Heme as trigger and target for trioxane-containing antimalarial drugs.

Abstract

Heme is not only just the binding site responsible for oxygen transport by hemoglobin, but it is also the prosthetic group of many different heme-containing enzymes, such as cytochromes P450, peroxidases, catalase, and several proteins involved in electron transfer. Heme plays a key role in the mechanism of action of many different antimalarial drugs. In degrading the host's hemoglobin, the malaria parasite Plasmodium and several other heme-eating parasites are faced with this redox-active metal complex. Heme is able to induce the toxic reductive cascade of molecular oxygen, which leads to the production of destructive hydroxyl radicals. Plasmodium detoxifies heme by converting it into a redox-inactive iron(III) polymer called hemozoin. Artemisinin, a natural drug containing a biologically important 1,2,4-trioxane structure, is now the first-line treatment for multidrug-resistant malaria. The peroxide moiety in artemisinin reacts in the presence of the flat, achiral iron(II)-heme; the mechanism does not reflect the classical "key and lock" paradigm for drugs. Instead, the reductive activation of the peroxide function generates a short-lived alkoxy radical, which quickly rearranges to a C-centered primary radical. This radical alkylates heme via an intramolecular process to produce covalent heme-drug adducts. The accumulation of non-polymerizable redox-active heme derivatives, a consequence of heme alkylation, is thought to be toxic for the parasite. The alkylation of heme by artemisinin has been demonstrated in malaria-infected mice, indicating that heme is acting as the trigger and target of artemisinin. The alkylation of heme by artemisinin is not limited to this natural compound: the mechanism is invoked for a large number of antimalarial semisynthetic derivatives. Synthetic trioxanes or trioxolanes also alkylate heme, and their alkylation ability correlates well with their antimalarial efficacy. In addition, several reports have demonstrated the cytotoxicity of artemisinin derivatives toward several tumor cell lines. Deoxy analogues were just one-fiftieth as active or less, showing the importance of the peroxide bridge. The involvement of heme in anticancer activity has thus also been proposed. The anticancer mechanism of endoperoxide-containing molecules, however, remains a challenging area, but one that offers promising rewards for research success. Although it is not a conventional biological target, heme is the master piece of the mechanism of action of peroxide-containing antimalarial drugs and could well serve as a target for future anticancer drugs.

• Authors: Bernard Meunier, Anne Robert
• Journal: Accounts of chemical research (Acc Chem Res) Vol. 43 Issue 11 Pg. 1444-51 (Nov 16 2010) ISSN: 1520-4898 [Electronic] United States
• PMID: 20804120 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Review)

Chemical References

• 1,2,4-trioxane
• Antimalarials
• Antineoplastic Agents
• Artemisinins
• Heterocyclic Compounds
• Heme
• artemisinin

Topics

• Antimalarials (chemical synthesis, chemistry, pharmacology)
• Antineoplastic Agents (chemical synthesis, chemistry, pharmacology)
• Artemisinins (chemical synthesis, chemistry, pharmacology)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Heme (chemistry)
• Heterocyclic Compounds (chemistry)
• Humans
• Plasmodium (drug effects)