Synthetic peroxides promote apoptosis of cancer cells inhibiting of P-glycoprotein ABCB5.

This article discloses a new horizon for the application of peroxides in medical chemistry. Stable cyclic peroxides demonstrated cytotoxic activity against cancer cells, besides a mechanism of cytotoxic action was proposed. Synthetic bridged 1,2,4,5-tetraoxanes and ozonides were effective against HepG2 cancer cells and some ozonides selectively targeted on liver cancer cells (SI for compounds 11b and 12a is 8 and 5 respectively). Tetraoxanes and ozonides in some cases were more specific than that of paclitaxel, artemisinin, and artesunic acid. Annexin V flow cytometry analysis revealed that the active ozonides 22a and 23a induced cell death of HepG2 via apoptosis. Further study showed that compounds 22a and 23a exhibited the strong inhibitory effect on P-glycoprotein (P-gp/ABCB5) overexpressing HepG2 cancer cells. ABCB5 is a key player in the multidrug-resistant phenotype on liver cancer. Peroxides failed to demonstrate a direct correlation between oxidative potential and their biological activity. To our knowledge for the first time it was found, that peroxide diastereoisomers seem to show stereospecific antimalarial action against the chloroquine sensitive 3D7 strain of P. falciparum . Stereoisomeric ozonide 12b is 11-times more active than stereoisomeric ozonide 12a (IC 50 5.81 microM vs IC 50 65.18 microM). Current findings merit further investigation of ozonides as potential therapeutic agent for drug-resistant hepatocellular carcinoma.