Bioorganic & Medicinal Chemistry Letters
Synthesis of coumarin derivatives and their cytoprotective effects on t-BHP-
induced oxidative damage in HepG2 cells
Tomomi Andoa, Mina Nagumob, Masayuki Ninomiyaa,b, Kaori Tanakac,d, Robert J. Linhardte,
a
Department of Materials Science and Technology, Faculty of Engineering, Gifu University, 1-1 Yanagido, Gifu 501-1193, Japan
Department of Chemistry and Biomolecular Science, Faculty of Engineering, Gifu University, 1-1 Yanagido, Gifu 501-1193, Japan
Division of Anaerobe Research, Life Science Research Center, Gifu University, 1-1 Yanagido, Gifu 501-1194, Japan
United Graduate School of Drug Discovery and Medicinal Information Sciences, Gifu University, 1-1 Yanagido, Gifu 501-1194, Japan
b
c
d
e
Center for Biotechnology and Interdisciplinary Studies, Rensselaer Polytechnic Institute, Troy, NY, 12180, United States
A R T I C L E I N F O
A B S T R A C T
Keywords:
Coumarin
Cytoprotection
Human hepatoma HepG2 cell
Coumarins are ubiquitous in higher plants and exhibit various biological actions. The aim of this study was to
investigate the structure-activity relationships of coumarin derivatives on tert-butyl hydroperoxide (t-BHP)-in-
duced oxidative damage in human hepatoma HepG2 cells. A series of coumarin derivatives were prepared and
assessed for their cytoprotective effects. Among these, a caffeoyl acid-conjugated dihydropyranocoumarin de-
rivative, caffeoyllomatin, efficiently protected against cell damage elicited by t-BHP. Our findings suggest that
caffeoyllomatin appears to be a potent cytoprotective agent.
Coumarins constitute a class of polyphenols that occur naturally in
higher plants. Their framework is comprised of fused benzene and α-
pyrone rings, which are produced from the shikimic acid pathway.1
Coumarins assume prominent functions in plant physiology, chemical
defense, and interactions between plants and their environment. During
winter, some coumarins inhibit seed germination by suppressing mi-
tosis until growth conditions are favorable.2 In addition, coumarins act
as phytoalexins against invading microbial pathogens and as defensive
compounds against insect herbivores.3–6 Thus, coumarin constituents
are of primary importance in plants.
In the view of the therapeutic use of coumarins in human health,
diovascular, and neuroprotective agents.7,8 Dicoumarol, a fermentation
product in Medicago sativa is a lead compound of warfarin, which is the
most frequently used oral anticoagulant worldwide.9 A linear-type
furanocoumarin, methoxsalen (also called ammoidin and xanthotoxin),
in Ammi majus is a drug used to treat psoriasis, eczema, and vitiligo in
clinical practice.10 It has been reported that simple plant coumarins,
esculetin and scoparone play a critical part in the prevention of oxi-
respectively.15 While diversely modified coumarins have been identi-
derivatives have been isolated.1 This study focuses on exploring struc-
ture-activity relationships of these rare coumarin derivatives with re-
spect to their protective effects on tert-butyl hydroperoxide (t-BHP)-
induced hepatic damage.
An isoprenyl unit and an ortho-substituted hydroxy group partici-
pate in the formation of either five-membered dihydrofuran or six-
membered dihydropyran rings, commonly encountered in natural pro-
ducts. The cyclization has been postulated to involve an epoxide in-
termediate, so that nucleophilic attack of the neighboring hydroxy
group on to the epoxide group can lead to formation of those hetero-
cycles. We therefore embarked on the preparation of osthenol and de-
methylsuberosin as synthetic precursors from readily available umbel-
liferone. The synthetic route is shown in Scheme 1. Because direct and
selective isoprenylation at the C6 or C8 positions of umbelliferone is
difficult to achieve, we employed an approach using a Claisen re-
arrangement.16 The O-1,1-dimethyl-2-propynylation of umbelliferone
using 3-chloro-3-methyl-1-butyne, DBU, and a catalytic amount of
CuCl2·2H2O furnished compound 1 (60% yield), which upon Lindlar
reduction afforded 1,1-dimethyl-2-propenyl product 2 in 76% yield.
The Claisen rearrangement of 2 in water at 75 °C offered ready access to
the desired osthenol 3 and demethylsuberosin 4 in 65% and 12% yields,
respectively.
Linear-type and angular-type p-coumaric acid-conjugated dihy-
drofuranocoumarin and dihydropyranocoumarin derivatives (angel-
Angelica pubescens,13 Lomatium columbianum,14 and Seseli coronatum,
⁎
Corresponding author at: Department of Chemistry and Biomolecular Science, Faculty of Engineering, Gifu University, 1-1 Yanagido, Gifu 501-1193, Japan.
Received 26 March 2018; Received in revised form 2 June 2018; Accepted 11 June 2018
Pleasecitethisarticleas:Ando,T.,Bioorganic&MedicinalChemistryLetters(2018),https://doi.org/10.1016/j.bmcl.2018.06.018