Bioorganic & Medicinal Chemistry Letters

Table 4
Heterozygote strain inhibition of parnafungins A–D
Species Strain 1/2 5 6
MIC in lg/mL a
C. albicans MY2323 (WT) 0.008 0.06 0.016
C. albicans MY2323 CLP1 +/ 0.004 0.03 0.004
C. albicans MY2323 YSH1 +/ 0.004 0.03 0.004
a MIC was determined in Sabarose Dextrose medium.
The biosynthesis of parnafungins is likely related to that of
ergochrome-derived secondary metabolites, which are based on a
series of polyketide condensations and cyclizations. 6,9 For the parnafungin
family of natural products, the extended ring system beyond
the typical xanthone unit as well as the incorporation of a
nitrogen atom and the closure of the isoxazolidinone ring make
the biosynthetic pathway an intriguing, but unresolved question.
Previously, we have identified by affinity selection/mass spec techniques
that the active form of the equilibrating mixture of isomers
is the straight parnafungin A. 10 The fact that parnafungins C and D
are direct analogs of parnafungin A and not parnafungin B supports
the hypothesis that it is parnafungin A that is directly synthesized
by these Fusarium spp. Subsequent methylation and oxidation of
parnafungin A would generate 5 and then 6. Practically, the methylation
of the C7 hydroxyl simplifies the chemical properties of
both of these compounds, preventing the formation of the corresponding
bent geometric isomers.
Species of the F. larvarum complex are assumed to be mycoparisites
associated with scale insects, aphids, lichens and the basidiomycete
fungus Septobasidium clelandii. 8,11–14 Additional to the F.
larvarum complex, the parnafungins have also been reported from
two other Hypocrealean mycoparasitic fungi, Trichonectria rectipila
and Cladobotryum pinarense. 8 With regards to the ecological role
that the parnafungins may convey to their producing organism, it
has been hypothesized that the compounds may act as potent antifungals,
providing a competitive advantage for growth and, moreover,
as a virulence factor mediating inter-organism interactions
while colonizing hosts, for example, lichenized and non-lichenized
fungi, insects, or plants. 8 The facile degradation of the parnafungins
to the inactive benzoquinoline forms has been correlated with a
change in pH, where ring opening was promoted in neutral or alkaline
conditions, while a stabilization of the molecule is favored in
acidic conditions. 5 Many fungi lower the pH of their growth medium
through the secretion of organic acids during their initial
phase of growth, and later, as the fungus reaches stationary
growth, the medium’s pH progressively becomes more alkaline; 15
in this case, alkalization of the growth medium following colonization
would, hypothetically, promote the accumulation of the ben-
D. Overy et al. / Bioorg. Med. Chem. Lett. 19 (2009) 1224–1227 1227
zoquinoline analogs and prevent the producing organism from
accumulating toxic levels of the parnafungins. 8
Since parnafungins A and B are efficacious in a murine model of
disseminated candidiasis with no observable toxicity, 1 this family
of compounds can be pursued as a novel class of antifungal agents
with a unique mechanism of action. The parnafungin analogs reported
here provide additional information as to the types of structural
modifications that are possible to the core structure while
maintaining antifungal activity. Parnafungins C and D expand the
available structure–activity information on this family of natural
products. Further synthetic exploration of this chemical scaffold
may provide parnafungin analogs with improved potency, spectrum
and chemical stability, and provide a route for the further
development of an antifungal agent that targets fungal RNA
processing.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.bmcl.2008.12.081.
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