酮取代了苯并吡喃酮。在本研究中，我们评估了此类衍生物对体外培养的正常人淋巴细胞和CHO细胞的抗增殖活性。化合物4显示出明显的抗增殖活性。通过研究染色体畸变和姐妹染色单体交换的诱导情况，我们证明化合物4对哺乳动物细胞具有致断裂作用。借助DNA过滤洗脱和蛋白质沉淀技术，我们评估了受试化合物产生的DNA损伤。在DNA合成抑制剂存在的情况下进行的一些实验表明，正在进行的DNA合成与衍生物4的细胞杀伤作用有关。获得的所有数据表明化合物4可干扰拓扑异构酶II的活性。用纯化的拓扑异构酶II和噬菌体DNA进行的催化研究证实了这一假设。
