Nitric oxide (NO) releasing poly ADP-ribose polymerase 1 (PARP-1) inhibitors targeted to glutathione S-transferase P1-overexpressing cancer cells.
Nitric oxide (NO) releasing poly ADP-ribose polymerase 1 (PARP-1) inhibitors targeted to glutathione S-transferase P1-overexpressing cancer cells.
复制标题
DOI：
10.1021/jm401550d
复制
发表时间：
2014-03-27
影响因子：
7.3
通讯作者：
Keefer LK
中科院分区：
文献类型：
--
作者：
Maciag AE;Holland RJ;Kim Y;Kumari V;Luthers CE;Sehareen WS;Biswas D;Morris NL;Ji X;Anderson LM;Saavedra JE;Keefer LK
我们报告了 PARP-1 抑制剂奥拉帕尼 (olaparib) 释放一氧化氮 (NO) 的衍生物的抗肿瘤作用 (1)。化合物5b是通过将3b的羧基与芳基化二氮烯鎓二醇化哌嗪4的游离氨基偶联而制备的。类似物5a具有相同的结构，只是F被H取代。化合物13与5b相同，只是在二硝基苯环的硝基的对位和邻位添加了Me2N-N(O)=NO-基团。所产生的前药在谷胱甘肽 S-转移酶 P1 (GSTP1) 加速的反应中被谷胱甘肽激活，谷胱甘肽 S-转移酶 P1 (GSTP1) 是一种在癌症中经常过度表达的酶。这种代谢同时产生 NO 和 PARP-1 抑制剂，消耗还原当量，导致 DNA 损伤并抑制 DNA 修复，并且在 13 的情况下诱导蛋白质的谷胱甘肽交联。化合物5b和13降低了A549人肺腺癌异种移植物的生长速率，且没有全身毒性的证据。
We report the antitumor effects of nitric oxide (NO) releasing derivatives of the PARP-1 inhibitor olaparib (1). Compound 5b was prepared by coupling the carboxyl group of 3b and the free amino group of arylated diazeniumdiolated piperazine 4. Analogue 5a has the same structure except that the F is replaced by H. Compound 13 is the same as 5b except that a Me2N–N(O)=NO– group was added para and ortho to the nitro groups of the dinitrophenyl ring. The resulting prodrugs are activated by glutathione in a reaction accelerated by glutathione S-transferase P1 (GSTP1), an enzyme frequently overexpressed in cancers. This metabolism generates NO plus a PARP-1 inhibitor simultaneously, consuming reducing equivalents, leading to DNA damage concomitant with inhibition of DNA repair, and in the case of 13 inducing cross-linking glutathionylation of proteins. Compounds 5b and 13 reduced the growth rates of A549 human lung adenocarcinoma xenografts with no evidence of systemic toxicity.
登录
查看更多内容
影响因子：
11.4
作者：
Maciag, Anna E.;Holland, Ryan J.;Cheng, Y. -S. Robert;Rodriguez, Luis G.;Saavedra, Joseph E.;Anderson, Lucy M.;Keefer, Larry K.
通讯作者：
Keefer, Larry K.
影响因子：
4.8
作者：
Ling, YH;Liebes, L;Perez-Soler, R
通讯作者：
Perez-Soler, R
影响因子：
8.8
作者：
Khan, O. A.;Gore, M.;Lorigan, P.;Stone, J.;Greystoke, A.;Burke, W.;Carmichael, J.;Watson, A. J.;McGown, G.;Thorncroft, M.;Margison, G. P.;Califano, R.;Larkin, J.;Wellman, S.;Middleton, M. R.
通讯作者：
Middleton, M. R.
影响因子：
7.3
作者：
Menear, Keith A.;Adcock, Claire;Martin, Niall M. B.
通讯作者：
Martin, Niall M. B.
DOI：
10.1158/1078-0432.ccr-11-2425
发表时间：
2012-04-15
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Rajan A;Carter CA;Kelly RJ;Gutierrez M;Kummar S;Szabo E;Yancey MA;Ji J;Mannargudi B;Woo S;Spencer S;Figg WD;Giaccone G
通讯作者：
Giaccone G