Heteroatom‐Interchanged Isomers of Lissoclinamide 5: Copper(II) Complexation, Halide Binding, and Biological Activity

Abstract

Cyclic peptides, especially those produced by marine cyanobacteria symbionts, are considered to play an important ecological role in host defence. Chemists have long compared the cyclic peptide cavitand architecture with that of macrocyclic ligands, and proposed that they mediate metal‐ion transport. The study presented herein investigated the metal chelation of non‐natural heteroatom‐interchanged (HI) isomers of lissoclinamide 5, by using MS, EPR, and DFT calculations. The latter identified three possible structures for the CuII complex with natural lissoclinamide 5, with the most likely determined to be that with the metal ion bound through the nitrogen donors of the thiazoles and one deprotonated amide. For HI‐lissoclinamide 5 the calculations suggest that the CuII ion is bound in a bidentate manner by the oxazoline nitrogen atom and one deprotonated amide nitrogen atom, with the S donor of the thiazole not involved in coordination. Along with evidence of copper binding these systems also bound halide ions. Evaluation of the anti‐cancer properties demonstrated that the biological activity of HI‐lissoclinamide 5 against T24 bladder cells was eleven‐fold lower as compared to natural lissoclinamide 5. Addition of a CuII salt had no effect on the activity of lissoclinamide 5. Overall, this comprehensive study of the HI concept has demonstrated that small changes propagate dramatic effects in complexation, halide binding, and biological activity.

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.…”

“…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.…”

“…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.…”