Synthetic Methodology And Biological Evaluation Of Endoperoxides

The incidence and mortality caused by cancer tend to increase quickly in recentyears. Due to the disadvantages of limited efficacy, serious side effects, and emergenceof cross resistance of the existing chemotherapy drugs, there is an urgent need todevelop new antitumor drugs.Artemisinin and semi-synthetic derivatives exhibit potent antitumor activity both invitro and in vivo. It has been proven that the peroxide bridge plays an important role forartemisinin to exert various biological activity. The use of aretemisinin derivatives incancer therapy are limited by their source, rigid structure, poor pharmacokineticproperties and unclear mechanism of action. Therefore, new methodology developmentfor synthetic peroxides may solve the above mentioned problems and provide newgeneration antitumor drugs. In this work, the synthetic methodology, antitumor activityand mechanism of action of endoperoxides1,2,4-trioxolanes,1,2,4-trioxanes and1,2,4,5-tetraoxanes were reported.1,2,4,5-Tetraoxanes exhibit potent antitumor, antimalarial and antibacterialactivities. But synthesis of1,2,4,5-tetraoxanes was limited by lack of efficient methodsand catalysts. In this work, we developed a phosphomolybdic acid catalyzed method forthe preparation of1,2,4,5-tetraoxanes. Using anhydrous magnesium sulfate asdehydrating agent, phosphomolybdic acid efficiently catalyzed the condensation of1,1-dihydroperoxides and carbonyl compounds to afford1,2,4,5-tetraoxanes in highyield. We proved phosphomolybdic acid is a convenient, economical and efficientcatalyst for the preparation of1,2,4,5-tetraoxanes.1,1-Dihydroperoxides and β-hydroxyhydroperoxides are important intermediatesfor biologically active1,2,4,5-tetraoxanes and1,2,4-trioxanes. The preparation of thesetwo hydroperoxides was limited by the lack of efficient method. In this work, we havedisclosed an oxirane-SnCl4-H2O2system which could convert oxiranes to eitherβ-hydroxyhydroperoxides or primary1,1-dihydroperoxides in moderate to good yields by adjusting the order of addition, reaction temperature and the amount of SnCl4. SnCl4acted as an efficient catalyst in the preparation of β-hydroxyhydroperoxides. In the caseof preparing primary1,1-dihydroperoxides, SnCl4first promoted rearrangement ofoxirane to aldehyde, then catalyzed the condensation reaction of aldehyde withhydrogen peroxide. This is the first report that primary1,1-dihydroperoxides could beefficiently prepared from corresponding oxirane via a two-step, one-pot tandemreaction.Both peroxide group and related auxiliary moiety contribute to the compoundantitumor activity. About thirty1,2,4-trioxolanes,1,2,4-trioxanes and1,2,4,5-tetraoxanes were designed, synthesized and evaluated for their antiproliferationactivity toward cancer cells. The results showed that presence of a primary amino groupseems critical for endoperoxides to display antitumor activity in1,2,4,5-tetraoxanes.It has been reported that activation of the peroxide bond, possiblely by the ferrousion, is essential for peroxidesto play biological effects. Base on this hypothesis,endoperoxide-ferrocene conjugates were designed and synthesized to synergize theirantitumor activity. Primary screening results showed that a1,2,4-trioxane conjugate anda non-peroxide conjugate exhibited excellent antitumor activity. The activity could notbeen impaired by deferoxamine, suggesting a pathway independent of iron metabolicpathway and peroxide group.Ferrous ion concentration in cancer cell is much higher than that in normalcell,thus cancer cells are more suspective to iron chelators and peroxides which need theactivation by ferrous ion. Based on this observation, endoperoxide-iron chelatorconjugates were designed and synthesized to enhance the efficacy and tumor cellselectivity. Our results showed that all pyrocatechol-and8-hydroxyquinoline-conjugates exhibited moderate or potent antitumor activity. The activity of theseconjugates could be impaired by deferoxamine, which proved that iron metabolicpathway may be involved in the antitumor mechanism and peroxide group playedimportant role in the antitumor activity.Endoperoxides could act as hydrogen bond receptor. The hydrogen bond donor inthe active site of target may bond to it and the interaction between them was enhanced.Based on the hypothesis, endoperoxide-enzyme inhibitor conjugates were designed andsynthesized. Primary results for these compounds toward cancer cells showed that theester derivative of endoperoxide-receptor tyrosine protein kinase inhibitor conjugates and all endoperoxide-histone deacetylase inhibitor conjugates exhibit potent antitumoractivity.The structural activity relationship and mechanism of these potent antitumorperoxides need further study.