New Theonellapeptolides from Indonesian Marine Sponge Theonella swinhoei as Anti-Austerity Agents

Abstract

We reported three new members of the theonellapeptolide family from theonellapeptolide II series, namely theonellapeptolides IIb (1), IIa (2), IIc (3), and three known members-IId (4), IIe (5), and Id (6)-from Kodingarengan marine sponge Theonella swinhoei collected in Makassar, Indonesia. The structures of tridecadepsipeptides 1-3, including the absolute configurations of their amino acids, were determined by the integrated NMR and tandem MS analyses followed by Marfey's analysis. To the best of our knowledge, 1 and 2 are the first theonellapeptolide-type compounds to have a valine residue with _D configuration at residue position 6. The isolated theonellapeptolide-type compounds 1-6 showed selective cytotoxic activity against human pancreatic MIA PaCa-2 cancer cells in a nutrient-deprived medium. Among them, the most potent preferential cytotoxicity was observed in new theonellapeptolide IIc (3) and known IId (4), IIe (5), and Id (6).

Keywords: Theonella swinhoei; anti-austerity agents; anti-pancreatic cancer agents; depsipeptide; marine sponge; preferential cytotoxicity; theonellapeptolide-type compounds.

Figure 1

The structure of theonellapeptolides IIb (1), IIa (2), and IIc (3), and known compounds IId (4), IIe (5), and Id (6).

Figure 2

Tandem mass analyses of the seco-acid methyl ester peptide of 1, 2, and 4 (A); 3 and 5 (B) showed their three predominant fragment ions.

Figure 3

Analysis of ¹H-¹H and ¹H-¹³C key correlations for compound 1.

Figure 4

Isolated peptide fragment for determining the amino acid configuration of repeated residues (A). Determination of absolute configuration of repeated amino acids (B).

Figure 5

Cytotoxic and anti-austerity activity of the compounds 1–6 against the human pancreatic cancer cell line MIA PaCa-2. Compound 1–6: theonellapeptolides IIb (1), IIa (2), and IIc (3), and known compounds IId (4), IIe (5), and Id (6).

Figure 6

(A) Morphological changes of MIA PaCa-2 cells induced by 4 in a nutrient-deprived medium (NDM). MIA PaCa-2 tumor cells were treated with 4 at the indicated concentrations in NDM in a 24-well plate and incubated for 24 h. The cells were stained with ethidium bromide (EB) and acridine orange (AO), and photographed in the fluorescence (red and green) under phase contrast modes using a Nikon sCMOS camera oxford instrument, Hamamatsu Photonics/Ti-E. (B) Structure of bioactive compound 4. (C) Effect of 4 on colony formation by MIA PaCa-2 cells in DMEM. (a) Graph showing the average values of the area occupied by MIA PaCa-2 cell colonies (three replicates). **** p < 0.0001 compared to the untreated control group. (b) Representative wells showing colonies of MIA PaCa-2 cells.

Figure 7

Captures of the live imaging of the effect of 10 μM of compound 4 (treated in NDM, below) compared to control (untreated in NDM, up) on MIA PaCa-2 cells at different intervals of time 4 h.