新型喹喔啉-2-甲腈-1,4-二氧化物衍生物可抑制癌细胞中的HIF1α活性并规避多药耐药性。
Novel Quinoxaline-2-Carbonitrile-1,4-Dioxide Derivatives Suppress HIF1α Activity and Circumvent MDR in Cancer Cells.
作者信息
Scherbakov Alexander M, Borunov Alexander M, Buravchenko Galina I, Andreeva Olga E, Kudryavtsev Igor A, Dezhenkova Lyubov G, Shchekotikhin Andrey E
机构信息
a Department of Experimental Tumor Biology , Blokhin N.N. National Medical Research Center of Oncology , Moscow , Russia.
b Laboratory of Chemical Transformations of Antibiotics , Gause Institute of New Antibiotics , Moscow , Russia.
出版信息
Cancer Invest. 2018 Mar 16;36(3):199-209. doi: 10.1080/07357907.2018.1453072. Epub 2018 Apr 6.
A series of 3-aryl/hetarylquinoxaline-2-carbonitrile-1,4-dioxides was synthesized and evaluated against breast cancer cell lines in normoxia and hypoxia. Selected compounds in this series demonstrated better cytotoxicity and comparable hypoxia selectivity than tirapazamine. In contrast to Dox, quinoxaline-1,4-dioxides showed potent cytotoxicity against different MDR cells. Compound 2g inhibits of cancer cell growth through p53-independent mechanisms. Our results showed that compound 2g sensitized MCF-7 cells to metformin in hypoxia. Treatment with 2g results in the increase of ROS accumulation in cancer cells. Compound 2g can be considered as the lead compound for further anticancer drug design, evaluation, and development of new potent antitumor agents.
合成了一系列3-芳基/杂芳基喹喔啉-2-甲腈-1,4-二氧化物，并在常氧和缺氧条件下对乳腺癌细胞系进行了评估。该系列中的选定化合物表现出比替拉扎明更好的细胞毒性和相当的缺氧选择性。与阿霉素不同，喹喔啉-1,4-二氧化物对不同的多药耐药细胞表现出强大的细胞毒性。化合物2g通过不依赖p53的机制抑制癌细胞生长。我们的结果表明，化合物2g在缺氧条件下使MCF-7细胞对二甲双胍敏感。用2g处理导致癌细胞中活性氧积累增加。化合物2g可被视为进一步抗癌药物设计、评估和开发新型强效抗肿瘤药物的先导化合物。
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