Dudawalamides A–D, Antiparasitic Cyclic Depsipeptides from the Marine Cyanobacterium <i>Moorea producens</i>

A family of 2,2-dimethyl-3-hydroxy-7-octynoic acid (Dhoya)-containing cyclic depsipeptides, named dudawalamides A–D (<b>1</b>–<b>4</b>), was isolated from a Papua New Guinean field collection of the cyanobacterium <i>Moorea producens</i> using bioassay-guided and spectroscopic approaches. The planar structures of dudawalamides A–D were determined by a combination of 1D and 2D NMR experiments and MS analysis, whereas the absolute configurations were determined by X-ray crystallography, modified Marfey’s analysis, chiral-phase GCMS, and chiral-phase HPLC. Dudawalamides A–D possess a broad spectrum of antiparasitic activity with minimal mammalian cell cytotoxicity. Comparative analysis of the Dhoya-containing class of lipopeptides reveals intriguing structure–activity relationship features of these NRPS–PKS-derived metabolites and their derivatives

Samholides, Swinholide-Related Metabolites from a Marine Cyanobacterium cf. <i>Phormidium</i> sp.

Cancer cell cytotoxicity was used to guide the isolation of nine new swinholide-related compounds, named samholides A–I (<b>1</b>–<b>9</b>), from an American Samoan marine cyanobacterium cf. <i>Phormidium</i> sp. Their structures were determined by extensive analysis of 1D and 2D NMR spectroscopic data. The new compounds share an unusual 20-demethyl 44-membered lactone ring composed of two monomers, and they demonstrate structural diversity arising from geometric isomerization of double bonds, sugar units with unique glyceryl moieties and varied methylation patterns. All of the new samholides were potently active against the H-460 human lung cancer cell line with IC₅₀ values ranging from 170 to 910 nM. The isolation of these new swinholide-related compounds from a marine cyanobacterium reinvigorates questions concerning the evolution and biosynthetic origin of these natural products

Table_1_The Metabolome of a Cyanobacterial Bloom Visualized by MS/MS-Based Molecular Networking Reveals New Neurotoxic Smenamide Analogs (C, D, and E).DOCX

<p>Members of the cyanobacterial genus Trichodesmium are well known for their substantial impact on nitrogen influx in ocean ecosystems and the enormous surface blooms they form in tropical and subtropical locations. However, the secondary metabolite composition of these complex environmental bloom events is not well known, nor the possibility of the production of potent toxins that have been observed in other bloom-forming marine and freshwater cyanobacteria species. In the present work, we aimed to characterize the metabolome of a Trichodesmium bloom utilizing MS/MS-based molecular networking. Furthermore, we integrated cytotoxicity assays in order to identify and ultimately isolate potential cyanotoxins from the bloom. These efforts led to the isolation and identification of several members of the smenamide family, including three new smenamide analogs (1–3) as well as the previously reported smenothiazole A-hybrid polyketide-peptide compounds. Two of these new smenamides possessed cytotoxicity to neuro-2A cells (1 and 3) and their presence elicits further questions as to their potential ecological roles. HPLC profiling and molecular networking of chromatography fractions from the bloom revealed an elaborate secondary metabolome, generating hypotheses with respect to the environmental role of these metabolites and the consistency of this chemical composition across genera, space and time.</p

Bastimolide B, an Antimalarial 24-Membered Marine Macrolide Possessing a <i>tert</i>-Butyl Group

We reported previously the discovery of the potent antimalarial 40-membered macrolide bastimolide A (<b>1</b>) from the tropical marine cyanobacterium <i>Okeania hirsute</i>. Continued investigation has led to the discovery of a new analogue, bastimolide B (<b>2</b>), a 24-membered polyhydroxy macrolide with a long aliphatic chain and unique terminal <i>tert</i>-butyl group. Its complete structure was determined by a combination of extensive spectroscopic methods and comparative analysis of its methanolysis products with those of bastimolide A. A methanolysis mechanism for bastimolide A is proposed, and one unexpected isomerization product of the C2–C3 double bond, 2-(<i>E</i>)-bastimolide A (<b>3</b>), was obtained. Bastimolide B (<b>2</b>) showed strong antimalarial activity against chloroquine-sensitive <i>Plasmodium falciparum</i> strain HB3. A preliminary investigation of the structure–activity relationship based on six analogues revealed the importance of the double bond as well as the 1,3-diol and 1,3,5-triol functionalities

Molecular Networking as a Dereplication Strategy

A major goal in natural product discovery programs is to rapidly dereplicate known entities from complex biological extracts. We demonstrate here that molecular networking, an approach that organizes MS/MS data based on chemical similarity, is a powerful complement to traditional dereplication strategies. Successful dereplication with molecular networks requires MS/MS spectra of the natural product mixture along with MS/MS spectra of known standards, synthetic compounds, or well-characterized organisms, preferably organized into robust databases. This approach can accommodate different ionization platforms, enabling cross correlations of MS/MS data from ambient ionization, direct infusion, and LC-based methods. Molecular networking not only dereplicates known molecules from complex mixtures, it also captures related analogues, a challenge for many other dereplication strategies. To illustrate its utility as a dereplication tool, we apply mass spectrometry-based molecular networking to a diverse array of marine and terrestrial microbial samples, illustrating the dereplication of 58 molecules including analogues