Unique iodine-containing meroditerpenes io-docallophycoic acid A (1) and iodocallophycols A–D (2–5) were discovered from the Fijian red alga Callophycus sp. Because flexibility of the molecular skeleton impaired full characterization of relative stereochemistries by NMR spectroscopy, a DFT-based theoretical model was developed to derive relevant interproton distances which were compared to those calculated from NOE measurements, yielding the relative stereochemistries. The correct 2S,6S,7S,10S,14S enantiomers were then identified by comparison of theoretical and experimental ECD spectra. Biological activities of these iodinated and brominated meroditerpenes and additional new, related bromophycoic acid F (6) and bromophycoic acid A methyl ester (7), were evaluated for relevant human disease targets. Iodocallophycoic acid A (1) showed moderate antibiotic activity against methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus faecium (VREF) with MIC values of 1.4 and 2.2 μg mL−1, respectively. It also potentiated the anti-MRSA activity of oxacillin in a synergistic fashion, resulting in an 8-fold increase in oxacillin potency, for a MIC of 16 μg mL−1.
Three related new alkylphenols, termed anaephenes A-C (1-3), containing different side chains, were isolated from an undescribed filamentous cyanobacterium (VPG 16-59) collected in Guam. Our 16S rDNA sequencing efforts indicated that VPG 16-59 is a member of the marine genus Hormoscilla (Oscillatoriales). The structures of anaephenes A-C (1-3) were elucidated by spectroscopic methods, and compounds assayed for growth inhibitory activity against prokaryotic and eukaryotic cell lines. Anaephene B (2), possessing a terminal alkyne, displayed moderate activity against B. cereus and S. aureus with MIC values of 6.1 μg/mL. While 1 and 3 showed no pronounced activity in these assays, their structural features highlight the unusual biosynthetic capacity of this cyanobacterium and warrant further study.
New modified depsipeptides and geometric
isomers, termed anaenamides A (1a) and B (1b), along with the presumptive biosynthetic intermediate, anaenoic
acid (2), were discovered from a marine cyanobacterium
from Guam. Structures were confirmed by total synthesis. The alkylsalicylic
acid fragment and the C-terminal α-chlorinated α,β-unsaturated ester are novelties in cyanobacterial natural products.
Cancer cell viability assays indicated that the C-terminal unit serves
as the pharmacophore and that the double-bond geometry impacts the
cytotoxicity.
Our ongoing efforts to explore the
chemical space associated with
marine cyanobacteria from coral reefs of Guam have yielded two new
members of the anaenamide family of natural products, anaenamides
C (3) and D (4). These compounds were isolated
from a novel Hormoscilla sp. (VPG16-58). Our phylogenetic
profiling (16S rDNA) of this cyanobacterium indicated that VPG16-58
is taxonomically distinct from the previously reported producer of
the anaephenes, VPG16-59 (Hormoscilla sp.), and other
previously documented species of the genus Hormoscilla. The planar structures of 3 and 4 were
determined via spectroscopic methods, and absolute configurations
of the α-hydroxy acids were assigned by enantioselective HPLC
analysis. To address the requirement for sufficient material for testing,
we first adapted our published linear synthetic approach for 1 and 2 to generate anaenoic acid (7), which served as a point for diversification, providing the primary
amides 3 and 4 from synthetic intermediates 5 and 6, respectively. The compounds were then
tested for effects on HCT116 colon cancer cell viability and in an
ARE-luciferase reporter gene assay for Nrf2 modulation using HEK293
human embryonic kidney cells. Our findings indicate that, in contrast
to cytotoxic methyl esters 1 and 2, the
primary amides 3 and 4 activate the Nrf2
pathway at noncytotoxic concentrations. Overall, our data suggest
that the anaenamide scaffold is tunable to produce differential biological
outcomes.
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