Hydrogen peroxide activated quinone methide precursors with enhanced DNA cross-linking capability and cytotoxicity towards cancer cells.
Hydrogen peroxide activated quinone methide precursors with enhanced DNA cross-linking capability and cytotoxicity towards cancer cells.
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DOI：
10.1016/j.ejmech.2017.03.041
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发表时间：
2017-06-16
影响因子：
6.7
通讯作者：
Peng X
中科院分区：
文献类型：
--
作者：
Wang Y;Fan H;Balakrishnan K;Lin Z;Cao S;Chen W;Fan Y;Guthrie QA;Sun H;Teske KA;Gandhi V;Arnold LA;Peng X
由内源性H2O2诱导形成的醌类化合物（QM）在生物医学领域具有广泛的应用前景。为了克服目前h2o2活化的QM前体生物活性低的局限性，我们在苯环的不同位置和/或不同的中性离开基上引入了几种新的芳基硼酸盐。用溴代替乙酰氧基，加快了芳基硼酸酯与H2O2的反应速度，并促进了双醌类化合物的生成和DNA交联。此外，在醌的新生的外亚甲基上放置一个给体基团，极大地改善了h2o2诱导的DNA链间交联的形成，并提高了细胞活性。多个供体基团降低了稳定性和DNA交联能力，从而导致细胞活性降低。基于细胞的筛选表明，含有OMe或OH基团的化合物2a和5a显著抑制各种组织源性癌细胞的生长，而正常细胞受到的影响较小。这些化合物在CLL淋巴细胞中诱导H2AX磷酸化，为细胞死亡和DNA损伤之间的相关性提供了证据。所述化合物具有较强的抗癌活性和选择性，为抗癌药物的开发提供了新的框架。
Quinone methide (QM) formation induced by endogenously generated H2O2 is attractive for biological and biomedical applications. To overcome current limitations due to low biological activity of H2O2-activated QM precursors, we are introducing herein several new arylboronates with electron donating substituents at different positions of benzene ring and/or different neutral leaving groups. The reaction rate of the arylboronate esters with H2O2 and subsequent bisquinone methides formation and DNA cross-linking was accelerated with the application of Br as a leaving group instead of acetoxy groups. Additionally, a donating group placed meta to the nascent exo-methylene group of the quinone methide greatly improves H2O2-induced DNA interstrand cross-link formation as well as enhances the cellular activity. Multiple donating groups decrease the stability and DNA cross-linking capability, which lead to low cellular activity. A cell-based screen demonstrated that compounds 2a and 5a with a OMe or OH group dramatically inhibited the growth of various tissue-derived cancer cells while normal cells were less affected. Induction of H2AX phosphorylation by these compounds in CLL lymphocytes provide evidence for a correlation between cell death and DNA damage. The compounds presented herein showed potent anticancer activities and selectivity, which represent a novel scaffold for anticancer drug development.
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影响因子：
4.2
作者：
Peng X;Gandhi V
通讯作者：
Gandhi V
影响因子：
7.3
作者：
MAUGER, AB;BURKE, PJ;KNOX, RJ
通讯作者：
KNOX, RJ
影响因子：
4.3
作者：
Cao, Sheng;Christiansen, Robin;Peng, Xiaohua
通讯作者：
Peng, Xiaohua
影响因子：
3.6
作者：
Cao, Sheng;Wang, Yibin;Peng, Xiaohua
通讯作者：
Peng, Xiaohua
活性氧 (ROS) 诱导 DNA 交联剂及其对癌细胞和正常淋巴细胞的影响
影响因子：
7.3
作者：
Chen, Wenbing;Balakrishnan, Kumudha;Peng, Xiaohua
通讯作者：
Peng, Xiaohua