Synthesis and structure-activity relationship of a microcionamide-inspired peptide

• Main Authors: Inocentes, Carl Rogel V., Salvador-Reyes, Lilibeth A., Villaraza, Aaron Joseph L.
• Format: text
• Published: Animo Repository 2019
• Subjects: Peptides; Chemistry
• Online Access: https://animorepository.dlsu.edu.ph/faculty_research/11430
• Institution: De La Salle University

Here we describe the facile synthesis of four microcionamide-inspired peptides where the atypical 2- phenylethylenamine in the marine natural product, microcionamide A, was substituted by a similarly-aromatic and more easily incorporated tryptophan residue. Compounds 1-4 were synthesized using a standard Fmoc-based solid-phase synthesis strategy followed by iodine-mediated on-resin cyclization for disulfide-bridged compounds 1-3. Biological activity evaluation revealed the strong antibacterial activity of compound 1 with MIC of 9.1 µM and 15 µM against S. aureus and P. aeruginosa, respectively. The inactivity of alanine analogues 2-4 against these pathogens suggests that the N-terminal Val, the cyclic scaffold, the contiguous lie residues and consequently, the hydrophobicity of compound 1 are essential for its antibacterial action. Compound 1 also favorably showed limited cytotoxicity against normal mammalian cell lines. Collectively, we have synthesized an analogue of microcionamide A, where replacement of the 2- phenylethylenamine moiety with a Trp residue retained the antibacterial activity and favorably diminished cytotoxicity.