Orally active and robust Artemisinin-derived trioxanes: Antimalarial, antiproliferative, and anticancer efficacies

Natural product artemisinin is a sesquiterpene lactone, which has been used for centuries for the treatment of fevers. Dimeric structures of artemisinin have been shown to exhibit an interesting antimalarial and antiproliferative potency.; A new series of C-10 carba dimers was prepared to overcome the hydrolytic instability of C-10 acetal dimers. The library of newly synthesized trioxane dimers includes three carbon linked and four carbon linked dimers with a variety of functional groups. Isobutyric acid dimer, especially, exhibited potent in vivo antimalarial activities against P. berghei infected mice for both oral and intravenous administration. An approximate therapeutic index of the promising isobutyric acid is six times better than clinically used sodium artesunate. This promising isobutyric acid could be prepared in four high yielding chemical steps from the natural product artemisinin in an overall 56 % yield. Notably, the isobutyric acid is stable at room temperature and open to air for at least six months.; The hollow fiber assay carried out at the NCI showed that the isobutyric acid and sulfone amide dimer were promising candidates for cancer drugs. They both have recorded high total (IP + SC) score and both dimers were noted for cell kill.; The mechanistic study of the isobutylene dimer shows that iron(II) mediated degradation of isobutylene dimer follows various pathways and produces a variety of cytotoxic intermediates. The loss of antiproliferative potency of bis-deoxy dimer clearly shows that the endoperoxide group is crucial for antiproliferative activity.