Synthesis and antitumor activity of N-sulfonyl derivatives of nucleobases and sulfonamido nucleoside derivatives

Article abstract of DOI:10.1081/NCN-120023084

The introduction of sulfonamido group on the C-2 position of pyrimidine nucleosides was achieved by ring opening of 2,2′- and 2,3′ -anhydronucleosides. N-sulfonyl derivatives of nucleobases and sulfonamido derivatives of nucleosides were assayed for in vitro antitumor activity.

Full text of DOI:10.1081/NCN-120023084

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Synthesis and Antitumor Activity of N-Sulfonyl
Derivatives of Nucleobases and Sulfonamido Nucleoside
Derivatives
a d
b
c
c
a
B. Žinić
, I. Krizmanić , Lj. Glavaš-Obrovac , I. Karner & M. Žinić
a
Ruder Bošković Institute , Zagreb, Croatia
b
c
d
HERBOS Chem. Industry , Sisak, Croatia
Clinical Hospital Osijek , Osijek, Croatia
Ruder Bošković Institute , Bijenička 54, 10 000, Zagreb, Croatia
Published online: 31 Aug 2006.
To cite this article: B. Žinić , I. Krizmanić , Lj. Glavaš-Obrovac , I. Karner & M. Žinić (2003) Synthesis and Antitumor Activity
of N-Sulfonyl Derivatives of Nucleobases and Sulfonamido Nucleoside Derivatives, Nucleosides, Nucleotides and Nucleic Acids,
22:5-8, 1623-1625, DOI: 10.1081/NCN-120023084
To link to this article: http://dx.doi.org/10.1081/NCN-120023084
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NUCLEOSIDES, NUCLEOTIDES & NUCLEIC ACIDS
Vol. 22, Nos. 5–8, pp. 1623–1625, 2003
Synthesis and Antitumor Activity of N-Sulfonyl Derivatives
of Nucleobases and Sulfonamido
Nucleoside Derivatives
1,*
2
3
ˇ
B. Zini c´ , I. Krizmani c´ , Lj. Glava sˇ -Obrovac,
3
1
ˇ
I. Karner, and M. Zinic´
1
Ruder Bo sˇ kovi c´ Institute, Zagreb, Croatia
HERBOS Chem. Industry, Sisak, Croatia
3
Clinical Hospital Osijek, Osijek, Croatia
2
ABSTRACT
The introduction of sulfonamido group on the C-2 position of pyrimidine nucleo-
0
0
sides was achieved by ring opening of 2,2 - and 2,3 -anhydronucleosides. N-sulfo-
nyl derivatives of nucleobases and sulfonamido derivatives of nucleosides were
assayed for in vitro antitumor activity.
Key Words: Anhydronucleosides; C-2 sulfonamido pyrimidine nucleosides;
In vitro antitumor activity.
We have designed and synthesized N-sulfonyl derivatives of pyrimidine bases
[
I as a new type of sulfonylcycloureas. The compounds showed potent growth
1]
inhibitory activity (25–75%) against human tumor cell lines in vitro, at concentra-
ꢀ
8
ꢀ5
tions of 10 ꢀ 10 M and some of them showed the ability to induce apoptosis
[2]
in treated tumor cells. These results directed our interest toward N-sulfonyl
ˇ
*
Correspondence: B. Zini c´ , Ruder Bo sˇ kovi c´ Institute, Bijeni cˇ ka 54, 10 000 Zagreb, Croatia;
Fax: +1 313 832 7294; E-mail: bzinic@rudjer.irb.hr.
1
623
DOI: 10.1081/NCN-120023084
Copyright # 2003 by Marcel Dekker, Inc.
1525-7770 (Print); 1532-2335 (Online)
www.dekker.com

ˇ
Zini c´ et al.
1624
Figure 1.
derivatives of purine bases II and sulfonamido derivatives of purine nucleosides III
[3]
(Fig. 1).
The introduction of sulfonamido group on the C-2 position of pyrimidine
0
0
nucleosides was achieved by ring opening of 2,2 - and 2,3 -anhydronucleosides with
selected sulfonamide anion as nucleophile (Sch. 1).
Scheme 1.

N-Sulfonyl Derivatives of Nucleobases
1625
0
In the reaction of 2,2 -anhydrocytidine hydrochloride 1 with Na-salt of p-tolue-
nesulfonamide, at room temperature, 4-imino-N2-tosylamino-1-(b-d-arabinofurano-
syl) pyrimidine 2 was isolated in 94% yield. Pyridinesulfonamido derivative of araC
3
dimethylnicotinamide as nucleophile.
, was synthesized in the same way (75% yield) using 2-(aminosulfonyl)-N,N-
0
Introduction of sulfonamido substituent on less reactive 2,2 -anhydrouridine 4
0
and 2,3 -anhydrothymidine 6 needs vigorous conditions (concentrated solutions
ꢁ
and heating at 100–110 C, 1–4 days) and gave reasonable yields, 41% for 5 and
67% for 7. These two anhydronucleosides does not react with weaker nucleophile
such as 2-(aminosulfonyl)-N,N-dimethylnicotinamide. The action of acetic acid or
ZnBr =CH Cl on the 2-sulfonamido derivative 7 leads to the cleavage of both the
protection group and the nucleoside bond.
2
2
2
The prepared derivatives were evaluated for their in vitro cytostatic activity
against different human tumor cell lines (CaCo2, SW620, HT-29, HeLa2, and MIA-
PACa2; MTT assay).
In comparison with 5-fluorouracil some of N-sulfonylpyrimidine derivatives I
showed 10 times stronger activity and some of them showed the ability to induce
apoptosis in treated tumor cells.
The N-sulfonylpurine and sulfonamido nucleoside derivatives showed lower
activity.
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ꢀ
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vatives as a new type of sulfonylcycloureas. Nucleosides & Nucleotides 1997, 16,
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