Tridiscorhabdin and Didiscorhabdin, the First Discorhabdin Oligomers Linked with a Direct C–N Bridge from the Sponge Latrunculia biformis Collected from the Deep Sea in Antarctica

Abstract

Guided by LC-MS/MS molecular networking-based metabolomics and cytotoxic activity, two new discorhabdin-type alkaloids, tridiscorhabdin (1) and didiscorhabdin (2), were isolated from the sponge Latrunculia biformis, collected from the Weddell Sea (Antarctica) at −291 m depth. Their structures were established by HRESIMS, NMR, [α] D , and ECD data coupled with DFT calculations. Both compounds bear a novel C−N bridge (C-1/N-13) between discorhabdin monomers, and 1 represents the first trimeric discorhabdin molecule isolated from Nature. Tridiscorhabdin (1) exhibited strong cytotoxic activity against the human colon cancer cell line HCT-116 (IC 50 value 0.31 μM).

Exploration of the Electrophilic Reactivity of the Cytotoxic Marine Alkaloid Discorhabdin C and Subsequent Discovery of a New Dimeric C-1/N-13-Linked Discorhabdin Natural Product

“…Analysis of the (+)-HRESI mass spectrum of 8 identified molecular ions at m/z 879/881/883/885, with the corresponding protonated doubly charged ions at m/z 440/441/442/443 also observed. The assigned molecular formula of C 36 H 30 Br 3 N 6 O 6 suggested the presence of a pseudo-dimer composed of two discorhabdin C-like fragments [ 6 ]. Interpretation of 1D and 2D NMR data revealed the presence of two distinct discorhabdin scaffolds, one of which was very similar to discorhabdin C (‘fragment A’), and the second (‘fragment B’) very similar to the keto-hydrate structure of aminopentane adduct 6 .…”

“…Similar to 6 , a fragment sequence of C-1′ (δ H 6.44; δc 54.1), C-2′ (δ H 4.29; δc 71.2); C-3′ (δc 98.4), C-4′ (δ H obscured; δc 58.6), C-5′ (δ H 4.16; δc 76.0) to C-6′ (δc 42.8) was established using a combination of COSY, HSQC and HMBC NMR data. Of particular note was the unusually deshielded resonance observed for H-1′ (δ H 6.44), identifying the presence of a highly electron withdrawing group at C-1′ [ 6 ]. Other proton spin-system resonances associated with fragment B were found to be almost identical to those observed for aminopentane adduct 6 including resonances for H 2 -7′ (δ H 2.31, 1.07), H 2 -8′ (δ H 3.89, 3.56), H-14′ (δ H 7.24), H 2 -16′ (δ H 3.06) and H 2 -17′ (δ H 4.13, 4.04).…”

“…Other proton spin-system resonances associated with fragment B were found to be almost identical to those observed for aminopentane adduct 6 including resonances for H 2 -7′ (δ H 2.31, 1.07), H 2 -8′ (δ H 3.89, 3.56), H-14′ (δ H 7.24), H 2 -16′ (δ H 3.06) and H 2 -17′ (δ H 4.13, 4.04). Connectivity between the two fragments was revealed by the observation of HMBC correlations from H-1′ (δ H 6.44) to both C-12 (δ C 126.6) and C-14 (δ C 130.1), establishing 8 to be a new example of a C-1′/N-13 linked discorhabdin dimer [ 6 ].…”

“…Usually derived from extracts of marine sponges of the genus Latrunculia , these alkaloids have attracted much attention from both chemists and biologists due to their complex structures and associated biological activities [ 1 , 2 ]. While some of the first examples of the discorhabdins e.g., discorhabdin B ( 1 ) and C ( 2 ) ( Figure 1 ) were structurally relatively simple [ 3 , 4 ], recent studies have unveiled unusual dimers [ 5 ], oligomers [ 6 ] and more complex polycyclic variants [ 7 , 8 ].…”

“…In many cases, discorhabdin alkaloids have been reported to exhibit cytotoxicity towards tumour cell lines [ 1 , 2 , 3 , 4 , 6 , 8 , 9 ], with additional biological activities also including inhibition of protein–protein interaction associated with hypoxia-inducible factor 1α and its transcriptional coactivator p300 [ 10 , 11 ], antibacterial [ 12 , 13 , 14 ] and antimalarial [ 13 ] properties. The biological activities of simple dienone-containing examples of the discorhabdins has been attributed to the electrophilic properties of this moiety [ 2 , 15 ].…”