Bistratamides M and N, Oxazole-Thiazole Containing Cyclic Hexapeptides Isolated from Lissoclinum bistratum Interaction of Zinc (II) with Bistratamide K

Abstract

Two novel oxazole-thiazole containing cyclic hexapeptides, bistratamides M (1) and N (2) have been isolated from the marine ascidian Lissoclinum bistratum (L. bistratum) collected in Raja Ampat (Papua Bar, Indonesia). The planar structure of 1 and 2 was assigned on the basis of extensive 1D and 2D NMR spectroscopy and mass spectrometry. The absolute configuration of the amino acid residues in 1 and 2 was determined by the application of the Marfey’s and advanced Marfey’s methods after ozonolysis followed by acid-catalyzed hydrolysis. The interaction between zinc (II) and the naturally known bistratamide K (3), a cyclic hexapeptide isolated from a different specimen of Lissoclinum bistratum, was monitored by 1H and 13C NMR. The results obtained are consistent with the proposal that these peptides are biosynthesized for binding to metal ions. Compounds 1 and 2 display moderate cytotoxicity against four human tumor cell lines with GI50 values in the micromolar range.

Naturally Occurring Oxazole-Containing Peptides

“…Two additional bistratamides with antitumor activity, M (17) and N (18), were also characterized, as reported by Urda et al Overall, the 1 H NMR data of 17 and 18 presented a similar pattern to that of Dolastatin E (30) [40]. Of note, the structures of the peptides westiellamide [42], Dendroamides 19-21 [43], and Nostocyclamides 22 and 23 [12] are all related to Bistratamides 12-18.…”

“…Bistratamides C, D, G, H, I, M, and N (12)(13)(14)(15)(16)(17)(18) are cyclic hexapeptides that were isolated from the cytotoxic extract from the ascidian Lissoclinum bistratum (Figure 7) [39,40]. Sharing a similar cyclic backbone, the structures of 12-18 were determined by means of 2D NMR spectroscopy, as well as mass spectrometry.…”

Marine natural products

“…The metabolites reported in 2017 included carbamates 1428-1431, ureas 1432-1435 and isoquinoline 1436 (Didemnum molle), 656 isoquinoline-quinones 1437-1439 (Ascidia virginea), 657 antibacterial cadiolides J-M 1440, 1441-1443 (Pseudodistoma antinboja), 658 new congeners in the mandelalide series 1444-1450 (Lissoclinum mandelai), 659 cytotoxic bistratamides M and N 1451, 1452 (L. bistratum), 660 and cyclic hexapeptide dimers antatollamides A 1453 and B 1454 (D. molle). 661 The absolute conguration of the constituent amino acids of antatollamide A were secured by making use of a new tryptophan-based chiral derivatisation reagent.…”

Ascidian Toxins with Potential for Drug Development

“…The copper concentration of ascidians is several orders of magnitude higher than seawater leading to the idea that some cyanobactins function in copper transport and storage, or detoxification [ 44 ]. Two novel cyclic hexapeptides—bistratamides M and N—differing only in the configuration of one alanine side chain ( Figure 1 ) have been isolated [ 45 ]. In the same study the authors also examined the metal binding of Bistratamide K and showed that it binds Zn(II).…”