Targeted Isolation of Tsitsikammamines from the Antarctic Deep-Sea Sponge Latrunculia biformis by Molecular Networking and Anticancer Activity

Abstract

The Antarctic deep-sea sponge Latrunculia (Latrunculia) biformis Kirkpatrick, 1908 (Class Demospongiae Sollas, Order Poecilosclerida Topsent, Latrunculiidae Topsent) was selected for chemical analyses due to its potent anticancer activity. Metabolomic analysis of its crude extract by HRMS/MS-based molecular networking showed the presence of several clusters of pyrroloiminoquinone alkaloids, i.e., discorhabdin and epinardin-type brominated pyridopyrroloquinolines and tsitsikammamines, the non-brominated bis-pyrroloiminoquinones. Molecular networking approach combined with a bioactivity-guided isolation led to the targeted isolation of the known pyrroloiminoquinone tsitsikammamine A (1) and its new analog 16,17-dehydrotsitsikammamine A (2). The chemical structures of the compounds 1 and 2 were elucidated by spectroscopic analysis (one-dimensional (1D) and two-dimensional (2D) NMR, HR-ESIMS). Due to minute amounts, molecular modeling and docking was used to assess potential affinities to potential targets of the isolated compounds, including DNA intercalation, topoisomerase I-II, and indoleamine 2,3-dioxygenase enzymes. Tsitsikammamines represent a small class of pyrroloiminoquinone alkaloids that have only previously been reported from the South African sponge genus Tsitsikamma Samaai & Kelly and an Australian species of the sponge genus Zyzzya de Laubenfels. This is the first report of tsitsikammamines from the genus Latrunculia du Bocage and the successful application of molecular networking in the identification of comprehensive chemical inventory of L. biformis followed by targeted isolation of new molecules. This study highlights the high productivity of secondary metabolites of Latrunculia sponges and may shed new light on their biosynthetic origin and chemotaxonomy.

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

“…Figure 5). The carbonyl signals belonging to C-11 and C-11' did not appear in the NMR spectra, which is a common case in many pyrroloiminoquinone alkaloids [11,12,14]. Our attempts to locate the two carbonyl carbons by using a high-resolution cryo NMR probe were unsuccessful, however, the structural homology was obvious based on the HRMS, 1D, and 2D NMR data and the comparison of the data with related compounds in the literature [18,19].…”

“…The members of this genus are predominately distributed in cold-water regions of the Southern Hemisphere [3,4]. Continuing reports of pyrroloiminoquinone-type alkaloids with strong anticancer activity from Latrunculia sponges have been the main driving force for in-depth chemical analyses of this genus [5][6][7][8][9][10][11][12]. So far, Latrunculia sponges represent one of the major reservoirs of pyrroloiminoquinone-type alkaloids.…”

Screening Fungal Endophytes Derived from Under-Explored Egyptian Marine Habitats for Antimicrobial and Antioxidant Properties in Factionalised Textiles

“…A molecular network consists of nodes which correspond to parent ions and are linked into groups with edges which represent a cosine similarity score. Molecular networking provides effective and rapid dereplication of large and complex MS/MS datasets and has been successfully implemented in natural product research to accelerate targeted isolation of potentially new metabolites [ 17 , 18 , 19 ].…”

Integrating Molecular Networking and 1H NMR Spectroscopy for Isolation of Bioactive Metabolites from the Persian Gulf Sponge Axinella sinoxea

“…More importantly, MN is able to map out the chemical space of a biological sample by grouping similar metabolites that produce similar MS/MS fragmentation in one cluster [ 15 ]. Our research group has been using MN successfully to uncover the detailed chemical machinery of various marine macro- and micro-organisms followed by targeted isolation of new and bioactive marine natural products [ 14 , 30 , 31 ]. However, in the current study, MN provided limited information on the chemical composition of A. sinoxea and only two natural product families, i.e., phospholipids and steroids, which are the major components of sponge cell walls [ 32 ], have been annotated.…”