Solution structure of the antitumor candidate trunkamide A by 2D NMR and restrained simulated annealing methods

Abstract

Trunkamide A (1) is a cyclic heptapeptide extracted from the ascidian Lissoclinum sp. and has shown very promising cytotoxic activity. This compound incorporates several of the motifs commonly observed in the Patellin family, including dimethylallyl (Dma) Thr and Ser side chains and a thiazoline heterocycle. Given that little is known about the structures adopted by the cyclopeptides of the Patellin family, and with the aim of establishing structure-activity relationships, we have carried out the conformational analysis of trunkamide A by a combination of 2D NMR experiments and simulated annealing calculations. Our results show that the conformation of 1 is very rigid and is dominated by the volume of the dimethylallyl side chains and two trans-annular hydrogen bonds. We have also studied the conformation of 2, the l-Phe diastereoisomer of 1, the analysis of which provides a possible rationale for its epimerization to 1, a process that is observed in solution. Finally, we show how a thorough NMR characterization can be used, in combination with simulated annealing methods, to confirm the configuration of a stereogenic center in the backbone of a rigid cyclic peptide such as trunkamide A (1).