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RSC Advances
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DOI: 10.1039/C6RA05373D
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stirred for 30 min. The organic material was then extracted
with ethyl acetate (3 x 30 mL), and the organic phases dried
Acknowledgements
Financial support for this work was provided by FONCYT
PICT2011-0918), CONICET (PIP 695) and Universidad Nacional
2 4
over Na SO and evaporated under reduced pressure. Yield
(
3.9 %.
de Rosario to R.L.F. PG Thank CONICET for her fellowship. IAR,
MOS and RLEF are CONICET researchers.
Biological activity quantification.
IC50 against XO was measured using a 96-well microplate assay
4
3
based on a method previously reported. Aliquots of ½
seriated DMSO dilutions (10 μL) starting in 45 mM for
allopurinol, and compounds 1 and 2, were added on each well
Notes and references
1
2
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E. C. Barnes, R. Kumar and R. A. Davis, Nat. Prod. Rep., 2016,
DOI: 10.1039/C5NP00121H.
(3.7 % well final concentration DMSO). The controls contained
DMSO instead of compound solutions. Percentage of inhibition
was calculated by comparing the rates for each sample to the
control and the IC50 was estimated by using GraphPad Prism
3
4
S. Rizzo and H. Waldmann, Chem. Rev., 2014, 114, 4621-
4
639.
K. C. Morrison and P. J. Hergenrother, Nat. Prod. Rep., 2014,
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5.01 (GraphPad Software, CA, USA).
3
1
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M. E. Maier, Org. Biomol. Chem., 2015, 13, 5302-5343.
K. Tomohara, T. Ito, N. Hasegawa, A. Kato and I. Adachi,
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Conclusions
Using a series of essential oils as starting material, we
demonstrated that the transformation of double bonds (a
highly common group in natural skeletons) is a promising
strategy to generate diversified mixtures of natural products.
Considering the average numbers, the applied reaction
protocol transforms more than 90 % of the components of the
starting natural mixtures, generating approximately two
products from each natural precursor molecule. The reaction
increases the molecular weight and decreases the polarity of
the molecules population. Assuming that the starting pool of
EOs is not redundant in composition, in this set of experiments
7
T. Wu, C. Jiang, L. Wang, S. L. Morris-Natschke, H. Miao, L.
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9
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1 Z. Lin, X. Ma, H. Wei, D. Li, Q. Gu and T. Zhu, RSC Adv., 2015,
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1
1
1
1
1
1
1
,
1
781 natural molecules were transformed to produce 1756
5
unnatural molecules.
2 I. A. Ramallo, M. O. Salazar, L. Mendez and R. L. E. Furlan,
Acc. Chem. Res., 2011, 44, 241-250.
The unsupervised multivariate analysis separated the samples
in natural and brominated, and indicates that the
transformation of double bonds is an important factor for such
discrimination, without previous knowledge of the detailed
chemical composition of any of the samples.
3 L. Méndez, M. O. Salazar, I. A. Ramallo and R. L. E. Furlan, ACS
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The use of a TLC autography assay allowed the quick
evaluation of the effect of the reaction on bioactivity, spotting
the mixtures where the effect was highest. Coupling the assay
to HRMS linked the observed XO inhibition to an
organobromine compound before any purification step.
Bioguided fractionation led to the isolation of (RS)-2-Bromo-1-
2
012,
6 Z.-R. Zhang, J.-H. Li, S. Li, A.-L. Liu, P.-M. Hoi, H.-Y. Tian, W.-C.
Ye, S. M.-Y. Lee and R.-W. Jiang, PLoS ONE, 2014, , e100416.
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9
1
1
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(4-methoxyphenyl) propan-1-one (1). This compound was
generated from the inactive natural precursor anethole and
showed inhibition properties similar to allopurinol.
1
9. G. W. Gribble, in Naturally Occurring Organohalogen
Compounds - A Comprehensive Update, Springer Vienna,
Vienna, 2010, pp. 9-348.
Besides the isolation of this particular xanthine oxidase
inhibitor, the results illustrate how the combination of a few
analytical tools can accelerate the generation, the chemical
and biological analyses and the fast identification of bioactive
natural products derivatives.
2
2
0 T. Iwagawa, M. Kaneko, H. Okamura, M. Nakatani and R. W.
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Compound
1
was generated as a minor component of one of
of the
34
complex mixtures (it represented 1.28 %
2
2
2
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chromatogram total area of the F. vulgare BEO), however the
described combination of tools has paved the way to its
characterization.
4 G. W. Gribble, Am. Sci., 2004, 92, 342.
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