Synthesis 2016; 48(04): 566-572
DOI: 10.1055/s-0035-1561277
paper
© Georg Thieme Verlag Stuttgart · New York

Synthesis and Investigation of the Antitumor Properties of Novel, Bicyclic Furopyrimidine, Pyrrolopyrimidine and Pyrimidopyridazine Nucleoside Analogues

Adam Mieczkowski*
a  Department of Biophysics, Institute of Biochemistry and Biophysics, Polish Academy of Sciences, 5a Pawinskiego Street, 02-106 Warsaw, Poland   Email: amiecz@ibb.waw.pl
,
Ewelina Tomczyk
a  Department of Biophysics, Institute of Biochemistry and Biophysics, Polish Academy of Sciences, 5a Pawinskiego Street, 02-106 Warsaw, Poland   Email: amiecz@ibb.waw.pl
b  Department of Chemistry, University of Warsaw, 1 Pasteura Street, 02-093 Warsaw, Poland
,
Małgorzata A. Makowska
a  Department of Biophysics, Institute of Biochemistry and Biophysics, Polish Academy of Sciences, 5a Pawinskiego Street, 02-106 Warsaw, Poland   Email: amiecz@ibb.waw.pl
,
Anna Nasulewicz-Goldeman
c  Department of Experimental Oncology, Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, 12 R. Weigl Street, 53-114 Wrocław, Poland
,
Roman Gajda
d  Biological and Chemical Research Centre, Department of Chemistry, University of Warsaw, 101 Zwirki i Wigury Street, 02-089 Warsaw, Poland
,
Krzysztof Woźniak
d  Biological and Chemical Research Centre, Department of Chemistry, University of Warsaw, 101 Zwirki i Wigury Street, 02-089 Warsaw, Poland
,
Joanna Wietrzyk
c  Department of Experimental Oncology, Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, 12 R. Weigl Street, 53-114 Wrocław, Poland
› Author Affiliations
Further Information

Publication History

Received: 28 September 2015

Accepted after revision: 13 November 2015

Publication Date:
29 December 2015 (online)


Abstract

A series of nine hitherto unknown bicyclic pyrimidine nucleoside analogues (BCNAs) bearing bicyclic furo[2,3-d]pyrimidin-2(3H)-one, 3H-pyrrolo[2,3-d]pyrimidin-2(7H)-one and 5,6-dihydropyrimido[4,5-c]pyridazin-7(8H)-one bases were prepared in a straightforward approach. Each of the synthesized compounds possesses a β-d-ribofuranose, β-d-2-deoxyribofuranose or β-d-arabinofuranose moiety attached to the heterocyclic ring system. This is one of few examples of the synthesis of pyrrolo[2,3-d]pyrimidin-2(7H)-one and dihydropyrimido[4,5-c]pyridazin-7(8H)-one nucleosides, and the first example of such nucleosides possessing an arabinose moiety. A key synthetic step involved a Sonogashira coupling reaction. For the coupling with 4-phenyl-1-butyne, deprotected 5-iodouridine, 5-iodo-2′-deoxyuridine and 5-iodoarabinouridine were used, and this reaction was followed by cycloisomerization and subsequent conversion of the furan ring into a pyrrole or a pyridazine ring. This approach resulted in the creation of a small library of compounds, which were evaluated for their antiproliferative properties against HL-60 and Jurkat E6.1 cell lines. Of all tested compounds, only 6-(2-phenylethyl)-3-(β-d-ribofuranosyl)furo[2,3-d]pyrimidin-2(3H)-one exhibited weak antiproliferative activity, with IC50 values of 54 and 81 μM for HL-60 and Jurkat E6.1 cells, respectively.

Supporting Information

 
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