Novel Peroxides as Promising Anticancer Agents with Unexpected Depressed Antimalarial Activity
Novel Peroxides as Promising Anticancer Agents with Unexpected Depressed Antimalarial Activity
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DOI：
10.1002/cmdc.201700804
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发表时间：
2018-05-08
期刊：
影响因子：
3.4
通讯作者：
Terent'ev, Alexander O.
中科院分区：
文献类型：
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作者：
Coghi, Paolo;Yaremenko, Ivan A.;Terent'ev, Alexander O.
26种过氧化物属于桥连1，2，4，5-四氧杂环己烷、桥连1，2，4-三氧杂环戊烷评价了它们对恶性疟原虫（3D 7）的体外抗疟活性和它们对永生化的人正常成纤维细胞（CCD 19 Lu）、肝（LO 2）、和肺（BEAS-2B）细胞系以及人肝癌（HepG 2）和肺癌（A549）细胞系。合成的臭氧化物显示出对HepG 2具有最高的细胞毒性（IC 50 =0.19-0.59m），并且这些化合物中的一些选择性靶向肝癌（化合物13 a和14 a的选择性指数值分别为20和28），在某些情况下，其水平高于紫杉醇、青蒿素和青蒿琥酯酸的水平。相反，一些臭氧化物对氯喹敏感的3D 7株恶性疟原虫仅显示出中等的抗疟活性（IC 50为2.76 - 24.2m; 12 b，IC 50 =2.76m; 13 a，IC 50 =20.14m; 14 a，IC 50 =6.32m）。这些结果表明，这些衍生物对癌细胞和疟疾感染的细胞具有不同的作用机制。进行了循环伏安法研究的过氧化物，但大多数的化合物没有表现出直接的相关性，在氧化能力的活动。我们的研究结果提供了一个新的来源，抗疟疾和抗癌药物通过结构修饰的过氧化物。
Twenty six peroxides belonging to bridged 1,2,4,5-tetraoxanes, bridged 1,2,4-trioxolanes (ozonides), and tricyclic monoperoxides were evaluated for their invitro antimalarial activity against Plasmodium falciparum (3D7) and for their cytotoxic activities against immortalized human normal fibroblast (CCD19Lu), liver (LO2), and lung (BEAS-2B) cell lines as well as human liver (HepG2) and lung (A549) cancer-cell lines. Synthetic ozonides were shown to have the highest cytotoxicity on HepG2 (IC50=0.19-0.59m), and some of these compounds selectively targeted liver cancer (selectivity index values for compounds 13a and 14a are 20 and 28, respectively) at levels that, in some cases, were higher than those of paclitaxel, artemisinin, and artesunic acid. In contrast some ozonides showed only moderate antimalarial activity against the chloroquine-sensitive 3D7 strain of P.falciparum (IC50 from 2.76 to 24.2m; 12b, IC50=2.76m; 13a, IC50=20.14m; 14a, IC50=6.32m). These results suggest that these derivatives have divergent mechanisms of action against cancer cells and malaria-infected cells. A cyclic voltammetry study of the peroxides was performed, but most of the compounds did not show direct correlation in oxidative capacity-activity. Our findings offer a new source of antimalarial and anticancer agents through structural modification of peroxide compounds.