A new route for the synthesis of N-substituted 11-aza-artemisinins, 1, was developed with 11-azaartemisinin, 2, as the starting material. In the course of optimizing reaction conditions for the preparation of 2 an unexpected product was isolated and its structure determined to be a cyclohexanone derivative Posner et al. Had isolated cyclohexanone analogs in their studies of the mechanism of action of artemisinin analogs and reported that they exhibited antimalarial activity. As part of our collaboration with Professor Meshnick on the mechanism of action of artemisinin derivatives and their in vitro and in vivo neurotoxicity, we prepared [3H]-dihydroartemisinin. Professor Meshnick and associates found that arteether and dihydroartemisinin caused acute neuronal necrosis in specific areas of the brain, especially the vestibular nuclei and red nuclei. Autoradiograms on SDS gels run from [3H]-dihydroartemisinin treated cells, showed that four neuronal proteins of molecular weights 27, 32, 40 and 81 kDa had reacted with dihydroartemisinin. The doses required to react with these proteins were 5,000 times the therapeutic dose.
