Myrtle medicine

German researchers have successfully devised and implemented a total synthesis of myrtucommulone A, tracking progress and structures using NMR spectroscopy. The compound is physiologically active in anticancer and antibacterial screens, and the synthesis opens up the potential for making simpler, but active analogues.

Johann Jauch, Hans Mueller, Michael Paul, David Hartmann, and Volker Huch of Saarland University, in Saarbruecken, and Dagmar Blaesius, Andreas Koeberle, and Oliver Werz of the Pharmaceuticals Institute, at the University of Tuebingen, Germany, report details in Angewandte Chemie.

Myrtle (Myrtus communis) is an evergreen, flowering shrub in the family Myrtaceae, that is native to the Mediterranean region of southern Europe and North Africa. Myrtle has aromatically scented, leathery leaves, small white flowers, and produces blue-black berries. The leaves and berries are occasionally used in Mediterranean cooking. It is mentioned widely in the ancient writings of Hippocrates, Pliny, Dioscorides, Galen, and the Arabian writers and has been considered a medicinal plant for centuries.

It contains several essential oils, as well as physiologically active compounds including the myrtucommulones. These compounds, known since the 1970s, have demonstrated a pharmacological activity as an antibacterial agent, an analgesic, and as a strong anti-inflammatory compound. Interest in these compounds diminished until 2002, when new properties and an interest in anti-oxidant activity rekindled scientific curiosity. More recently, scientists have demonstrated that it has a highly selective cytostatic effect on tumour growth.

Now, Jauch and his team have successfully synthesized myrtucommulone A in the laboratory from readily available starting materials and compounds such as isobutyryl phloroglucinol, which can be synthesised relatively easily. The extraction of myrtucommulones from the leaves of the myrtle is a difficult task and produces only small yields. "The synthetic preparation of myrtucommulones would make these substances available in quantities sufficient to better examine their pharmacological properties," explains Jauch. "Also, we could develop analogues that may be more effective than the original substances. The strength of the natural substance could thus be augmented."

The researchers have also synthesized two variants of the compound, myrtucommulone C and F, and a novel analogue in a single-step reaction (acid catalysed) or a two-step reaction (base catalysed version). They point out that it is possible to make a wide range of variations on the theme simply by changing the three building blocks used to construct the basic skeleton of the myrtucommulones.

They used X-ray crystallography and NMR spectroscopy structures to confirm the structure of the compounds synthesised. However, NMR analysis was extremely difficult the team concedes.

Indeed, the researchers had to resort to derivitisation of the product, which led to formation of various isomers that required separation before they could obtain adequate spectra to confirm the structure of the synthetic product. Ultimately, however, the demonstrated that synthetic and natural myrtucommulone A had identical NMR spectra. To complete the work thoroughly, the scientists next plan to determine the absolute spatial configuration of the enantiomerically pure compound.

"Laboratory tests demonstrated that the synthetic myrtucommulone A has just as strong an anti-inflammatory effect as the natural compound," adds Jauch. "Just like the agent derived from the plant extract, it triggers programmed cell death (apoptosis) in tumour cells." Indeed, the various assays against which the team tested synthetic myrtucommulones, including a test for anti-inflammatory activity based on the enzyme prostaglandin E synthase 1, showed almost no distinction between the synthetic version and the naturally derived myrtucommulone. 

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