Novel Peroxides as Promising Anticancer Agents with Unexpected Depressed Antimalarial Activity

作者：Paolo Saul Coghi, Ivan Andreevich Yaremenko, Parichat Prommana, Peter S. Radulov, Mikhail A. Syroeshkin, Yu Jun Wu, Jia Ying Gao, Floria M. Gordillo, Simon Wing Fai Mok, Vincent Kam Wai Wong, Chairat Uthaipibull, Alexander Olegovich Terent'ev · 发表于：ChemMedChem · 年份：2018 · DOI：10.1002/cmdc.201700804 · 被引用次数：59 · 研究领域：Malaria Research and Control、Synthesis and Catalytic Reactions、Synthesis and biological activity

Abstract Twenty six peroxides belonging to bridged 1,2,4,5‐tetraoxanes, bridged 1,2,4‐trioxolanes (ozonides), and tricyclic monoperoxides were evaluated for their in vitro 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=0.19–0.59 μm), and some of these compounds selectively targeted liver cancer (selectivity index values for compounds 13 a and 14 a 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 24.2 μm; 12 b, IC50=2.76 μm; 13 a, IC50=20.14 μm; 14 a, IC50=6.32 μm). 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.