Abstract
Bioassay-guided isolation of the lipophilic extract of Trichodesmium thiebautii bloom material led to the purification and structure characterization of two new hybrid polyketide-non-ribosomal peptide (PKS-NRPS) macrocyclic compounds, tricholides A and B (1 and 2). A third macrocyclic compound, unnarmicin D (3), was identified as a new depsipeptide in the unnarmicin family, given its structural similarity to the existing compounds in this group. The planar structures of 1–3 were determined using 1D and 2D NMR spectra and complementary spectroscopic and spectrometric procedures. The absolute configurations of the amino acid components of 1–3 were determined via acid hydrolysis, derivitization with Marfey’s reagent and HPLC-UV comparison to authentic amino acid standards. The absolute configuration of the 3-hydroxydodecanoic acid moiety in 3 was determined using a modified Mosher’s esterification procedure on a linear derivative of tricharmicin (4) and additionally by a comparison of 13C NMR shifts of 3 to known depsipeptides with β-hydroxy acid subunits. Tricholide B (2) showed moderate cytotoxicity to Neuro-2A murine neuroblastoma cells (EC50: 14.5 ± 6.2 μM).
Highlights
Marine cyanobacteria have been fertile grounds for the isolation of a diverse array of structurally intriguing secondary metabolites with a broad-spectrum of biological activities [1,2,3,4]
Many cyanobacterial macrocycles are peptides and depsipeptides [11] derived from NRPS
The trichotoxins, chlorinated polyketides have been isolated from environmental collections of Trichodesmium thiebautii [26,27]
Summary
Marine cyanobacteria have been fertile grounds for the isolation of a diverse array of structurally intriguing secondary metabolites with a broad-spectrum of biological activities [1,2,3,4]. A notable class of these compounds are the macrocyclic hybrid polyketide-non-ribosomal peptides (PKS-NRPS). Macrocycles have been prolific structures in drug discovery, perhaps most notably as antibiotics [7] This class displays diverse bioactivities including antitumor [8], antimalarial [9] and neuroactive properties, including sodium channel inhibition [10]. We detail the isolation and structure characterization of three new additions (1–3) to the PKS-NRPS macrocycles from Trichodesmium thiebautii bloom biomass. Trichophycin A and the trichotoxins, chlorinated polyketides have been isolated from environmental collections of Trichodesmium thiebautii [26,27] Two of these metabolites in the current work, tricholides A and B (1 and 2), represent a new class of polyketide macrolactones, each incorporating a single proline residue and predicted 2-methylhexanoic acid residue. The third compound, unnarmicin D, departs from previously described unnarmicins by featuring a 3-hydroxydodecanoic acid residue
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