First Total Synthesis and Structure–Activity Relationship of Iheyamide A, an Antitrypanosomal Linear Peptide Isolated from a Dapis sp. Marine Cyanobacterium

• Published in: Journal of natural products (Washington, D.C.) D.C.), 2021-09, Vol.84 (9), p.2587-2593
• Main Authors: Iwasaki, Arihiro, Teranuma, Kazuya, Kurisawa, Naoaki, Rahmawati, Yulia, Jeelani, Ghulam, Nozaki, Tomoyoshi, Gerwick, William H, Suenaga, Kiyotake
• Format: Article
• Language: English
• Subjects: Aquatic Organisms - chemistry; Cyanobacteria - chemistry; Japan; Molecular Structure; Peptides - isolation & purification; Peptides - pharmacology; Structure-Activity Relationship; Trypanocidal Agents - isolation & purification; Trypanocidal Agents - pharmacology; Trypanosoma brucei brucei - drug effects
• ISSN: 0163-3864; 1520-6025
• DOI: 10.1021/acs.jnatprod.1c00792

Iheyamide A (1) is an antitrypanosomal linear peptide isolated from a Dapis sp. marine cyanobacterium by our group in 2020, and based on structure–activity relationships of its natural analogues, the C-terminal pyrrolinone moiety has been identified as the phamacophore for its antiparasitic activity. Further, we isolated this pyrrolinone moiety by itself as a new natural product from the marine cyanobacterium and named it iheyanone (2). As expected, iheyanone (2) showed antitrypanosomal activity, but its potency was weaker than iheyamide A (1). To clarify more detailed structure–activity relationships, we completed a total synthesis of iheyamide A (1) along with iheyanone (2) and evaluated the antitrypanosomal activities of several synthetic intermediates. As a result, we found that the longer the peptide chain, the stronger the antitrypanosomal activity. As iheyamide A (1) showed selective toxicity against Trypanosoma brucei rhodesiense, these findings can provide design guidelines for antitrypanosomal drugs.