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Stable cyclic peroxides are demonstrated to have cytotoxic activity against cancer cells; in addition a mechanism of cytotoxic action is proposed. Synthetic bridged 1,2,4,5\u2010tetraoxanes and ozonides were effective against HepG2 cancer cells and some ozonides selectively targeted liver cancer cells (the selectivity indexes for compounds <jats:bold>11\u2009b<\/jats:bold> and <jats:bold>12\u2009a<\/jats:bold> are 8 and 5, respectively). In some cases, tetraoxanes and ozonides were more selective than paclitaxel, artemisinin, and artesunic acid. Annexin V flow\u2010cytometry analysis revealed that the active ozonides <jats:bold>22\u2009a<\/jats:bold> and <jats:bold>23\u2009a<\/jats:bold> induced cell death of HepG2 by apoptosis. Further study showed that compounds <jats:bold>22\u2009a<\/jats:bold> and <jats:bold>23\u2009a<\/jats:bold> exhibited a strong inhibitory effect on P\u2010glycoprotein (P\u2010gp\/ABCB5)\u2010overexpressing HepG2 cancer cells. ABCB5 is a key player in the multidrug\u2010resistant phenotype of liver cancer. Peroxides failed to demonstrate a direct correlation between oxidative potential and their biological activity. To our knowledge this is the first time that peroxide diastereoisomers have been found to show stereospecific antimalarial action against the chloroquine\u2010sensitive 3D7 strain of <jats:italic>Plasmodium falciparum<\/jats:italic>. Stereoisomeric ozonide <jats:bold>12\u2009b<\/jats:bold> is 11 times more active than stereoisomeric ozonide <jats:bold>12\u2009a<\/jats:bold> (IC<jats:sub>50<\/jats:sub>=5.81 vs 65.18\u2005\u03bc<jats:sc>m<\/jats:sc>). Current findings mean that ozonides merit further investigation as potential therapeutic agents for drug\u2010resistant hepatocellular carcinoma.<\/jats:p>","DOI":"10.1002\/cmdc.202000042","type":"journal-article","created":{"date-parts":[[2020,3,10]],"date-time":"2020-03-10T06:14:12Z","timestamp":1583820852000},"page":"1118-1127","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":42,"title":["Synthetic Peroxides Promote Apoptosis of Cancer Cells by Inhibiting P\u2010Glycoprotein ABCB5"],"prefix":"10.1002","volume":"15","author":[{"given":"Ivan A.","family":"Yaremenko","sequence":"first","affiliation":[{"name":"N.D. 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