Stereoselective Access to Antimelanoma Agents by Hybridization and Dimerization of Dihydroartemisinin and Artesunic acid

A library of five hybrids and six dimers of dihydroartemisinin and artesunic acid has been synthetized in a stereo‐controlled manner and evaluated for the anticancer activity against metastatic melanoma cell line (RPMI7951). Among novel derivatives, three artesunic acid dimers showed antimelanoma activity and cancer selectivity, being not toxic on normal human fibroblast (C3PV) cell line. Among the three dimers, the one bearing 4‐hydroxybenzyl alcohol as a spacer showed no cytotoxic effect (CC50>300 μM) and high antimelanoma activity (IC50=0.05 μM), which was two orders of magnitude higher than that of parent artesunic acid, and of the same order of commercial drug paclitaxel. In addition, this dimer showed cancer‐type selectivity towards melanoma compared to prostate (PC3) and breast (MDA‐MB‐231) tumors. The occurrence of a radical mechanism was hypothesized by DFO and EPR analyses. Qualitative structure activity relationships highlighted the role of artesunic acid scaffold in the control of toxicity and antimelanoma activity.
Accessing antimelanoma agents: The artesunic acid dimer 22‐α,α, bearing 4‐hydroxybenzyl alcohol as linker, showed higher antimelanoma effect and lower cytotoxicity compared to the parent dimer 8 bearing 4‐hydroxyphenetyl alcohol (tyrosol), highlighting the importance of a methylene group in the final effect. In addition, a melanoma cancer‐type selectivity was registered as well as a correlation between the presence of iron and the biological activity.