Cyclic Heptapeptides Axinastatin 2, 3, and 4: Conformational analysis and evaluation of the biological potential

Abstract

Abstract The conformational analysis of naturally occurring cytostatic cyclic heptapeptides axinastatin 2, 3, and 4 was carried out by two‐dimensional NMR spectroscopy in combination with distance‐geometry (DG) and molecular‐dynamics (MD) calculations in explicit solvents. The synthesized secondary metabolites were examined in (D 6 )DMSO. Axinastatin 2 was also investigated in CD 3 OH. In all structures, Pro 2 is in the i + 1 position of a βI turn and Pro 6 occupies the i + 2 position of a βVIa turn about the cis amide bond between residue 5 and Pro 6. In all peptides, a bifurcated H‐bond occurs between residue 4 CO and the amide protons of residue 1 and 7. For axinastatin 2 and 3, an Asn I g turn was found about Asn 1 and Pro 2. We compared these structures with conformations of cyclic heptapeptides obtained by X‐ray and NMR studies. A β‐bulge motif with two β turns and one bifurcated H‐bond is found as the dominating backbone conformation of cyclic all‐L‐heptapeptides. Axinastatin 2, 3, and 4 can be characterized by six trans and one cis amide bond resulting in a β/βVI(a)‐turn motif, a conformation found for many cyclic heptapeptides. Detailed biological tests of the synthetic compounds in different human cancer cell lines indicates these axinastatins to be inactive or of low activity.