Modulation of the Antimelanoma Activity Imparted to Artemisinin Hybrids by the Monoterpene Counterpart

TL;DR

This study shows that combining artemisinin derivatives with certain monoterpenes enhances their effectiveness against melanoma, especially metastatic forms.

Contribution

The novel contribution is the discovery that hybridizing artemisinin derivatives with specific monoterpenes significantly improves their antimelanoma activity and selectivity.

Findings

Most hybrid compounds showed micromolar antimelanoma activity and selectivity for metastatic melanoma.

Hybrids with perillyl alcohol, citronellol, and nerol were the most effective, with nerol showing activity with both sesquiterpenes.

Activity of hybrids depends on the formation of carbon- and oxygen-centered radical species.

Abstract

Molecular hybridization is a widely used strategy in drug discovery and development processes that consists of the combination of two bioactive compounds toward a novel entity. In the current study, two libraries of hybrid derivatives coming from the linkage of sesquiterpene counterparts dihydroartemisinin and artesunic acid, with a series of monoterpenes, were synthesized and evaluated by cell viability assay on primary and metastatic melanoma cell lines. Almost all the obtained compounds showed micromolar antimelanoma activity and selectivity toward the metastatic form of this cancer. Four hybrid derivatives containing perillyl alcohol, citronellol, and nerol as monoterpene counterpart emerged as the best compounds of the series, with nerol being active in combination with both sesquiterpenes, dihydroartemisinin and artesunic acid. Preliminary studies on the mechanism of action have shown the dependence of the pharmacological activity of newly synthesized hybrids on the formation of carbon- and oxygen-centered radical species. This study demonstrated the positive modulation of the pharmacodynamic effect of artemisinin semisynthetic derivatives dihydroartemisinin and artesunic acid due to the hybridization with monoterpene counterparts.

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