The human 20S proteasome inhibitor scytonemide A (1), a macrocyclic imine originally isolated from the cyanobacterium Scytonema hofmanni, was synthesized via a biomimetic solid-phase peptide synthesis (SPPS) approach employing the Weinreb AM resin. Utilizing this approach, cyclization of the protected heptapeptide via formation of the imine bond occurred spontaneously upon cleavage from the resin in the presence of a reducing agent and subsequent aqueous workup. The final deprotection step necessary to produce the natural product was accomplished under slightly basic conditions, facilitating cleavage of the silyl ether group while leaving the macrocycle intact. Purification of the synthetic scytonemide A was accomplished via normal-phase flash column chromatography, potentially facilitating larger scale preparation of the compound necessary for future mechanistic and SAR studies. The structure of the target compound was confirmed by NMR spectroscopy, which also shed light on differences in the spectroscopic data obtained for the synthetic and natural scytonemide A samples for some of the amide and alcohol signals in the H NMR spectrum.
A new linear lipopeptide, phormidepistatin
(1), containing
an epi-statine amino acid was isolated from cf. Phormidium sp. strain UIC 10484. The planar structure was elucidated by 1D
and 2D NMR experimentation. The relative configuration was determined
by J-based configurational analysis and the absolute
configuration by advanced Marfey’s analysis. Given that the
statine moiety is an established pharmacophore known to inhibit aspartic
proteases, phormidepistatin was evaluated against cathepsin D and
displayed limited activity. With 1 containing a statine-like
moiety, we sought to assess the distribution of this γ-amino
acid within the phylum Cyanobacteria. In-depth MS/MS analysis identified
the presence of phormidepistatin in cf. Phormidium sp. UIC 10045 and cf. Trichormus sp. UIC 10039.
A structure database search identified 33 known cyanobacterial metabolites
containing a statine or statine-like amino acid and, along with phormidepistatin,
were grouped into 10 distinct compound classes. A phylogenetic tree
was built comprising all cyanobacteria with established 16S rRNA sequences
known to produce statine or statine-like-containing compound classes.
This analysis suggests the incorporation of the γ-amino acid
into secondary metabolites is taxonomically widespread within the
phylum. Overall, it is our assessment that cyanobacteria are a potential
source for statine or statine-like-containing compounds.
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