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Bioorganic & Medicinal Chemistry 17 (2009) 2544–2554
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Bioorganic & Medicinal Chemistry
Effect of 3,4-ethylenedioxy-extension of thiophene core on the DNA/RNA
binding properties and biological activity of bisbenzimidazole amidines
a
b
c
c
d
´
´
Ivana Stolic , Katarina Miškovic , Anahi Magdaleno , Ariel Mariano Silber , Ivo Piantanida ,
a,
b,
*
*
´
Miroslav Bajic , Ljubica Glavaš-Obrovac
a Department of Chemistry and Biochemistry, Faculty of Veterinary Medicine, University of Zagreb, Heinzelova 55, 10000 Zagreb, Croatia
b Department of Medical Chemistry and Biochemistry, School of Medicine, J.J. Strossmayer University of Osijek, 31000 Osijek, Croatia
c Department of Parasitology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil
d
´
Division of Organic Chemistry and Biochemistry, Ruder Boškovic Institute, Zagreb, Croatia
a r t i c l e i n f o
a b s t r a c t
Article history:
Novel bisbenzimidazoles (4–6), characterized by 3,4-ethylenedioxy-extension of thiophene core,
revealed pronounced affinity and strong thermal stabilization effect toward ds-DNA. They interact within
ds-DNA grooves as dimmers or even oligomers and agglomerate along ds-RNA. Compounds 4–6 have
shown moderate to strong antiproliferative effect toward panel of eight carcinoma cell lines. Compound
5 displayed the best inhibitory potential and in equitoxic concentration (IC50 = 1 ꢀ 10ꢁ6 M) induced accu-
mulation of cells in G2/M phase after 48 h of incubation. Fluorescence microscopy showed that 5 entered
into live HeLa cells within 30 min, but did not accumulate in nuclei even after 2.5 h. Compound 5 inhib-
ited the growth of Trypanosome cruzi epimastigotes (IC50 = 4.3 ꢀ 10ꢁ6 M).
Received 2 October 2008
Revised 20 January 2009
Accepted 22 January 2009
Available online 5 February 2009
Keywords:
Benzimidazole amidine
DNA/RNA binding
Antiproliferative activity
Antiparasitic activity
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
antitumor bioactivity cells resistant to cisplatinum.10–18 Although
the mechanism of action of aromatic diamidines is not fully eluci-
In recent years many efforts have been focused at targeting
specific sequences of macromolecules, especially specific DNA
sequences, with the aim at designing both leads for medicinal
chemistry and molecular probes for DNA polymorphism.1–3 Nat-
ural products and synthetic organic cations that bind specifically
and selectively to the DNA minor groove have therapeutic po-
tential in a wide range of applications. These compounds bind
to minor groove by a combination of ionic, hydrophobic and
hydrogen bonding interaction.4–6 For this purpose small mole-
cules have to meet ‘classical’ structural criteria for optimum
DNA fit and interaction: a crescent shape that complements
the helical DNA minor groove, recognition units (H-bond donors
and acceptors) on the side of the molecule facing DNA, cationic
centre at terminals of the molecules to enhance electrostatic
interactions, and an extended unfused heterocyclic structure to
allow optimization of the compound for DNA minor groove
interactions.7–9
dated, it has been proven that their bioactivity is the result of DNA
binding and subsequent inhibition of DNA-dependent enzymes
(topoisomerases, polymerases, and nucleases) or possibly by direct
inhibition of transcription.10,19 A large number of DNA minor
groove binders containing one or more benzimidazole heterocy-
cles have been reported to date reveal promising antitumor and
antiparasitic activities.5,10,20–23 Benzimidazole units are often
key structural elements in the aromatic frame work for the more
effective diamidines.24,25 In addition, an important role in deter-
mining biological activity and DNA binding affinity also plays
the structure and the rigidity of the linker between the two aro-
matic amidine moieties.16,25 Biophysical studies of previously
synthesized minor groove binding compounds have suggested
that structural features that increase van der Waals interactions
of small molecules with the walls of the groove should increase
the DNA affinity of these molecules.7,26,27 On the basis of our pre-
vious research on aromatic diamidine in benzo[c]thiophene ser-
ies,28 three new bisbenzimidazole amidines (4–6) with 3,4-
ethylenedioxythiophene as central unit were synthesized and
their biological potential and binding affinity using calf thymus
DNA, and ds-RNA (poly A-poly U) were studied. The crescent
shape of the new compounds matches the curvature of the minor
groove of DNA. The 3,4-ethylenedioxy extension of thiophene
core in the central unit should increase electron-donating
Aromatic diamidines which have been shown to fit snugly into
the minor groove of DNA and interact selectively with AT-rich se-
quences exhibited outstanding antimicrobial activity as well as
* Corresponding authors. Fax: +385 1 2441390 (M.B.), +385 31 512 227 (L.G.-O.).
Glavaš-Obrovac).
0968-0896/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2009.01.071