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Proceedings of the 31 st European Peptide SymposiumMichal Lebl, Morten Meldal, Knud J. Jensen, Thomas Hoeg-Jensen (Editors)European Peptide Society, 2010“Clicktophycin-52”: A Bioactive Cryptophycin-52Triazole AnalogueTobias Bogner, Markus Nahrwold, and Norbert SewaldBielefeld University, Organic and Bioorganic Chemistry, Bielefeld, 33615, GermanyIntroductionCryptophycins are a family of cytotoxic, 16-membered macrocyclic depsipeptides. Thename is based on their high toxicity against yeasts of the genus cryptococcus. Researchersat Merck isolated the first cryptophycin, cryptophycin-1 (Figure 1), from cyanobacteriaNostoc sp. (ATCC 53789) in 1990. Many different cryptophycins were later discovered incyanobacteria, but also in marine sponges. Because of their high cytotoxicity cryptophycinswere investigated as potential anti-cancer drugs. However, cryptophycin-52 (1), a syntheticanalogue of cryptophycin-1, failed in clinical phase II studies due to high neurotoxicity andlack of efficacy [2].Retrosynthetically, cryptophycinscan be divided into four building blocks(units A-D). Units A and D are hydroxyacids and units B and C are amino acids.These units are connected via two esterbonds and two amide bonds. The linkbetween units A and B is a cis-amidebond. We envisioned to replace thetrans-amide bond between units B and Cby a 1,4-disubstituted triazole ring tostudy the effect of the substitution on thebiological activity [1]. It is known thatthese triazoles can be used as transamidemimetics, despite their larger sizeFig. 1. Cryptophycin-52, "clicktophycin-52".and dipole moment.Results and DiscussionWe used two different coupling strategies: Either, ring closure via macrolactamization(Figure 2), wherein the click reaction is used to connect units B and C, or ring closure viaclick reaction (Figure 3). The key intermediate in both synthetic routes to “clicktophycin-52” is the unit B-alkyne building block 5.Azidopivalic acid 8 and the unit D precursor 7 were condensed to give the CDsegment 9. Then alkyne 5 was coupled via Cu(I)-catalysed cycloaddition to the CDsegment 9, yielding compound 10. After hydrogenolytic cleavage of the benzyl ester theFig. 2. Coupling strategy 1: ring closure by macrolactamization.330