New 1,4-anthracenedione derivatives with fused
heterocyclic rings: synthesis and biological
evaluation†
Ma. ´ Angeles Castro,
*
a
Ana Ma. Gamito,
a
Ver
´
onica Tangarife-Casta
˜
no,
b
Vicky Roa-
Linares,
b
Jos
´
e Ma. Miguel del Corral,
a
Ana C. Mesa-Arango,
*
b
Liliana Betancur-
Galvis,
b
Andr
´
es M. Francesch
c
and Arturo San Feliciano
a
Several terpenylquinones derived from 1,4-anthracenedione (1,4-anthracenequinone, AQ) have been
prepared by addition or substitution nucleophilic reactions and further transformed into extended
polycyclic systems, which mainly kept the 1,4-quinone moiety fused to different nitrogen-heterocyclic
rings (pyrrole, imidazole, pyrazine or quinoxaline) into the structure. The compounds synthesized were
evaluated for their antineoplastic, antifungal and antiviral activities. GI
50
antineoplastic values remained
under mM levels for AQs, while the heterocyclic derivatives showed antifungal MIC values in the low
mg mL
1
range against yeasts and filamentous fungi. Only few compounds displayed a discrete non-
selective antiherpetic activity in the mg mL
1
range.
1. Introduction
The quinone/hydroquinone moiety is a common structural
feature in a large number of natural and synthetic compounds
with a wide range of biological activities such as anticancer,
1–4
antiparasitic,
5
antimicrobial,
6
antifungal,
7
antiviral,
8
anti-oxi-
dant,
1b,9
etc., and it is possible to nd agents, derived from
benzoquinone (BQ), naphthoquinone (NQ) or anthracenequi-
none (AQ), used clinically as anticancer agents
10
such as
daunorubicin or mitomycin C (Fig. 1A). The mechanisms of the
antineoplastic cytotoxicity of quinone derivatives have been
widely studied, and it is known that they usually participate in
important biological redox processes and can also act as inter-
calating or alkylating agents.
11
The potential of quinones to
generate reactive oxygen species (ROS) has been described in
the literature,
12
as well as the different targets that might be
involved in its molecular mechanisms of action depending on
the tumour cell type.
13
For instance, the DNA cross-linking and
monoalkylation by mitomycin C require the reduction of the
quinone ring, while furonaphthoquinones are able to modify
the mitochondrial permeability through ROS generation.
12c
In
this sense, quinones can be considered as multi-target drugs.
14
Several of those bioactive quinones bore a heterocyclic fragment
fused to the quinone moiety, including ve and six-membered
heterocycles with nitrogen,
15
oxygen
16
and/or sulphur
17
atoms.
Fig. 1 (A) Structure of clinically used anticancer quinones. (B) Struc-
ture of several monoterpene-derived (MTQ) and diterpene-derived
(DTQ) antineoplastic quinones.
a
Departamento de Qu´ ımica Farmac´ eutica, Facultad de Farmacia, CIETUS-IBSAL,
Campus Miguel de Unamuno, Universidad de Salamanca, E-37007 Salamanca,
Spain. E-mail: macg@usal.es; Fax: +34 923 294515; Tel: +34 923 294528
b
Grupo de Investigaci´ on Dermatol´ ogica, Facultad de Medicina, Departamento de
Medicina Interna, Universidad de Antioquia, Medell´ ın, Colombia. E-mail: ana.
mesa@udea.edu.co; Tel: +57 4 2196064
c
PharmaMar S.A., Avda. de los Reyes, P.I. La Mina Norte, E-28770 Colmenar Viejo,
Madrid, Spain
† Electronic supplementary information (ESI) available:
13
C NMR data and
complete assignments for the
1
H and
13
C NMR signals are included together
with HMQC and HMBC spectra for several separated regioisomers.
Complementary antifungal, antiviral and Vero cytotoxicity data for all the
compounds tested. See DOI: 10.1039/c4ra11726c
Cite this: RSC Adv. , 2015, 5, 1244
Received 3rd October 2014
Accepted 21st November 2014
DOI: 10.1039/c4ra11726c
www.rsc.org/advances
1244 | RSC Adv., 2015, 5, 1244–1261 This journal is © The Royal Society of Chemistry 2015
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