Antimalarial and Antitumor Evaluation of Novel C-10 Non-Acetal Dimers of 10β-(2-Hydroxyethyl)deoxoartemisinin

Abstract

Four series of C-10 non-acetal dimers were prepared from key trioxane alcohol 10beta-(2-hydroxyethyl)deoxoartemisinin (9b). All of the dimers prepared displayed potent low nanomolar antimalarial activity versus the K1 and HB3 strains of Plasmodium falciparum. The most potent compound assayed was phosphate dimer 14a, which was greater than 50 times more potent than the parent drug artemisinin and about 15 times more potent than the clinically used acetal artemether. In contrast to their potent activity versus malaria parasites, virtually all of the dimers expressed poor anticancer activity apart from the trioxane phosphate ester dimers 14a and 14b, which expressed nanomolar growth inhibitory (GI50) values versus a range of cancer cell lines in the NCI 60 human cell line screen. Further detailed studies on these dimers in vitro in HL60 cells demonstrate that both phosphate ester dimers (14a and 14b) are more potent than the anticancer agent doxorubicin. Interestingly, phosphate ester monomers 9c and 9d, antimalarially active in the low nanomolar region versus P. falciparum, are inactive as anticancer agents even at concentrations in the millimolar region. This observation emphasizes the importance of two trioxane units for high antiproliferative activity, and we propose that the nature of the linker in dimers of this type plays a crucial role in imparting potent anticancer activity.

Evidence for the Involvement of Carbon-centered Radicals in the Induction of Apoptotic Cell Death by Artemisinin Compounds

“…These drugs are widely used, with over 100 million courses administered annually (54), despite the fact that embryotoxicity in rats and rabbits (55,56) and in vivo and in vitro neurotoxicity (57, 58) have been reported. Artemisinins can display cytotoxic activity in actively proliferating mammalian cells (5)(6)(7)(8)(9)(10)(11)(12), and it is suggested that toxicity is related to high intracellular iron concentrations (15,16,18). It is therefore essential that the chemical and molecular mechanisms of endoperoxide cytotoxicity are defined to assess the safe and effective use of this class of drugs in the established area of malaria and their potential use in the treatment of cancer.…”

Development of artemisinin compounds for cancer treatment

“…For the dimers, linkages with one amideor one sulfur centered two ethylene groups are essential for high anticancer activity. Antitumor activity of deoxoartemisinin dimers has also been studied by Jeyadevan et al [106] and Posner et al [107]. Cho et al [108] synthesized 10-substitured triazolylartemisinin compounds and tested them on various cancer cell lines (human colorectal adenocarcinoma, human glioma, human cervical carcinoma and mouse melanoma).…”

Recent advances in antimalarial drug development

“…90 The potential drawback of these dimers is the presence of metabolically unstable C-10 acetal linkage. Jeyadevan et al 91 and O'Neill et al 92 have recently reported antimalarial and antitumor activities of some non-acetal C-10 carba dimers and two most potent derivatives were 8 and 9 (see Fig. 3).…”

“…Derivative 8 displayed about 62-fold increase in antimalarial activity with IC 50 value of 0.3 nM against K1 strain. 91 The isobutyric acid dimeric analog 9, on the other hand upon single dose ip administration to mice was found to be safe and displayed a therapeutic index six times that of sodium artesunate. 92 It is commonly known that acetal-type DHA derivatives undergo a facile hydrolysis under the acidic conditions in addition to enzymatic oxidation resulting in the formation of DHA.…”