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The elegant path to an anticancer agent:

Berkeley researcher moves to LMU

Munich, 08/04/2008

Professor Dirk Trauner, recently of the University of California, Berkeley, has taken on a professorship for chemical biology and genetics at Ludwig-Maximilians-Universität (LMU) München. Here, he shall continue his work on the production of biologically active natural substances by biomimetic synthesis, primarily as part of the cluster of excellence “Center for Integrated Protein Science Munich” (CIPSM). Natural products can be synthesized using this approach, in which biosynthetic steps are imitated in the laboratory. This approach quite often leads to more elegant and more efficient synthesis paths. “We intend to produce immunosuppressants, that is substances that can be used after an organ transplant or even in the case of autoimmune diseases,” states Trauner. “Aside from that, we are also interested in anti-cancer agents.” This is demonstrated nicely by a study just recently published in the journal “Nature Chemical Biology”. In this work, a team of scientists working under Trauner was successful in biomimetically synthesizing the two IDO inhibitors exiguamine A and B. These substances that occur in marine sponges have a unique chemical structure and an important property: "Both agents inhibit the enzyme IDO, which protects tumor cells against the body’s own immune defenses,” explains Trauner. “Hence, these inhibitors could play an important part in cancer therapy – across a whole series of cancerous conditions.”

Many marine sponges contain pharmaceutically active substances. Neopetrosia exigua from the waters of Papua New Guinea is just one example of this. This sponge contains the substances exiguamine A and B which, as so-called IDO inhibitors, inhibit the action of indoleamine-2,3-dioxygenase. This enzyme, called IDO for short, protects the fetus during pregnancy against an immune response of the mother. After all, such a defense mechanism could otherwise act against the foreign tissue, potentially causing severe damage to the fetus. But this is not the only situation in which IDO blocks the immune response.

Because many tumor cells – as is frequently the case in breast cancer and bladder cancer – could activate these fetal mechanisms, they too are protected against the body’s defenses, thanks to IDO. “Ultimately, IDO lends the cancer cells immunotolerance,” says Trauner. “This enzyme can do so by breaking down the amino acid tryptophan, which is essential for T-cells. But these immune cells are required by the body’s immune response for destroying tumors. As such, IDO inhibitors – and our substances are only two of many such agents – could be employed in cancer therapy in future, for a large number tumors.”

In addition to biomimetic synthesis, Trauner is also engaged in studying fundamental organic reactions. “We have achieved the first asymmetrical Nazarov cyclizations and the first catalytic 6pi electrocyclizations,” states the chemist. “These are important methods for synthesizing five and six-member rings that play a central role in the chemistry of natural products. I am convinced that the large majority of natural products are still unknown and that a multitude of interesting discoveries regarding their chemistry and biology are awaiting us. What fascinates me most is the structural beauty and functional elegance of the naturally occurring substances.” The total synthesis of these products gives an insight into their activity and their origin. Also, their synthesis is an ideal platform for inventing and discovering new synthetic methods.

Aside from natural substances, Trauner is equally captivated by neurobiology. “For me, it is one of the most exciting frontiers in research,” Trauner tells us. “We are progressively learning more about the molecular mechanisms that underlie our sensory experiences and thought processes, and the entire field is radically changing: it is becoming more and more the figurehead of science, as genetics was before.” Until recently, the field of neuroscience had been lacking the technical methods to clarify open questions. “But that has changed now,” says Trauner. “I think that the time for synthetic organic chemistry has come. After all, ever more complex molecules have to be synthesized in order to decipher the structures and mechanisms of nervous systems.” He has already succeeded in manipulating some of the fundamental switches of nerve cells, potassium channels and glutamate receptors in such a way that they become light-sensitive. These modified switches could one day be used to explore nerve connections – or perhaps even to restore the visual process in the case of blindness.

 

Publication:
“Biomimetic synthesis of the IDO inhibitors exiguamine A and B”,
Matthew Volgraf, Jean-Philip Lumb, Harry C Brastianos, Gavin Carr, Marco
K W Chung, Martin Münzel, A Grant Mauk, Raymond J Andersen & Dirk Trauner
Nature Chemical Biology, online on 1st August 2008

Contact:
Professor Dr. Dirk Trauner
Department for Chemistry and Biochemistry at LMU Munich
Tel.: ++49 (0) 89 /2180 – 77800
E-mail: trauner@berkeley.edu
Web: www.cipsm.de

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