Developing Cyclic Peptide Heteroatom Interchange: Synthesis and DFT Modelling of a HI‐Ascidiacyclamide Isomer

Abstract

Cyclic peptides isolated from tunicates have captured wide scientific attention from both a drug discovery and ecological perspective. For these reasons cyclic peptides have witnessed considerable synthetic attention, especially those containing azoles. Further pursued herein is the application of the heteroatom interchange (HI) concept to cyclic peptides, in particular ascidiacyclamide. In the HI‐ascidiacyclamide case, the nitrogen and sulfur atoms of both thiazole rings have been transposed through the incorporation of thiazole‐5‐carboxamide units rather than the native thiazole‐4‐carboxamides. Presented herein are the synthesis of an HI‐ascidiacyclamide isomer, a molecular‐mechanics study of its three‐dimensional structure, and a mass spectrometric and density functional theory study of its copper‐binding properties.

Contemplating 1,2,4-Thiadiazole-Inspired Cyclic Peptide Mimics: A Computational Investigation

“…As mentioned above, in the course of developing the synthesis of the HI-cyclic peptides (e.g. 3 and 4), [25,26] 5-carboxy-1,3-thiazole building blocks were required (e.g. 6), which at the time demanded de novo synthetic routes to be developed.…”

“…[22][23][24] To explore the metal binding features of these systems further we recently introduced the concept of heteroatom-interchanged (HI) cyclic peptides. [25,26] Lissoclinamide 5 (1) [27][28][29][30][31] was investigated first as a working template, followed subsequently by ascidiacyclamide (2), [32][33][34] which led to the synthesis of four HI-isomers (e.g. 3) of lissoclinamide 5 and one HI-isomer 4 of ascidiacyclamide ( Fig.…”

“…Metal ion binding studies using mass spectrometry (MS), electronparamagnetic resonance (EPR), and density functional theory (DFT) revealed that the HI-lissoclinamides (e.g. 3) form complexes with one Cu II ion, whereas the HI-ascidiacyclamide isomer 4 was a weaker ligand for Cu II , [25,26] suggesting small changes can have a dramatic effect on co-ordination, conformation, [35] and biological activity. [25,35] To enable the heteroatom-interchange concept, naturally occurring 4-carboxy-1,3-thiazole units (i.e.…”

“…5) were replaced by non-natural 5-carboxy-1,3-thiazole derivatives 6, which required new methodologies to be evaluated in pursuit of obtaining suitable 5-carboxy-1,3-thiazole building blocks. [25,26] Numerous synthetic methods to access 5-carboxy-1,3-thiazoles were evaluated, and in one case valine-and phenylalaninederived 1,2,4-thiadiazoles (i.e. 7 and 8) were produced unexpectedly.…”

A bis-copper(II)–[D-βVal3,7]ascidiacyclamide complex enveloping two square pyramids and sharing an apex atom from a carbonate anion

“…Therefore, the two pyramids connected at their common apex are arranged symmetrically. Recently, the heteroatoms of Thz were interchanged in order to study of copper-binding properties of ASC (Xie et al, 2018). This modification had a very small effect on the chemical structure of ASC, but the coordinate structure and affinity for the copper ion were greatly modified.…”