Total Synthesis and Bioactivity Evaluation of Hydrophobic Microcionamide-Inspired Peptides |
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Authors: | Carl Rogel V. Inocentes Lilibeth A. Salvador-Reyes Aaron Joseph L. Villaraza |
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Affiliation: | 1. Institute of Chemistry, University of the Philippines Diliman, Diliman, Quezon City, 1101 Philippines;2. Marine Science Institute, University of the Philippines Diliman, Diliman, Quezon City, 1101 Philippines |
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Abstract: | In this report, we describe the facile synthesis of four microcionamide-inspired peptides where the atypical 2-phenylethylenamine (2-PEA) functional group in the marine natural product, microcionamide A, was replaced with a similarly-aromatic but more easily incorporated tryptophan (Trp) 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 . Compound 1 showed antimicrobial activity against Staphylococcus aureus and Pseudomonas aeruginosa, with minimum inhibitory concentrations (MICs) of 9.1 μM and 15 μM, respectively. The inactivity of alanine analogs 2 – 4 against these pathogens suggests that the N-terminal Val, the cyclic scaffold, the contiguous Ile residues, and consequently, the hydrophobicity of compound 1 are essential for antibacterial activity. Compound 1 also favorably exhibited minimal cytotoxicity against normal mammalian cell lines. In summary, we have synthesized an analog of microcionamide A where replacement of the 2-PEA moiety with a Trp residue retained the antibacterial activity and with favorably low cytotoxicity. |
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Keywords: | solid-phase synthesis structure–activity relationships peptides disulfide antibiotics |
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