Issue Date: August 4, 2008
Biomimetically Built Cancer Inhibitors
An international research team has reported the total syntheses of exiguamine A and B, which are potent inhibitors of a promising enzyme target implicated in several types of cancer (Nat. Chem. Biol., DOI: 10.1038/nchembio.107). Raymond J. Andersen of the University of British Columbia, Vancouver; Dirk Trauner of the University of California, Berkeley; and coworkers employed a biomimetic strategy to synthesize the compounds. They built a quinone intermediate using simple amino acid-derived building blocks and then proceeded to exiguamine A and B by means of an oxidative cascade of reactions. Exiguamine A and B are natural products derived from a marine sponge found in the waters of Papua New Guinea. The compounds inhibit the enzyme indoleamine-2,3-dioxygenase (IDO) with nanomolar affinity. IDO is involved in the degradation of tryptophan, and it protects a growing fetus from its mother's immune system. But the enzyme is also overexpressed in many tumor cell lines, correlates with a poor prognosis for certain cancers, and seems to play a role in the "immune escape" mechanisms that solid tumors use to avoid recognition by the immune system, the authors note. "Our general synthetic strategy should give rise to many exiguamine analogs, which could serve as useful candidates for drug development," they write.
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