Chemical Biology Laboratory, Leidos Biomedical Research, Inc. , Frederick National Laboratory for Cancer Research, Frederick, Maryland 21702, United States.
J Med Chem. 2014 Mar 27;57(6):2292-302. doi: 10.1021/jm401550d. Epub 2014 Feb 25.
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.
我们报告了一氧化氮（NO）释放衍生物对 PARP-1 抑制剂奥拉帕利（1）的抗肿瘤作用。化合物 5b 通过将 3b 的羧基与芳基重氮二氮杂环戊烷 4 的游离氨基偶联制备得到。类似物 5a 除了 F 被 H 取代外，具有相同的结构。化合物 13 与 5b 相同，只是在二硝基苯基环的硝基的对位和邻位添加了 Me2N-N(O)═NO-基团。这些前药在谷胱甘肽 S-转移酶 P1（GSTP1）加速的反应中被谷胱甘肽激活，GSTP1 是癌症中经常过度表达的一种酶。这种代谢同时生成 NO 和 PARP-1 抑制剂，消耗还原当量，导致 DNA 损伤，同时抑制 DNA 修复，而在 13 的情况下诱导蛋白质的交联谷胱甘肽化。化合物 5b 和 13 降低了人肺腺癌细胞系 A549 异种移植物的生长速度，没有全身毒性的证据。
