Tetrahedron Letters
Hetero-annulation reaction between 2-acylnaphthoquinones and 2-
aminobenzothiazoles. A new synthetic route to antiproliferative
benzo[g]benzothiazolo[2,3-b]quinazoline-7,12-quinones
b
c
Jaime A. Valderrama a,b, , David Ríos , Giulio G. Muccioli , Pedro Buc Calderon b,d, Iván Brito e,
⇑
Julio Benites a,b
a Instituto de Ciencias Exactas y Naturales, Universidad Arturo Prat, Casilla 121, Iquique, Chile
b Facultad de Ciencias de la Salud, Universidad Arturo Prat, Casilla 121, Iquique, Chile
c Bioanalysis and Pharmacology of Bioactive Lipids Laboratory, Louvain Drug Research Institute, Université Catholique de Louvain, 72 Avenue E. Mounier, BPBL 7201, 1200
Brussels, Belgium
d Toxicology and Cancer Biology Research Group, Louvain Drug Research Institute, Université Catholique de Louvain, 73 Avenue E. Mounier, GTOX 7309, 1200 Brussels, Belgium
e Departamento de Química, Facultad de Ciencias Básicas Universidad de Antofagasta, Casilla 170, Universidad de Antofagasta, Chile
a r t i c l e i n f o
a b s t r a c t
Article history:
A convenient two-step method is developed for the preparation of benzo[g]benzothiazolo[2,3-b]quinazo-
line-7,12-quinones from 2-acylnaphthohydroquinones and 2-aminobenzothiazoles. The structure of the
heterocyclic quinones is supported by X-ray crystallography. This protocol provides an operationally sim-
ple strategy to prepare the title compounds and shows good functional flexibility and easily available
starting materials. Evidences are reported on the significant in vitro antiproliferative activities of some
of the obtained heterocyclic quinones on prostate, bladder, and breast human-derived tumor cell lines.
Ó 2015 Published by Elsevier Ltd.
Received 17 June 2015
Revised 10 July 2015
Accepted 11 July 2015
Available online 17 July 2015
Keywords:
Acylnaphthoquinones
Aminobenzothiazoles
Hetero-annulation
Antiproliferative activity
MTT assay
Introduction
of isoquinoline-containing polycyclic quinones.11 It is worth men-
tioning that a number of the reported N-heterocyclic quinones
Quinones are ubiquitous in nature and comprise one of the lar-
gest classes of anticancer agents.1–3 Anticancer quinones are cur-
rently the focus of intensive research because of their biological
activity and complex modes of action, which differ depending on
their particular structure. The biological processes involved with
the antitumor activity of quinones are based mainly on DNA inter-
calation, bioreductive alkylation of biomolecules, and generation of
reactive oxygen species (ROS) through redox cycling.4–8 The DNA
intercalative ability of quinonoid antitumor agents, such as
daunorubicine, doxorubicine, mitoxantrone, and mitomycin C, is
due to their large and planar polycyclic structures, which facilitates
the binding between the base pairs through hydrogen bonds and
exhibit inhibition of topoisomerase I and activation of caspase-3
in HL-60 cells.12 Our synthetic strategy to entry into isoquino-
line-containing polycyclic quinones is based on the hetero-annula-
tion reaction of 2-acyl-1,4-quinones with primary acyclic- and
endocyclic enaminones, where the electrophilic
a,b-unsaturated
acyl fragment of the quinone and the ambident nucleophile
H2NACH@CRA group of the enaminone are involved in the N-hete-
rocyclic ring formation.13–15 Taking into account the similar chem-
ical reactivity of enaminones16 and 2-aminobenzothiazoles17 to act
as ambident nucleophiles with
a,b-unsaturated carbonyl com-
pounds to give heterocycles, we decided to explore the synthesis
of benzo[g]benzothiazolo[2,3-b]quinazoline-7,12-quinones from
2-acylnaphthoquinones and 2-aminobenzothiazoles. To the best
of our knowledge, the sole precedent regarding the synthesis
of antiproliferative benzo[g]benzothiazolo[2,3-b]quinazolinequin
ones is the recent report on amberlyst-15 catalyzed three-compo-
nent condensation of 2-aminobenzothiazole, aromatic aldehydes,
and 2-hydroxy-1,4-naphthoquinone.18 Herein, we wish to
p
-stacking interactions.9,10 Our research group has especially
focused on biologically active compounds based on quinone cores
fused to heterocyclic rings. In this context we have reported the
synthesis and antiproliferative activity on cancer cells of a variety
⇑
Corresponding author. Tel.: +56 57 252 6215; fax: +56 57 2252 6395.
report
that
benzo[g]benzothiazolo[2,3-b]quinazoline-7,12-
0040-4039/Ó 2015 Published by Elsevier Ltd.