Heteroatom‐Interchanged Isomers of Lissoclinamide 5: Copper(II) Complexation, Halide Binding, and Biological Activity. Issue 12 (25th March 2018)

• Record Type: Journal Article
• Authors: Xie, Sida; Savchenko, Andrei I.; Kerscher, Marion; Grange, Rebecca L.; Krenske, Elizabeth H.; Harmer, Jeffrey R.; Bauer, Michelle J.; Broit, Natasa; Watters, Dianne J.; Boyle, Glen M.; Bernhardt, Paul V.; Parsons, Peter G.; Comba, Peter; Gahan, Lawrence R.; Williams, Craig M.
• Is Part Of: European journal of organic chemistry. Issue 12(2018)
• Page Start: 1465
• Page End: 1476
• Publication Date: 2018-03-25
• Subjects: Cyanobacteria -- Peptides -- Lissoclinamide 5 -- Heteroatom interchange -- Cavitands -- Natural products; Chemistry, Organic -- Periodicals; Organic compounds -- Synthesis -- Periodicals; Bioorganic chemistry -- Periodicals; Chemistry, Physical organic -- Periodicals; 547
• DOI: 10.1002/ejoc.201701659
• Languages: English
• ISSNs: 1434-193X

Abstract

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 Cu II 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 Cu II 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 Cu II 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. Abstract : Cyclic peptides found in nature are often proposed as biological metal chelators owing to their cavitand architectures. This theory was probed by synthesizing and evaluating the physical and biological properties of heteroatom‐interchanged variants. A comprehensive study reaffirmed that small structural changes induce dramatic effects in complexation, halide binding, and biological activity.