Prenylated β-diketones, two new additions to the family of biologically active Hypericum perforatum L. (Hypericaceae) secondary metabolites

Article abstract of DOI:10.1016/j.fct.2018.05.009

Two novel β-diketones, 2,6,9-trimethyl-8-decene-3,5-dione (A) and 3,7,10-trimethyl-9-undecene-4,6-dione (B), were identified from the renowned medicinal plant Hypericum perforatum L. The structures of β-diketones A and B were corroborated by syntheses (4 steps starting from methyl acetoacetate, overall yields 30% and 23%, respectively). In solution, these β-diketones predominantly exist as two rapidly interconverting β-keto-enol tautomers. The structures of A and B show some common fragments with the molecules of hyperforin and adhyperforin, respectively, the acknowledged multi-target secondary metabolites from St. John's wort. It is therefore not surprising that A displayed a noteworthy biological activity profile as well (including brine shrimp toxicity, antinociceptive, antidepressant and acetylcholinesterase inhibitory activity). β-Diketone A manifested the most outstanding potency as an acetylcholinesterase inhibitor with IC₅₀ value of 1.51 μM pointing again to the β-keto-enol moiety as a promising lead structure for the development of drugs that could lessen symptoms of Alzheimer's disease (such as dementia, depression and pain).

Full text of DOI:10.1016/j.fct.2018.05.009

Evaluation Only. Created with Aspose.PDF. Copyright 2002-2021 Aspose Pty Ltd.
Accepted Manuscript
Prenylated β-diketones, two new additions to the family of biologically active
Hypericum perforatum L. (Hypericaceae) secondary metabolites
Niko S. Radulović, Marija S. Genčić, Nikola M. Stojanović, Pavle J. Randjelović,
Nicolas Baldovini, Vanya Kurteva
PII:
S0278-6915(18)30299-0
10.1016/j.fct.2018.05.009
FCT 9763
DOI:
Reference:
To appear in: Food and Chemical Toxicology
Received Date: 3 April 2018
Revised Date: 2 May 2018
Accepted Date: 4 May 2018
Please cite this article as: Radulović, N.S., Genčić, M.S., Stojanović, N.M., Randjelović, P.J., Baldovini,
N., Kurteva, V., Prenylated β-diketones, two new additions to the family of biologically active Hypericum
perforatum L. (Hypericaceae) secondary metabolites, Food and Chemical Toxicology (2018), doi:
10.1016/j.fct.2018.05.009.
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to
our customers we are providing this early version of the manuscript. The manuscript will undergo
copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please
note that during the production process errors may be discovered which could affect the content, and all
legal disclaimers that apply to the journal pertain.

Evaluation Only. Created with Aspose.PDF. Copyright 2002-2021 Aspose Pty Ltd.
ACCEPTED MANUSCRIPT
Graphical abstract
1

Evaluation Only. Created with Aspose.PDF. Copyright 2002-2021 Aspose Pty Ltd.
ACCEPTED MANUSCRIPT
Prenylated β-diketones, two new additions to the family of biologically active Hypericum
perforatum L. (Hypericaceae) secondary metabolites
Niko S. Radulovića,*, Marija S. Genčića, Nikola M. Stojanovićb, Pavle J. Randjelovićc,
Nicolas Baldovinid, Vanya Kurtevae
a
Department of Chemistry, Faculty of Sciences and Mathematics, University of Niš,
Višegradska 33, 18000 Niš, Serbia
b Faculty of Medicine, University of Niš, Bulevar Zorana Đinđića 81, 18000 Niš, Serbia
c Department of Physiology, Faculty of Medicine, University of Niš, Bulevar Zorana Đinđića
81, 18000 Niš, Serbia
d
Institut de Chimie de Nice, Faculté des Sciences, Université de Nice-Sophia Antipolis,
UMR 7272 CNRS, Parc Valrose, 06108 Nice, France
e
Institute of Organic Chemistry with Centre of Phytochemistry, Bulgarian Academy of
Sciences, Bl. 9, Acad. G. Bonchev Str., 1113 Sofia, Bulgaria
* Corresponding author. Niko S. Radulović, Department of Chemistry, Faculty of Science
and Mathematics, University of Niš, Višegradska 33, 18000 Niš, Serbia. Tel.: +381 18 533
015; fax: +381 18 533 014. E-mail address: nikoradulovic@yahoo.com.
Abstract: Two novel β-diketones, 2,6,9-trimethyl-8-decene-3,5-dione (A) and 3,7,10-
trimethyl-9-undecene-4,6-dione (B), were identified from the renowned medicinal plant
Hypericum perforatum L. The structures of β-diketones A and B were corroborated by
syntheses (4 steps starting from methyl acetoacetate, overall yields 30% and 23%,
respectively). In solution, these β-diketones predominantly exist as two rapidly
2

Evaluation Only. Created with Aspose.PDF. Copyright 2002-2021 Aspose Pty Ltd.
ACCEPTED MANUSCRIPT
interconverting β-keto-enol tautomers. The structures of A and B show some common
fragments with the molecules of hyperforin and adhyperforin, respectively, the acknowledged
multi-target secondary metabolites from St. John’s wort. It is therefore not surprising that A
displayed a noteworthy biological activity profile as well (including brine shrimp toxicity,
antinociceptive, antidepressant and acetylcholinesterase inhibitory activity). β-Diketone A
manifested the most outstanding potency as an acetylcholinesterase inhibitor with IC50 value
of 1.51 µM pointing again to the β-keto-enol moiety as a promising lead structure for the
development of drugs that could lessen symptoms of Alzheimer’s disease (such as dementia,
depression and pain).
Keywords: St. John's wort, β-diketones, multi-targeted natural products, toxicity,
antinociceptive and antidepressant activities, acetylcholinesterase inhibitory activity
1. Introduction
Today, foodstuff is no longer perceived only as a source of nourishment, but also of
ingredients that may provide health benefits. It is no surprise that in recent years, there has
been a growing interest in such “functional foods” (Cencic and Chingwaru, 2010). One of the
most widespread bioactive botanicals, that are most frequently utilized in the form of water
infusions, includes St. John’s wort, Hypericum perforatum L. (Hypericaceae). The use of this
plant species dates back to the time of ancient Greeks and it remains a popular treatment for
various ailments still today (Barnes et al., 2001). For instance, extracts of St. John’s wort
have been commonly applied externally to treat minor burns, wounds, inflammation of the
skin, and hemorrhoids, while a herbal tea has been widely taken internally to treat fevers and
nervous conditions including depression and anxiety (Klemow et al., 2011). St. John’s wort
preparations are counted among the most popular and best-selling herbal medicinal products
3