Synthesis and anticancer properties of new (dihydro)pyranonaphthoquinones and their epoxy analogs

Article abstract of DOI:10.1016/j.bmcl.2015.05.051

Abstract 1,4-Dihydroxy-2-naphthoic acid was used as a substrate for a straightforward five-step synthesis of 3-substituted 1H-benzo[g]isochromene-5,10-diones, with a Michael addition of N-acylmethylpyridinium ylides across 2-hydroxymethyl-1,4-naphthoquino

Full text of DOI:10.1016/j.bmcl.2015.05.051

Accepted Manuscript
Synthesis and anticancer properties of new (dihydro)pyranonaphthoquinones
and their epoxy analogs
Tuyet Anh Dang Thi, Thu Ha Vu Thi, Hoang Thi Phuong, Thanh Ha Nguyen,
Chinh Pham The, Cuong Vu Duc, Yves Depetter, Tuyen Van Nguyen, Matthias
D’hooghe
PII:
S0960-894X(15)00525-9
DOI:
http://dx.doi.org/10.1016/j.bmcl.2015.05.051
BMCL 22741
Reference:
Bioorganic & Medicinal Chemistry Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
7 April 2015
19 May 2015
20 May 2015
Please cite this article as: Dang Thi, T.A., Vu Thi, T.H., Thi Phuong, H., Ha Nguyen, T., Pham The, C., Vu Duc,
C., Depetter, Y., Van Nguyen, T., D’hooghe, M., Synthesis and anticancer properties of new
(dihydro)pyranonaphthoquinones and their epoxy analogs, Bioorganic & Medicinal Chemistry Letters (2015), doi:
http://dx.doi.org/10.1016/j.bmcl.2015.05.051
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Synthesis and anticancer properties of new
(dihydro)pyranonaphthoquinones and their epoxy analogs
Tuyet Anh Dang Thi,1 Thu Ha Vu Thi,1 Hoang Thi Phuong,1 Thanh Ha Nguyen,1 Chinh Pham The,1
Cuong Vu Duc,1 Yves Depetter,2 Tuyen Van Nguyen,1,∗ Matthias D’hooghe2
1Institute of Chemistry, Vietnam Academy of Science and Technology, 18-Hoang Quoc Viet, CauGiay, Hanoi, Vietnam
2SynBioC Research Group, Department of Sustainable Organic Chemistry and Technology, Faculty of Bioscience
Engineering, Ghent University, Coupure links 653, B-9000 Ghent, Belgium
Abstract
1,4-Dihydroxy-2-naphthoic acid was used as a substrate for a straightforward five-step synthesis of 3-
substituted 1H-benzo[g]isochromene-5,10-diones, with a Michael addition of N-acylmethylpyridinium
ylides across 2-hydroxymethyl-1,4-naphthoquinone and a subsequent acid-mediated dehydratation of
intermediate hemiacetals as the key steps. The obtained benzo[g]isochromene-5,10-diones were
subsequently deployed for further synthetic elaboration to produce new 3,4-dihydrobenzo[g]isochromene-
5,10-diones and (3,4-dihydro-)4a,10a-epoxybenzo[g]isochromene-5,10-diones. All compounds were
screened for their cytotoxic and antimicrobial effects, revealing an interesting cytotoxic activity of 1H-
benzo[g]isochromene-5,10-diones against different cancer cell lines.
Naturally occurring (dihydro)pyranonaphthoquinones can be found in bacteria, fungi and higher
plants, pointing to their biochemical relevance in nature.1 Many of these pyranonaphthoquinone
derivatives have indeed been discovered to possess diverse and pronounced biological activities,
including antimicrobial, antiparasitic, antiviral and anticancer properties.2 For example, the
dihydropyranonaphthoquinones eleutherin 1 and psychorubrin 2 and the pyranonaphthoquinones
pentalongin 3, dehydroherbarin 4a and analogs 4b, 4c have been shown to exhibit interesting
antimicrobial, antiparasitic, phytotoxic and antineoplastic activities (Fig. 1).3 Furthermore,
pyranonaphthoquinone-derived epoxides such as nanaomycin antibiotics 5 (nanaomycin E 5a,
nanaomycin αE 5b and nanaomycin βE 5c), isolated from Streptomyces rosa var. notoensis,4 and
frenolicin 6, isolated from Streptomyces fladiae,5 are known to display biological activity against
mycoplasmas, fungi and gram-positive bacteria (Fig. 1).6
These and many other examples of bioactive synthetic and natural pyranonaphthoquinones have
clearly elicited an interest in the preparation of novel analogs of these classes of compounds, and
the synthesis of 1H-benzo[g]isochromene-5,10-diones (also referred to as naphtho[2,3-c]pyran-
5,10-diones) has thus been the subject of several studies in the chemical literature.
∗
ngvtuyen@hotmail.com, tel: +84917683979
1

Figure 1. Examples of bioactive (dihydro)pyranonaphthoquinone(-derived) natural products
For example, Michael addition of N-acylmethylpyridinium ylides to 2-methyl-1,4-naphthoquinone,
followed by α-bromination with respect to the keto group, dehydrobromination and hetero-Diels-
Alder cyclization has been reported to furnish pyranonaphthoquinones, albeit in rather low yields
due to a cumbersome bromination step.7 An improvement of this synthetic strategy involved the
use of 2-(phenoxymethyl)naphthoquinone, allowing for a more straightforward approach to
pyranonaphthoquinone structures due to the less reactive (and thus more controllable) nature of
the phenoxy moiety as a leaving group.8 Another variant of this approach was based on the
Michael addition of N-acylmethylpyridinium ylides to 2-(1-hydroxyethyl)-1,4-naphthoquinone,
affording intermediate hemiacetals prone to undergo p-toluenesulfonic acid-mediated
dehydratation to yield the desired naphtho[2,3-c]pyran-5,10-diones.9 A synthetically different
approach comprised transformation of 2-bromo-1,4-naphthoquinone into 3-allyl-2-(1-
hydroxyethyl)-1,4-dimethyoxynaphthalene via a number of steps, which then underwent
subsequent Lemieux-Johnson oxidation, oxidative demethylation and acid-catalyzed dehydration
to produce 1-methylpentalongin.10 Other routes toward the 1H-benzo[g]isochromene-5,10-dione
scaffold involve for example the reaction of imines with 2-(1-hydroxyalkyl)-1,4-naphthoquinones11
and an intramolecular Heck reaction of 3-bromo-2-formyl-1,4-dimethoxynaphthalene with 3-
hydroxybut-1-ene.12 Intensive efforts have also been devoted to the synthesis of diverse
pyranonaphthoquinone natural products, such as 9-demethoxy(iso)eleutherin,13 crisamicin A,14
kalafungin,15 and many others.
In continuation of our synthetic interest in naphthoquinone derivatives,16 in the present paper we
disclose a straightforward synthesis toward new 1H-benzo[g]isochromene-5,10-diones and their
further transformation into 3,4-dihydro-1H-benzo[g]isochromene-5,10-diones and epoxy
derivatives. Furthermore, the cytotoxicity with regard to different cancer cell lines and the
antimicrobial potential of these compounds will be discussed as well.
The strategy deployed in this work elaborates on our previous study on the Michael addition of N-
acylmethylpyridinium ylides to 2-(1-hydroxyethyl)-1,4-naphthoquinone and the subsequent acid-
mediated dehydratation of intermediate hemiacetals to deliver 3-substituted 1-
methylnaphtho[2,3-c]pyran-5,10-diones.9 In the present work, a new variant of this approach is
described to provide an entry into 3-functionalized naphtho[2,3-c]pyran-5,10-diones bearing no
2

substituent at the 1-position – as is the case in many natural products. To that end, a 5-step
synthetic strategy was designed starting from 1,4-dihydroxy-2-naphthoic acid 7 (Scheme 1).
The first step involved a triple methylation of naphthoic acid 7 with dimethyl sulfate (4 equiv) in
Et2O in the presence of K2CO3 (4 equiv) to give methyl 1,4-dimethoxy-2-naphthoate 8 in 83% yield
after KOH addition.17 Reduction of the latter methyl ester 8 was carried out by treatment with
lithium aluminium hydride (2 molar equiv) in Et2O to give rise to 2-hydroxymethyl-1,4-
dimethoxynaphthalene 9 in excellent yield (95%).18 Oxidative demethylation of this 1,4-
dimethoxynaphthalene system 9 upon treatment with cerium ammonium nitrate (CAN, 2 equiv) in
a CH3CN/H2O (1:1) solvent mixture afforded 2-hydroxymethyl-1,4-naphthoquinone 10 in 92%
yield.11 Subsequently, the introduction of acylmethyl groups onto 2-hydroxymethyl-1,4-
naphthoquinone 10 was effected by employing N-acylmethylpyridinium ylides (1 equiv) in CH3CN
in the presence of triethylamine,9 providing a clean and high-yielding access to 1H-
benzo[g]isochromene-5,10-diones 13 upon p-toluenesulfonic acid-catalyzed dehydratation in
toluene.19 Apparently, the initially formed addition products 11 spontaneously cyclized to give
hemiacetals 12, which underwent an acid-promoted elimination of water to afford 3-substituted
pyranonaphthoquinones 13a-h in excellent yields (Scheme 1).20
Scheme 1. Five-step synthesis of 1H-benzo[g]isochromene-5,10-diones 13 starting from 1,4-dihydroxy-2-
naphthoic acid 7
In order to expand our synthetic approach toward the saturated counterparts of tricycles 13, the
reduction of the olefinic moiety in the oxacyclic ring was tackled. Thus, treatment of
benzo[g]isochromene-5,10-diones 13 with a combination of CF3COOH (16 equiv) and Et3SiH (8
equiv) in CH2Cl2 provided the desired 3,4-dihydro-1H-benzo[g]isochromene-5,10-diones 14a-d21 in
good yields (Scheme 2).22 This reduction is believed to proceed via initial protonation of the vinyl
ether moiety in compounds 13 toward oxonium intermediates, which are then trapped by hydride
addition across the C-O double bond.
Given the occurrence of biologically interesting pyranonaphthoquinone-derived epoxides in
nature (e.g. nanaomycin antibiotics 5), efforts were also made toward the epoxidation of
(dihydro)benzo[g]isochromene-5,10-diones 13/14. This goal was realized by reaction of both
3

substrates with H2O2 (32% aqueous solution, 62 equiv) in CH2Cl2 in the presence of Na2CO3 (5
equiv), as an alternative for the tert-butyl hydrogen peroxide-based procedure described in the
literature,23 affording novel epoxybenzo[g]isochromene-5,10-diones 15a-c and 3,4-dihydro-
epoxybenzo[g]isochromene-5,10-diones 16a-c in acceptable yields (Scheme 2). These epoxidation
reactions are presumed to involve initial Michael addition of the hydroperoxide anion across the
quinone system followed by enolate-induced cyclization with concomitant hydroxide
displacement. The epoxidation of dihydropyrane compounds 14 produced structures 16 as single
isomers after purification. All attempts to assign the relative stereochemistry of these compounds
(e.g. by means of X-ray analysis), however, failed.
O
O
1) 16 equiv. CF3COOH
CH2Cl2, rt., 12 h
14a
14b
14c
14d
(R = Me, 61%)
(R = CH(CH3)2, 62%)
(R = C6H5, 68%)
O
O
2) 8 equiv. Et3SiH
CH2Cl2, rt., 12 h
R
R
(R = 4-F-C6H4, 62%)
O
O
13
14
62 equiv. H2O2 (32%)
5.0 equiv. Na2CO3
CH2Cl2, rt., 12 h
62 equiv. H2O2 (32%)
5.0 equiv. Na2CO3
CH2Cl2, rt., 12 h
O
O
O
O
O
O
O
O
R
R
15a
15b
15c
16a
16b
16c
(R = Me, 45%)
(R = C6H5, 47%)
(R = 4-F-C6H4, 50%)
(R = Me, 48%)
(R = CH(CH3)2, 50%)
(R = 4-F-C6H4, 52%)
Scheme 2. Synthesis of 3,4-dihydrobenzo[g]isochromene-5,10-diones 14, epoxybenzo[g]isochromene-5,10-
diones 15 and 3,4-dihydro-epoxybenzo[g]isochromene-5,10-diones 16
With this set of compounds in hand, the biological activity spectrum of these molecules was
investigated in the next part. In particular, (dihydro)pyranonaphthoquinones 13, 14, 15 and 16
were screened for their cytotoxicity against four cancer cell lines (KB, Hep-G2, MCF7 and Lu) and
for their antimicrobial properties against two gram-positive bacteria (B. subtilis and S. aureus), two
gram-negative bacteria (E. coli and P. aeruginosa) and one yeast strain (C. albicans).
Pyranonaphthoquinones are known to act as bioreductive DNA alkylating agents via quinone
methide intermediates, resulting in cross-linking of DNA strands and thus interference with the
cell replication process.24 The cytotoxicity test data clearly show that also benzo[g]isochromene-
5,10-diones 13 and, to a lesser extent, 3,4-dihydrobenzo[g]isochromene-5,10-diones 14 exhibit
reasonable anticancer effects (Table 1). On the other hand, (3,4-dihydro-
)epoxybenzo[g]isochromene-5,10-diones 15 and 16 do not display any cytotoxic effect at all,
pointing to the conclusion that the presence of a quinone moiety is probably crucial to convey
cytotoxicity to these molecules. Within the series of benzo[g]isochromene-5,10-diones 13,
isopropyl derivative 13b and 4-chlorophenyl derivative 13d seem to display a considerable
cytotoxic effect against all four cell lines, and compound 13d exhibits a particularly strong
anticancer effect against KB cells with an IC50-value (1.5 µM) similar to that of ellipticine (1.3 µM).
Saturation of the C-C double bond in compounds 13 to form dihydro analogs 14 appears to result
4

in slightly less, albeit still reasonably, active compounds, which might be attributable to the higher
sp3 fraction (and thus lower intercalation potential) of the latter systems. The inactivity of the
epoxy analogs 15b and 16, lacking the quinone system and having a distinct 3D structure,
corroborates the assumption that biological activity in this case is probably associated with flat
molecules bearing a quinone motif.
Table.1. Cytotoxicity evaluation of (dihydro)pyranonaphthoquinones 13, 14, 15 and 16a
Entry
1
Compound
13a
IC50 (µM) KB
IC50 (µM) Hep-G2 IC50 (µM) MCF7
IC50 (µM) Lu
5.6
6.7
29.5
6.7
13.1
4.1
10.7
12.2
3.6
14.9
2
13b
7.5
>34.7
12.9
>34.7
11.5
3
13c
1.5
4
13d
25.3
17.5
16.1
20.6
>41.3
>32.9
>31.0
>41.0
>32.6
>30.8
1.3
22.5
19.8
18.7
23.4
>41.3
>32.9
>31.0
>41.0
>32.6
>30.8
1.3
22.1
23.2
5
14a
26.2
>39.0
> 34.4
22.1
6
14b
27.2
7
14c
>32.4
>41.3
>32.9
>31.0
>41.0
>32.6
>30.8
1.8
8
14d
>41.3
>32.9
>31.0
>41.0
>32.6
>30.8
2.2
9
15a
10
11
12
13
14
15
15b
15c
16a
16b
16c
Ellipticine
a Purity of all compounds >95% based on NMR
The antimicrobial assessment of the same compounds, however, revealed a poor biological
activity profile, and only benzo[g]isochromene-5,10-diones 13a and 13b showed moderate anti-
Staphylococcus aureus activity.
In conclusion, a series of pynanonaphthoquinones was conveniently and selectively synthesized in
excellent yields via introduction of acylmethyl groups onto 2-hydroxymethyl-1,4-naphthoquinone
by using N-acylmethylpyridinium ylides followed by intramolecular cyclization and acid-mediated
dehydratation. These pynanonaphthoquinones were further synthetically exploited to generate
the corresponding new dihydro analogs and their epoxy derivatives. Biological assessment of all
these compounds demonstrated a significant cytotoxic effect of benzo[g]isochromene-5,10-diones
against different cancer cell lines, pointing to the biological relevance of these scaffolds. However,
the mechanism of action may be promiscuous given the fact that the quinone fragment often
occur in the scaffold of pan-assay interference compounds (PAINS)25 and hence a more rigid study
is required to demonstrate target selectivity and true anti-cancer potential.
5

Acknowledgments
The authors are indebted to the Vietnamese National Foundation for Science and Technology
Development (NAFOSTED, code: 104.01-2013.27) and to Ghent University – Belgium (BOF) for
financial support.
References
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19
As an example, the synthesis of pyranonaphthoquinone 13d is described here. To a solution of 2-
hydroxymethyl-1,4-naphthoquinone 10 (100 mg, 0.53 mmol) and 1-[2-(4-chlorophenyl)-2-
oxoethyl]pyridinium bromide (245 mg, 0.79 mmol) in acetonitrile (10 mL) under N2 at 50°C was added
dropwise a solution of Et3N (80 mg, 0.79 mmol) in acetonitrile (5 mL). This mixture was stirred for 4 hours
at room temperature. Afterwards the solvent was evaporated in vacuo and the residue was quenched with
water and extracted with CH2Cl2. The extract was then washed with 1 M HCl, water and dried (MgSO4). The
solvent was evaporated in vacuo to give the crude intermediate reaction product 11d/12d. This product
was dissolved in toluene (15 mL), and p-TsOH (0.005 mmol) was added. The reaction mixture was heated
under reflux for 10 min, after which the mixture was poured into water and extracted with EtOAc. The
extract was washed with water and dried (MgSO4). The solvent was evaporated in vacuo to give the crude
product, which was purified by column chromatography on silica gel (n-hexane/ethyl acetate 9/1) to afford
154 mg of the pure product 13d (90%).
20
The spectral data of compound 13a and 13c correspond well with those reported in the literature: Ref.
11, Ref. 8.
21
The spectral data of compound 14a correspond well with those reported in the literature: Sawant, R. T.;
Jadhav, S. G.; Waghmode, S. B. Eur. J. Org. Chem. 2010, 4442-4449.
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7

Graphical Abstract