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. Iheyamide A (1) showed moderate antitrypanosomal activities against Trypanosoma brucei rhodesiense and Trypanosoma brucei
brucei (IC50 = 1.5 μM), but the other two
analogues, iheyamides B (2) and C (3), did
not (IC50 > 20 μM, respectively). The structure–activity
relationship clarified that an isopropyl-O-Me-pyrrolinone
moiety was necessary for the antitrypanosomal activity. Furthermore,
the cytotoxicity of 1 against normal human cells, WI-38,
was 10 times weaker than its antitrypanosomal activity (IC50 = 18 μM).
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 (IC 50 2.3 μM). However, it exhibited a weaker cytotoxicity against normal human cells (IC 50 55 μM).
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.
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