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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.

Kinenzoline (1), a new linear depsipeptide, was isolated from a marine Salileptolyngbya sp. cyanobacterium. Its structure was elucidated by spectroscopic analyses and degradation reactions. In addition, we achieved a total synthesis of 1 and confirmed its structure. Kinenzoline (1) showed highly selective antiproliferative activity against the causative organism of sleeping sickness, Trypanosoma brucei rhodesiense (IC50 4.5 μM), compared to normal human cells (WI-38, IC50 > 100 μM). Kinenzoline (1) is a promising lead compound for the development of new antitrypanosomal drugs.

Motobamide (1), a new cyclic peptide containing a C-prenylated cyclotryptophan residue, was isolated from a marine Leptolyngbya sp. cyanobacterium. Its planar structure was established by spectroscopic and MS/MS analyses. The absolute configuration was elucidated based on a combination of chemical degradations, chiral-phase HPLC analyses, spectroscopic analyses, and computational chemistry. Motobamide (1) moderately inhibited the growth of bloodstream forms of Trypanosoma brucei rhodesiense (IC50 2.3 µM). However, it exhibited a weaker cytotoxicity against normal human cells (IC50 55 µM).

Iheyamides A (1), B (2), and C (3), new linear peptides, were isolated from a marine Dapis sp. cyanobacterium. Their structures were elucidated by spectroscopic analyses and degradation reactions. ...