Novel stable camptothecin derivatives replacing the E-ring lactone by a ketone function are potent inhibitors of topoisomerase I and promising antitumor drugs
Novel stable camptothecin derivatives replacing the E-ring lactone by a ketone function are potent inhibitors of topoisomerase I and promising antitumor drugs
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DOI：
10.1124/mol.107.034637
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发表时间：
2007-08-01
影响因子：
3.6
通讯作者：
Pierre, Alain
中科院分区：
文献类型：
--
作者：
Lansiaux, Amelie;Leonce, Stephane;Pierre, Alain
E-环内酯是喜树碱衍生物的致命弱点：尽管它被认为是抑制拓扑异构酶I（topo 1）所必需的，但内酯打开成羧酸酯消除了topo 1介导的DNA断裂的产生。S38809是一种新型喜树碱类似物，具有稳定的5元E环酮;因此，它缺乏内酯功能。DNA松弛和切割试验表明，S38809通过刺激T向下箭头G位点的DNA切割来发挥典型的topo 1毒物的作用。活性强烈依赖于带有羟基的C-7碳原子的立体化学。在一组31种人肿瘤细胞系中，S38809被证明是一种强效细胞毒性药物，平均IC 50为5.4 nM，而拓扑替康为11.6 nM，SN 38（伊立替康的活性代谢产物）为3.3 nM。S38809的细胞毒性及其稳定可裂解复合物的能力在表达突变的topo 1的喜树碱抗性细胞中显著降低，证实topo 1是其主要靶点。topo 1中毒诱导的细胞死亡需要将DNA单链断裂转化为双链断裂，这可以通过磷酸化组蛋白H2 AX的形成来检测。在HCT 116细胞中，托泊替康、SN 38和S38809在细胞周期的S期诱导组蛋白H2 AX磷酸化，S38809与SN 38一样有效，比托泊替康有效5倍。在体内，S38809对HCT 116异种移植物显示出显著的抗肿瘤活性。这些发现为提高喜树碱衍生物的药理活性开辟了一条新的途径。
The E-ring lactone is the Achilles' heel of camptothecin derivatives: although it is considered necessary for the inhibition of the enzyme topoisomerase I (topo1), the opening of the lactone into a carboxylate abolishes the generation of topo1-mediated DNA breaks. S38809 is a novel camptothecin analog with a stable 5-membered E-ring ketone; therefore, it lacks the lactone function. DNA relaxation and cleavage assays revealed that S38809 functions as a typical topo1 poison by stimulating DNA cleavage at T down arrow G sites. The activity was strongly dependent on the stereochemistry of the C-7 carbon atom that bears the hydroxy group. S38809 proved to be a potent cytotoxic agent, with a mean IC50 of 5.4 nM versus 11.6 nM for topotecan and 3.3 nM for SN38 (the active metabolite of irinotecan) on a panel of 31 human tumor cell lines. The cytotoxicity of S38809 and its ability to stabilize cleavable complexes was considerably reduced in camptothecin-resistant cells that express a mutated topo1, confirming that topo1 is its primary target. Cell death induced by topo1 poisoning requires the conversion of DNA single-strand breaks into double-strand breaks that can be detected by the formation of phosphorylated histone H2AX. In HCT116 cells, topotecan, SN38, and S38809 induced histone H2AX phosphorylation in S phase of the cell cycle, with S38809 being as potent as SN38 and 5-fold more potent than topotecan. In vivo, S38809 showed a marked antitumor activity against HCT116 xenografts. These findings open a new route for improving the pharmacological properties of camptothecin derivatives.