Chloroethylating and methylating dual function antineoplastic agents display superior cytotoxicity against repair proficient tumor cells.
Chloroethylating and methylating dual function antineoplastic agents display superior cytotoxicity against repair proficient tumor cells.
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DOI：
10.1016/j.bmcl.2013.01.016
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发表时间：
2013-03-15
影响因子：
2.7
通讯作者：
Sartorelli, Alan C.
中科院分区：
文献类型：
--
作者：
Zhu, Rui;Baumann, Raymond P.;Patridge, Eric;Penketh, Philip G.;Shyam, Krishnamurthy;Ishiguro, Kimiko;Sartorelli, Alan C.
关键词：
以临床活性前药拉莫司汀的结构为基础，合成了两种新型药物。2-（2-氯乙基）-N-甲基-1,2-双（甲基磺酰基）-N-亚硝基肼甲酰胺(1)和N-（2-氯乙基）-2-甲基-1,2-双（甲基磺酰基）-N-亚硝基肼甲酰胺(2)保留了拉莫司汀有效的氯乙基化和DNA交联功能，并获得了在鸟嘌呤O-6位置甲基化DNA的能力，同时缺乏拉莫司汀的氨基甲酰化活性。甲基化臂的引入是为了消耗DNA修复蛋白o6 -烷基鸟嘌呤-DNA烷基转移酶（AGT）。化合物1对AGT - EMT6小鼠乳腺癌细胞和高AGT表达DU145人前列腺癌细胞的细胞毒性均明显高于拉莫司汀。DNA交联研究表明，其交联效率与预测的活性分解产物1,2-二（甲基磺酰基）-1-（2-氯乙基）肼（90CE）几乎相同，后者也是由拉莫司汀产生的。在DU145细胞中进行的AGT消融研究表明，1可以有效地消耗AGT。研究分析了1和2对水的甲基化和氯乙基化产生的甲醇和2-氯乙醇，证实了它们作为甲基化和氯乙基化剂的能力，并为1的优越活性提供了见解。
Two new agents based upon the structure of the clinically active prodrug laromustine were synthesized. These agents, 2-(2-chloroethyl)-N-methyl-1,2-bis(methylsulfonyl)-N-nitrosohydrazinecarboxamide (1) and N-(2-chloroethyl)-2-methyl-1,2-bis(methylsulfonyl)-N-nitrosohydrazinecarboxamide (2), were designed to retain the potent chloroethylating and DNA cross-linking functions of laromustine, and gain the ability to methylate DNA at the O-6 position of guanine, while lacking the carbamoylating activity of laromustine. The methylating arm was introduced with the intent of depleting the DNA repair protein O6-alkylguanine-DNA alkyltransferase (AGT). Compound 1 is markedly more cytotoxic than laromustine in both AGT minus EMT6 mouse mammary carcinoma cells and high AGT expressing DU145 human prostate carcinoma cells. DNA cross-linking studies indicated that its cross-linking efficiency is nearly identical to its predicted active decomposition product, 1,2-bis(methylsulfonyl)-1-(2-chloroethyl)hydrazine (90CE), which is also produced by laromustine. AGT ablation studies in DU145 cells demonstrated that 1 can efficiently deplete AGT. Studies assaying methanol and 2-chloroethanol production as a consequence of the methylation and chloroethylation of water by 1 and 2 confirmed their ability to function as methylating and chloroethylating agents and provided insights into the superior activity of 1.
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DOI：
10.1016/j.bbrc.2008.11.042
发表时间：
2009-01-16
影响因子：
3.1
作者：
Frederick, Abbie M.;Davis, Marguerite L.;Rice, Kevin P.
通讯作者：
Rice, Kevin P.
影响因子：
5.8
作者：
Baumann, Raymond P.;Penketh, Philip G.;Ishiguro, Kimiko;Shyam, Krishnamurthy;Zhu, Yong L.;Sartorelli, Alan C.
通讯作者：
Sartorelli, Alan C.
影响因子：
3.1
作者：
Baumann, RP;Seow, HA;Sartorelli, AC
通讯作者：
Sartorelli, AC
影响因子：
5.8
作者：
Penketh, PG;Shyam, K;Sartorelli, AC
通讯作者：
Sartorelli, AC
影响因子：
2.7
作者：
Rizzieri, David;LoRusso, Samantha;Gerson, Stanton L.
通讯作者：
Gerson, Stanton L.