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July 3, 2009

Natural products: Cage closed

Synthesis of a complex substructure of a biologically active plant-derived organic compound will allow investigation of its mechanism of action

Figure 1: A fruit from a plant of the Physalis genus, the source of the biologically interesting natural product physalin B.

A team of RIKEN researchers has synthesized a key fragment of the natural product called physalin B, which shows both antitumor and anti-inflammatory activity. The work will make an important contribution towards the goal of synthesizing the whole compound, which has eluded chemists since its discovery in 1969. Mikiko Sodeoka from the Advanced Science Institute and co-workers report their achievement in the journal Angewandte Chemie International Edition1.

Physalin B is a secondary metabolite of plants of the genus Physalis—commonly known as ground cherries. This group of plants is native to tropical and warm temperate regions and is related to the tomato. The round fruit are encased in a papery husk and have a red/orange skin. Some members of the group are decorated as lanterns in honor of ancestors during Japan’s Obon season (Fig. 1). Some are also a popular food in France, and are a well-known ingredient of traditional Chinese medicine.

“Physalin B contains 8 rings and 11 stereocenters in a very compact structure,” explains Sodeoka. “We were interested by the biological activity of the compound, but as synthetic chemists, we also found the complex structure of the compound intriguing.”

On close examination, the octacyclic structure of physalin B contains a bicyclic structure common in a number of natural products, and a far less common tetracyclic cage-like structure (Fig. 2). Sodeoka and colleagues anticipate that the interesting biological activity of physalin B arises from this unusual structure. They also expected that synthesis of this fragment of the structure would be challenging, as it contains a large number of stereocenters—in this case, carbon atoms with four different substituents that have non-identical mirror images—each of which must be constructed in a selective fashion.

“The key to our process is a four-step sequence of chemical reactions that occur in a single pot under very mild conditions,” says Sodeoka. “The occurrence of [so-called] domino reaction sequences under such mild conditions points towards how these molecules arise in nature,” she continues.

Ultimately, Sodeoka and co-workers plan to complete a total synthesis of physalin B. Alongside this, the team hopes to construct synthetic analogues of physalin B to identify which parts of the complex structure are important for the biological activity. They hope that this will allow them to identify which proteins the physalin B binds to and help to determine the mechanism of action of this interesting molecule.

References

  1. Ohkubo, M., Hirai, G. & Sodeoka, M. Synthesis of the DFGH ring system of type B physalins: highly oxygenated, cage-shaped molecules. Angewandte Chemie International Edition 48, 3862–3866 (2009). |  | (Link)