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Glutathione S-Transferase π-Activatable O2-(Sulfonylethyl Derived) Diazeniumdiolates Potently Suppress Melanoma in Vitro and in Vivo
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2018-02-08 00:00:00 , DOI: 10.1021/acs.jmedchem.7b01178 Zhangjian Huang 1 , Jianbing Wu 1 , Yu Zou 1 , Haoliang Yuan 1 , Yinqiu Zhang 1 , Yue Fei 1 , Atul Bhardwaj 2 , Jatinder Kaur 2 , Edward E. Knaus 2 , Yihua Zhang 1
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2018-02-08 00:00:00 , DOI: 10.1021/acs.jmedchem.7b01178 Zhangjian Huang 1 , Jianbing Wu 1 , Yu Zou 1 , Haoliang Yuan 1 , Yinqiu Zhang 1 , Yue Fei 1 , Atul Bhardwaj 2 , Jatinder Kaur 2 , Edward E. Knaus 2 , Yihua Zhang 1
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A group of glutathione S-transferase π (GSTπ) activatable O2-(sulfonylethyl derived) diazeniumdiolates 5–12 were designed and synthesized. These compounds could be activated by GSTπ to initiate the β-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 GSTπ 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.
中文翻译：
谷胱甘肽S转移酶π可活化的O 2-（磺酰基乙基衍生）二醇二氮烯鎓在体内和体外有效抑制黑色素瘤。
A组谷胱甘肽š转移酶π（GSTπ）活化Ö 2 - （sulfonylethyl派生）二醇二氮烯5 - 12设计并合成。这些化合物可被GSTπ活化以引发β-消除反应，释放出活性的乙烯基砜基GSH衍生物和二醇二氮烯二酸酯阴离子，后者随后就地释放NO。活性最高的化合物6释放出相对较高的NO含量，并抑制了黑色素瘤B16细胞的增殖，优于基于二醇二氮烯鎓的抗癌剂JS-K（1）。重要的是，6对正常上皮JB6 Cl 30-7b细胞的抑制活性要低8倍。的抑制活性NO清除剂或GSTπ抑制剂可以减少6。此外，6诱导线粒体酪氨酸在B16细胞中硝化并在小鼠中接种B16肿瘤，这可能是导致蛋白质氧化导致肿瘤抑制的原因。最后，在小鼠异种移植模型中，有6种显着抑制了B16细胞的生长。这些发现表明6可能具有治疗黑色素瘤的潜力。
更新日期：2018-02-08
中文翻译：
谷胱甘肽S转移酶π可活化的O 2-（磺酰基乙基衍生）二醇二氮烯鎓在体内和体外有效抑制黑色素瘤。
A组谷胱甘肽š转移酶π（GSTπ）活化Ö 2 - （sulfonylethyl派生）二醇二氮烯5 - 12设计并合成。这些化合物可被GSTπ活化以引发β-消除反应，释放出活性的乙烯基砜基GSH衍生物和二醇二氮烯二酸酯阴离子，后者随后就地释放NO。活性最高的化合物6释放出相对较高的NO含量，并抑制了黑色素瘤B16细胞的增殖，优于基于二醇二氮烯鎓的抗癌剂JS-K（1）。重要的是，6对正常上皮JB6 Cl 30-7b细胞的抑制活性要低8倍。的抑制活性NO清除剂或GSTπ抑制剂可以减少6。此外，6诱导线粒体酪氨酸在B16细胞中硝化并在小鼠中接种B16肿瘤，这可能是导致蛋白质氧化导致肿瘤抑制的原因。最后，在小鼠异种移植模型中，有6种显着抑制了B16细胞的生长。这些发现表明6可能具有治疗黑色素瘤的潜力。
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