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

Abstract

Dedicated to Ernst B q e r on the occasion of his 70th birthday (24.11.97) 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- 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 1, turn was found about Asn' and Pro'. We compared these structures with conformations of cyclic heptapeptides obtained by X-ray and NMR studies. A P-bulge motif with two 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 fruns and one cis amide bond resulting in a PI/PVI(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.

Isolation and Structural Elucidation of Euryjanicins B−D, Proline-Containing Cycloheptapeptides from the Caribbean Marine Sponge Prosuberites laughlini

“…21,22 Adjacent cis and trans proline residues, which have been previously found in cyclic peptides such as wainunuamide 11 and phakellistatin 8, 23 are known to be powerful β -turn inducers. 4a …”

Free energy based populations of interconverting microstates of a cyclic peptide lead to the experimental NMR data

“…74,75 Preliminary studies show that the ASPs developed in paper I are transferable. For example, for the pentapeptide, E tot leads to 5 NOE violations (two of them very small, of only 0.1 Å) as opposed to the 10 NOE violations obtained with E GRO ; correspondingly, much better results for the 3 J coupling constants are obtained with E tot than with E GRO .…”

Performance of efficient minimization algorithms as applied to models of peptides and proteins

“…Asn ᎐Pro ᎐Phe ᎐Val ᎐Leu ᎐Pro ᎐Val n s 62 whose structures were investigated with nuclear magnetic resonance by Kessler's group. 47,48 The Ž x-ray atomic coordinates of BPTI 58 resides, n s . 568 were taken from the Brookhaven Protein Data Ž .…”