New Discorhabdin Alkaloids from the Antarctic Deep-Sea Sponge Latrunculia biformis

Abstract

The sponge genus Latrunculia is a prolific source of discorhabdin type pyrroloiminoquinone alkaloids. In the continuation of our research interest into this genus, we studied the Antarctic deep-sea sponge Latrunculia biformis that showed potent in vitro anticancer activity. A targeted isolation process guided by bioactivity and molecular networking-based metabolomics yielded three known discorhabdins, (−)-discorhabdin L (1), (+)-discorhabdin A (2), (+)-discorhabdin Q (3), and three new discorhabdin analogs (−)-2-bromo-discorhabdin D (4), (−)-1-acetyl-discorhabdin L (5), and (+)-1-octacosatrienoyl-discorhabdin L (6) from the MeOH-soluble portion of the organic extract. The chemical structures of 1–6 were elucidated by extensive NMR, HR-ESIMS, FT-IR, [α]D, and ECD (Electronic Circular Dichroism) spectroscopy analyses. Compounds 1, 5, and 6 showed promising anticancer activity with IC50 values of 0.94, 2.71, and 34.0 µM, respectively. Compounds 1–6 and the enantiomer of 1 ((+)-discorhabdin L, 1e) were docked to the active sites of two anticancer targets, topoisomerase I-II and indoleamine 2,3-dioxygenase (IDO1), to reveal, for the first time, the binding potential of discorhabdins to these proteins. Compounds 5 and 6 are the first discorhabdin analogs with an ester function at C-1 and 6 is the first discorhabdin bearing a long-chain fatty acid at this position. This study confirms Latrunculia sponges to be excellent sources of chemically diverse discorhabdin alkaloids.

New Discorhabdin B Dimers with Anticancer Activity from the Antarctic Deep-Sea Sponge Latrunculia biformis

“…The 2D COSY cross-peak between H-1 and H-2, and the HMBC correlations between H-1/C-5, H-1/C-6, H-1/C-20, H-2/C-1, H-2/C-3, H-2/C-6, H-4/C-2, and H-4/C-6 supported the presence of a cyclohexanone substitution at the spiro center, C-6. The down-field shifted resonances of C-5 (δ C 174.4), C-8 (δ C 62.8), and H-8 (δ H 5.58) indicated the presence of a sulfide bridge between C-5 and C-8 [9][10][11]14]. This assumption was further supported by a diagnostic HMBC correlation between H-8 and C-5 ( Figure 2).…”

“…As described previously [14], the sponge material was desalted with water, and extracted by methanol and dichloromethane, respectively. The combined organic extract was partitioned between MeOH and n-hexane.…”

“…A detailed analysis of the 1D and 2D NMR data of 2 suggested the presence of five sp 3 methylenes, three sp 3 methenes, seven sp 2 methenes, and 21 quaternary carbon signals belonging to two sp 3 and 19 sp 2 carbon atoms (Tables 1 and 2). To facilitate the structure elucidation and interpretation of the NMR data of 2, we assigned the letters A and B for each discorhabdin monomer ( Figure 2 [9][10][11]14]. The tetracyclic pyrroloiminoquinone core structure of component A was readily ascertained by the 2D COSY and HMBC correlations shown in Figure 2.…”

“…So far, Latrunculia sponges represent one of the major reservoirs of pyrroloiminoquinone-type alkaloids. More than 40 pyrroloiminoquinone alkaloids belonging to the subclasses tsitsikammamines, makaluvamines, and discorhabdins have been reported from this genus, the discorhabdins being the largest and the most diverse [5,8,13,14]. Discorhabdins are a unique class of nitrogenous pigments possessing a characteristic tetracyclic pyrido [2,3-h]pyrrolo [4,3,2-de]quinoline core bound to a cyclohexanone substituent at the spiro center C-6 [5].…”

“…In a recent study, we reported new discorhabdin monomers from the MeOH subextract of the Antarctic deep-sea sponge L. biformis [14]. In the continuation of the chemical investigation of this sponge, we have now focused on its n-hexane-soluble portion.…”