Second Generation, Orally Active, Antimalarial, Artemisinin-Derived Trioxane Dimers with High Stability, Efficacy, and Anticancer Activity

Abstract

In only two steps and in 63% overall yield, naturally occurring 1,2,4-trioxane artemisinin (1) was converted into C-10-carba trioxane conjugated diene dimer 4. This new dimer was then transformed easily in one additional 4 + 2-cycloaddition step into phthalate dimer 5, and further modification led to bis-benzyl alcohol dimer 7 and its phosphorylated analogues 8 and 9. Bis-benzyl alcohol dimer 7 is the most antimalarially active in vitro, 10 times more potent than artemisinin (1). Bis-benzyl alcohol dimer 7 is approximately 1.5 times more orally efficacious in rodents than the antimalarial drug sodium artesunate and is about 37 times more efficacious than sodium artesunate via subcutaneous administration. Both dimers 5 and 7 are thermally stable neat even at 60 degrees C for 24 h. Phthalate dimer 5 is very highly growth inhibitory but not cytotoxic toward several human cancer cell lines; both dimers 5 and 7 very efficiently and selectively kill human cervical cancer cells in vitro in a dose-dependent manner with no cytotoxic effects on normal cervical cells.

Development of artemisinin compounds for cancer treatment

“…The increase in potency varies from 10-to 200-fold [106,127,128,[130][131][132]. Artemisinin dimers have also been shown to be as or even more potent than some chemotherapeutic agents, such as doxorubicin [133], and much less toxic to normal cells than cancer cells [130,134]. Posner et al [135] reported a high therapeutic index (>150) for some of the dimers they synthesized.…”

Artemisinin Blocks Prostate Cancer Growth and Cell Cycle Progression by Disrupting Sp1 Interactions with the Cyclin-dependent Kinase-4 (CDK4) Promoter and Inhibiting CDK4 Gene Expression

“…One study that analyzed 55 cell lines of the Developmental Therapeutics Program of NCI, National Institutes of Health, showed that artesunate, the semisynthetic derivative of artemisinin, has anti-cancer activities against leukemic, colon, melanoma, breast, ovarian, prostate, central nervous system, and renal cancer cell lines (12). More-over, the highly stable artemisinin-derived trioxane dimmers was shown to inhibit the growth of and selectively kill several human cancer cell lines without inducing cytotoxic effects on normal neighboring cells (13). The molecular mechanism and gene expression changes that mediate the anti-proliferative activity of artemisinin are not well characterized.…”

A golden phoenix arising from the herbal nest — A review and reflection on the study of antimalarial drug Qinghaosu

“…Later, two unsymmetric dimers were prepared and found to be comparable to arteether when tested in K-173-infected mice [264] (Figure 32). Since the end of the 20th century, a number of new types of deoxoartemisinin dimers ( Figure 33) have been developed [265][266][267][268][269][270][271][272]. Most compounds had both antimalarial and antitumor activities.…”