Highly Selective Suppression of Melanoma Cells by Inducible DNA Cross-Linking Agents: Bis(catechol) Derivatives
Highly Selective Suppression of Melanoma Cells by Inducible DNA Cross-Linking Agents: Bis(catechol) Derivatives
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通过诱导型 DNA 交联剂：双（儿茶酚）衍生物高度选择性抑制黑色素瘤细胞
DOI：
10.1021/ja106637e
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发表时间：
2010-11-03
影响因子：
15
通讯作者：
Zhou, Xiang
中科院分区：
文献类型：
--
作者：
Bai, Minghui;Huang, Jing;Zhou, Xiang
设计并合成了一系列双（儿茶酚）季铵衍生物。我们利用亲核试剂3-甲基-2-苯并噻唑啉酮腙（MBTH）对酪氨酸酶诱导的DNA交联能力进行了研究，发现邻醌是这一过程的关键中间体。用MU法检测其对B16F1、Hela和CHO细胞的细胞毒性。这种杀死酪氨酸酶高效黑色素瘤细胞的特殊和有效的能力激发了我们探索其交联DNA能力与其对细胞的选择性细胞毒性之间关系的兴趣。通过细胞内成像检测二羟基苯基、碱性彗星测定和γ - h2ax免疫荧光测定等综合方法，证实了这一推测。双（儿茶酚）季铵衍生物显示出显著的细胞选择性，因为它们在被酪氨酸酶氧化后显示出细胞毒性，并且它们能够有效地靶向酪氨酸酶高效黑色素瘤细胞中的DNA，形成烷基化和交联的物种。
A series of bis(catechol) quaternary ammonium derivatives were designed and synthesized. We investigated their ability to cross-link DNA induced by tyrosinase and found that the o-quinone is key intermediate in the process by using the nucleophile 3-methyl-2-benzothiazolinone hydrazone (MBTH) in the tyrosinase assay. Their cytotoxicities to B16F1, Hela, and CHO cells were tested by MU assays. The specific and potent abilities to kill the tyrosinase-efficient melanoma cells kindled our interest in exploring the relationship between their abilities of cross-linking DNA and their selective cytotoxicities to cells. Through an integrated approach including intracellular imaging for detection of the dihydroxyphenyl groups, alkaline comet assays, and gamma-H2AX immunofluorescence assays, the speculation was confirmed. The bis(catechol) quaternary ammonium derivatives showed notable cell selectivity because they displayed cytotoxicities after being oxidized by tyrosinase, and they were able to target the DNA efficiently in the tyrosinase-efficient melanoma cells, forming both alkylated and cross-linked species.