Total Synthesis of Ukabamide, a Drug Candidate against Sleeping Sickness

Human African trypanosomiasis, also known as “sleeping sickness”, is a tropical disease caused by Trypanosoma parasites that are transmitted by tsetse flies. Untreated, it is generally fatal. Drugs that treat this disease are called antitrypanosomals. Some existing examples of this type of pharmaceutical, which are used to treat severe cases, can have dangerous side effects and/or limited effectiveness, making new drugs desirable research targets. In addition, new antitrypanosomal drugs would be useful against drug-resistant parasites.

Kiyotake Suenaga, Keio University, Kanagawa, Japan, and colleagues have isolated the lipopeptide ukabamide (pictured) from a marine cyanobacterium, found that it has potent antitrypanosomal activity, and confirmed its structure by total synthesis. The team extracted the compound from a Moorena sp. cyanobacterium collected at Ukabi Island, an uninhabited island in Japan. Its structure was determined using mass spectrometry, NMR spectroscopy, and degradation reactions followed by chiral high-performance liquid chromatography (HPLC). The team found that ukabamide is a hydrophobic lipopeptide with a relatively rare odd-numbered C₅ fatty acid.

The structure was confirmed via total synthesis, which also served to provide a larger supply of ukabamide. The team started from 2-bromothiazole, which was lithiated and formylated, followed by conversion to an oxime. The intermediate oxime was reduced to give an amine, and then condensed with a protected N-Me-L-isoleucine. Successive deprotection and condensation steps with amino acids and pentanoic acid then led to the desired product in an overall yield of 10.5 %. The spectroscopic data of the synthesized lipopeptide matched those of the natural product.

The team found that ukabamide shows selective and potent antitrypanosomal activity. It shows the potential of lipopeptides from marine cyanobacteria and could serve as a lead compound for drug development.