Discovery of Ircinianin Lactones B and C-Two New Cyclic Sesterterpenes from the Marine Sponge Ircinia wistarii

Abstract

Two new ircinianin-type sesterterpenoids, ircinianin lactone B and ircinianin lactone C (7 and 8), together with five known entities from the ircinianin compound family (1, 3-6) were isolated from the marine sponge Ircinia wistarii. Ircinianin lactones B and C (7 and 8) represent new ircinianin terpenoids with a modified oxidation pattern. Despite their labile nature, the structures could be established using a combination of spectroscopic data, including HRESIMS and 1D/2D NMR techniques, as well as computational chemistry and quantum-mechanical calculations. In a broad screening approach for biological activity, the class-defining compound ircinianin (1) showed moderate antiprotozoal activity against Plasmodium falciparum (IC₅₀ 25.4 μM) and Leishmania donovani (IC₅₀ 16.6 μM).

Keywords: Ircinia wistarii; Leishmania donovani; NCI-60; Plasmodium falciparum; antiprotozoal activity; bioactivity screening; ircinianin-derivates; sesterterpene; sponge.

Figure 1

Structures of the ircinianin-sesterterpene family. The center image depicts the Ircinia wistarii sample of this study.

Figure 2

Stacked ¹H-NMR spectra of ircinianin (1) and ircinianin lactones A-C (6–8), recorded in d₄-MeOH with the characteristic “signal-fingerprint” of the ircinianin-like scaffold in the 0.6 to 5.4 ppm region (red box with solid lines). The signals of the sidechain heterocycles appear between 5.5 to 7.5 ppm. Symbols denote the peak assignments in all ¹H NMR spectra, which are visualized in the chemical structure on the right (red box with dashed lines). Key: blue symbols denote hydrogens of the tricyclic spirotetronic acid backbone; green symbols denote hydrogens of the alkyl side chain, R = terminal sidechain heterocycle. Hash symbol denotes residual methanol.

Figure 3

Key NMR correlations for 7.

Figure 4

Key NMR correlations for 8.

Figure 5

(A) Superimposition of the lowest energy conformer obtained for the 1S- (purple) and 1R-(brown) epimer of ircinianin lactone C (8). Dashed lines indicate the hydrogen bonds formed by OH-1 and OH-22. (B) 1R-epimer of 8. Dashed lines indicate distance measurements; green through space interactions are in agreement with observed NOE correlations, while the red contact was expected to be detectable, but was absent in the corresponding NOESY NMR spectrum. (C) 1S-epimer of 8. Green dashed lines indicate through space interactions, which agree with the observed NOE correlations.

Figure 6

Proposed biosynthetic pathway. Substructures in green boxes are associated with isolated molecules, as mentioned above. Red-framed structures indicate what are so far only hypothetical structure analogues following the predicted biosynthetic scheme.