Glutathione S-Transferase π-Activatable O2-(Sulfonylethyl Derived) Diazeniumdiolates Potently Suppress Melanoma in Vitro and in Vivo

被引：18

作者：

Huang, Zhangjian ^{[1
]}

Wu, Jianbing ^{[1
]}

Zou, Yu ^{[1
]}

Yuan, Haoliang ^{[1
]}

Zhang, Yinqiu ^{[1
]}

Fei, Yue ^{[1
]}

Bhardwaj, Atul ^{[2
]}

Kaur, Jatinder ^{[2
]}

Knaus, Edward E. ^{[2
]}

Zhang, Yihua ^{[1
]}

机构：

[1] China Pharmaceut Univ, State Key Lab Nat Med, Jiangsu Key Lab Drug Discovery Metab Dis, Ctr Drug Discovery, Nanjing 210009, Jiangsu, Peoples R China

[2] Univ Alberta, Fac Pharm & Pharmaceut Sci, Edmonton, AB T6G 2E1, Canada

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2018年 / 61卷 / 05期

基金：

中国国家自然科学基金;

关键词：

NITRIC-OXIDE DONORS; RESISTANT OVARIAN-CANCER; ANTICANCER ACTIVITY; THERAPEUTIC AGENTS; ALKYLATING-AGENTS; DRUG-RESISTANCE; PRODRUG; TLK286; NO; PACLITAXEL;

D O I：

10.1021/acs.jmedchem.7b01178

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

A group of glutathione S-transferase pi (GST pi) activatable O-2-(sulfonylethyl derived) diazeniumdiolates 5-12 were designed and synthesized. These compounds could be activated by GST pi to initiate the beta-elimination reaction, liberating an active vinyl sulfone-based GSH derivative and a diazeniumdiolate anion which subsequently releases NO in situ. The most active compound 6 released relatively high levels of NO and inhibited proliferation of melanoma B16 cells, superior to a diazeniumdiolate-based anticancer agent JS-K (1). Importantly, 6 had 8-fold less inhibitory activity against normal epithelial JB6 Cl 30-7b cells. The inhibitory activity of 6 could be diminished by an NO scavenger or GST pi inhibitor. Furthermore, 6 induced nitration of mitochondrial tyrosine in B16 cells and inoculated B16 tumors in mice, which might be responsible for oxidation of protein leading to tumor suppression. Finally, 6 significantly retarded the B16 cells growth in a mouse xenograft model. These findings suggest that 6 may have a potential to treat melanoma.

引用

页码：1833 / 1844

页数：12

共 58 条

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