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Isoquinolinequinone N-oxides as anticancer agents effective against drug resistant cell lines.
Organic & Biomolecular Chemistry ( IF 3.2 ) Pub Date : 2020-01-22 , DOI: 10.1039/c9ob02441g
Ryan D Kruschel 1 , Alyah Buzid , Udaya B Rao Khandavilli , Simon E Lawrence , Jeremy D Glennon , Florence O McCarthy
Affiliation  

The isoquinolinequinone (IQQ) pharmacophore is a privileged framework in known cytotoxic natural product families, caulibugulones and mansouramycins. Exploiting both families as a chemical starting point, we report on the structured development of an IQQ N-oxide anticancer framework which exhibits growth inhibition in the nM range across melanoma, ovarian and leukaemia cancer cell lines. A new lead compound (16, R6 = benzyl, R7 = H) exhibits nM GI50 values against 31/57 human tumour cell lines screened as part of the NCI60 panel and shows activity against doxorubicin resistant tumour cell lines. An electrochemical study highlights a correlation between electropositivity of the IQQ N-oxide framework and cytotoxicity. Adduct binding to sulfur based biological nucleophiles glutathione and cysteine was observed in vitro. This new framework possesses significant anticancer potential.

中文翻译:

异喹啉醌N-氧化物作为抗癌剂,可有效抵抗耐药细胞株。

异喹啉醌(IQQ)药效基团是已知细胞毒性天然产物家族,花椰菜酮和曼古拉霉素中的一种特权架构。利用这两个家族作为化学起点,我们报告了IQQ N-氧化物抗癌框架的结构化开发,该框架在黑色素瘤,卵巢癌和白血病癌细胞系的nM范围内均显示出生长抑制作用。一种新的先导化合物(16,R6 =苄基,R7 = H)相对于作为NCI60面板的一部分筛选的31/57个人肿瘤细胞系显示nM GI50值,并显示出对阿霉素抗性肿瘤细胞系的活性。电化学研究突出了IQQ N-氧化物骨架的正电性与细胞毒性之间的相关性。在体外观察到加合物与基于硫的生物亲核试剂谷胱甘肽和半胱氨酸结合。
更新日期:2020-01-02
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