Molecular Networking-Guided Isolation of New Etzionin-Type Diketopiperazine Hydroxamates from the Persian Gulf Sponge Cliona celata

Abstract

The Persian Gulf is a unique and biologically diverse marine environment dominated by invertebrates. In continuation of our research interest in the chemistry and biological activity of marine sponges from the Persian Gulf, we selected the excavating sponge Cliona celata for detailed metabolome analyses, in vitro bioactivity screening, and chemical isolation studies. A UPLC-MS/MS (MS2) molecular-networking-based dereplication strategy allowed annotation and structural prediction of various diketopiperazines (DKPs) and etzionin-type diketopiperazine hydroxamates (DKPHs) in the crude sponge extract. The molecular-networking-guided isolation approach applied to the crude extract afforded the DKPH etzionin (1) and its two new derivatives, clioetzionin A (2) and clioetzionin B (3). Another new modified DKP (4) was identified by MS/MS analyses but could not be isolated in sufficient quantities to confirm its structure. The chemical characterization of the purified DKPHs 1–3 was performed by a combination of 1D and 2D NMR spectroscopy, HRMS, HRMS/MS, and [α]D analyses. Compounds 1 and 2 exhibited broad antibacterial, antifungal, and anticancer activities, with IC50 values ranging from 19.6 to 159.1 µM. This is the first study investigating the chemical constituents of a C. celata specimen from the Persian Gulf. It is also the first report of full spectroscopic data of etzionin based on extensive spectroscopic analyses.

Marine natural products

“…419 Originally an ascidian-derived compound, the structure of etzionin 981 has been revised following its re-isolation along with related diketopiperazines clioetzionins A 982 and B 983 from Cliona celata. 420 An unusual fused g-lactam 984 was reported from Aplysina aerophoba, 421 while new hydantoin-containing alkaloids 985-988 were obtained from Aaptos aaptos and Hemimycale sponges. 414,422 Thorectandrin A 989 is a brominated tryptophan-derived alkaloid isolated from Thorectandra choanoides, collected in the Great Australian Bight.…”

Metabolites Profiling and In Vitro Biological Characterization of Different Fractions of Cliona sp. Marine Sponge from the Red Sea Egypt

“…Cliona tenuis contains various compounds, especially Clionapyrrolidine A, which can kill Acropora palmata (stony coral) tissues [ 9 ]. Although the genus has not received much chemical research, the few studies that have been done on it so far have shown that it contains a variety of natural product classes, including steroids, alkaloids, and peptides with variable biological activities [ 10 ]. Investigation of Cliona viridis from the Morocco Atlantic coast by GC-MS revealed various fatty acids such as stearic, palmitoleic, palmitic, oleic, and linoleic acids as well as variable sterols (campesterol, brassicasterol, β-sitosterol, cholesterol, avenasterol, and stigmasterol) [ 11 ].…”

The Total Synthesis of Raistrickindole A

“…The hydroxylamine moiety may be part of an additional ring, rather than being present as a free hydroxyl group. Etzionin 1 and 14-hydroxyterezine 2 are examples with free hydroxyl groups, while gliovirin 3 is an example with the hydroxylamine moiety being part of an additional ring. Mycelianamide 4 is an example of a DKP in which both nitrogen atoms are hydroxylated …”