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find use as redox probes. For compounds 6–10 redox activity
generally increased with increasing ring size, which mirrored the
cytotoxicity data. From this we suggest that cytotoxicity may
occur at least partially from redox activity in ellagitannins, but
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phenolic oxygens increased protein precipitation ability, consist-
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medium/large ring appeared to reduce the ability to precipitate
protein, however solubility problems prevented further evalu-
ation. Given that the concentration of compound required to
obtain pronounced protein precipitation was high (150 times the
BSA concentration), we predict that the effects observed are not
physiologically relevant. This may also explain the lack of corre-
lation with the cytotoxicity data. However, larger and polymeric
ellagitannins may be more adept at efficiently forming a
complex with, and precipitating, protein in vivo.
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In conclusion, we have shown that tellimagrandin I can be syn-
thesized in five linear steps with an overall yield of 38% using an
atropdiastereoselective oxidative biaryl coupling as the key step.
Tellimagrandin I and analogues were used to explore the SAR of
ellagitannin components. We have adapted several rapid assays
for benchmarking ellagitannin activity in two of its most com-
monly associated biological properties and shown how this trans-
lates into a cellular setting. Cytotoxicity increased with ring size
and was lost with the removal of the medium ring. This data cor-
related with the redox activity but not with the ability to precipi-
tate protein, suggesting the importance of the former in
ellagitannin bioactivity. Additionally, a new analogue (10) was
identified which was significantly more potent than tellimagran-
din I but structurally and synthetically simpler. Our data suggests
that the biological activity of ellagitannins can be optimised for
the required properties and that complex scaffolds may not be
required to exert this activity. We have uncovered a novel class of
redox modulating agents (12 and 13) which are only weakly
cytotoxic at high concentrations and which may find applications
as redox probes. The synthetic methodology for ellagitannin syn-
thesis and the screening cascade outlined are extremely valuable
in profiling other members of the ellagitannin and related families
of natural products, which will be reported in due course.
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Notes and references
26 The same protocol was also applied to tellimagrandin I and squalene mono-
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