NEW ALIPHATIC N-SULFONYLAMIDINO THYMINE DERIVATIVES
Biserka Žinić,1* Luka Krstulović,2 Miroslav Bajić,2 Hamit Ismaili,3 and Ljubica Glavaš-Obrovac4,5
Ruđer Bošković Institute, Bijenička c 54, 10000 Zagreb, Croatia, 2Faculty of Veterinary Medicine, University of Zagreb,
Croatia, 3Faculty of natural science, University of Pristine, Pristine, Kosovo, 3University Hospital Centre Osijek, Osijek,
Croatia, 4Faculty of Medicine, University J.J. Strossmayer in Osijek, Osijek, Croatia.
1
* Correspondence to: bzinic@irb.
ABSTRACT
Novel N-sulfonylamidine derivatives in thymine series
were synthesized by Cu-catalyzed three-component coupling of propargyl thymine, sulfonyl azides and amines.
Obtained derivatives were tested for their cytostatic activity.
INTRODUCTION,
CONCLUSION
RESULTS AND
DISCUSSION,
Treatment of cancer cells is the main battlefield of modern medicine. Due to their variability and heterogeneity,
there is a constant urge for new drugs. As a part of our program directed toward the synthesis and characterization of
biologically active nucleobase derivatives, we have recently
described the synthesis of novel N-sulfonylpyrimidine derivatives which showed strong antitumor activity in in vitro
and in vivo conditions.[1-4]
The idea behind this work was to link three biologically
attractive pharmacophores: pyrimidine nucleobase, Nsulfonyl group and an amidine group, which will create new
aliphatic derivatives of thymine nucleobases with Nsulfonylamidino group (Figure 1).
Recently Chang et al. reported a new route for the synthesis of amidines via copper-catalyzed tandem reactions of
O-bis(trimethylsilyl)acetamide (BSA) in acetonitrile and
treated with propargyl bromide giving exclusively N-1 alkylated product.[6] Cu-catalyzed three-component coupling
reactions of propargyl thymine were conducted at room
temperature in THF, with p-toluenesulfonyl, pacetamidobenzenesulfonyl and 4-carboxybenzenesulfonyl
azide in the presence of CuI catalyst and primary and secondary amines. We have also examined the synthesis of
unsubstituted N-sulfonylamidine derivatives in the Cucatalyzed three-component reaction of propargyl thymine
and sulfonyl azides with ammonium salts leading to Nunprotected amidines.
Reactions with secondary amines (diisopropyl amine, diethyl amine) were more efficient than those with primary
amines (cyclopentyl amine, isopropyl amine) or amine salts
[ammonium chloride, 4-(aminomethyl)benzonitrile hydrochloride].
The cytotoxicity of compounds were tested against normal cells (MDCKI) and human tumor cell lines of different
origin (HeLa, CaCo2, NCI-H358, Jurkat, K562, Raji, and
HuT78) and some of them showed considerable activity.
Synthesis of new derivatives in this class of molecules is
underway in our laboratory.
REFERENCES
1.
O
HN
O
2.
O
N
R'
N S
O
N
R''
R
Figure 1. Aliphatic N-sulfonylamidino thymine derivatives.
sulfonyl azides and alkynes in the presence of primary or
secondary amines.[5]
The synthesis of our target molecules was achieved by
three components, one-pot, copper catalyzed reaction of
propargylated thymine with different aromatic sulfonyl azides and primary and secondary amines.
Propargyl thymine was obtained by slightly modified
Woodmans method. For this, thymine was activated with N,
3.
4.
5.
6.
Žinić, B., Žinić, M., Krizmanić, EP 0 877 022 B1 Synthesis of the Sulfonylpyrimidine Derivatives with Anticancer Activity, 2003.
Pavlak, M., Stojković, R., Radačić-Aumiler, M.,
Kašnar-Šamprec, J., Jerčić, J., Vlahović, K., Žinić B.,
Radačić, M. J. Cancer. Res. Clin. Oncol. 2005, 131,
829-836.
Supek, F., Kralj, M., Marjanović, M., Šuman, L., Šmuc,
T., Krizmanić, I., Žinić, B. Invest. New Drugs 2008, 26,
97–110.
Kašnar-Šamprec, J., Ratkaj, I., Mišković, K., Pavlak,
M., Baus-Lončar, M., Kraljević Pavelić, S., GlavašObrovac Lj., Žinić, B. Invest. New Drugs 2012 on line,
http://www.springerlink.com/content/2607497u1024v0
7t/).
Bae, I.; Han, H.; Chang, S. J. Am. Chem. Soc. 2005,
127, 2038-2039.
Lindsell, W. E., Murray, C., Preston, P. N., Woodman,
T. A. J. Tetrahedron 2000, 56, 1233-1245.