Artemisinin-polypyrrole conjugates: synthesis, DNA binding studies and preliminary antiproliferative evaluation

Abstract

Artemisinin-based combination therapies (ACTs) are currently the recommended treatment for uncomplicated and severe cases of malaria.[1] Additionally, artemisinins, as well as a number of other sesquiterpene lactones (SLs), are currently in phase I–II clinical trials against breast, colorectal and nonsmall-cell lung cancers.[2] As outlined by the iron-dependent activation hypothesis,[3] the activity of artemisinin (ART) is dependent on the endoperoxide bridge.[4] The peroxide is cleaved by endogenous sources of FeII to generate highly reactive carbon-centred radicals (CCRs), which are believed to react with critical cellular targets.[3] ART demonstrates selectivity towards rapidly proliferating cancer cell lines that possess a high intracellular iron content required to sustain their characteristic high rates of multiplication.[5] Iron activation links this particular potency of ART towards rapidly proliferating cancer cell lines; differentiation between healthy and cancerous cells by variation of iron concentration provides a strategy for selective cytotoxicity by ART and its derivatives.[4] The mechanism by which ART exerts its cytotoxic activity still remains elusive. ART acts by disruption of proliferation,[6, 7] oxidative stress,[8] anti-angiogenesis,[9] NF-kB signalling,[10] apoptosis[4] and interfering with iron uptake and metabolism.[6] ART also induces DNA breakage,[11] and it has been reported that artesunate-mediated DNA damage contributes to its therapeutic efficacy.