Synthesis and Antitumor Screening of Novel 3-Phenylthiazolo [4,5-d]pyrimidin-2-thione Derivatives

Abstract

A series of new derivatives of 3-phenylthiazolo[4,5-d]pyrimidine-2-thiones were synthesized by the cyclization of 4-amino-5-alkyl(aryl) carboxamido-2,3-dihydrothiazolo-2-thione with aromatic aldehydes. Amine moieties were substituted in position 7 of the obtained bicyclic compounds. The synthesized compounds were characterized by elemental analysis, IR, 1H-NMR, and 13C-NMR spectral data. Some of the newly synthesized compounds were selected by the U.S. National Cancer Institute for in vitro antitumor screening. The two compounds 3d 7-chloro-5-(4-fluorophenyl)-3-phenyl-4,5-dihydro-3H-thiazolo[4,5-d]pyrinimidine-2-thione and 4i 5-(2-chlorophenyl)-7-(4-fluorobenzylaxnlno)-3-phenyl-4,5-dihydro-3H-thiazolo[4,5-dipyrhflldlfle-2thione proved to be the most active in the present study and their antitumor activities against 60 human tumor cell lines were described.

Synthesis and anticancer evaluation of novel 3,5-diaryl-thiazolo[4,5-d]pyrimidin-2-one derivatives

“…The method involved subsequent treatment of the appropriate 3,5-diaryl-2-thioxo-5,6-dihydro-4 H -thiazolo[4,5- d ]pyrimidin-7-ones ( 2 ) and 7-chloro-3,5-diaryl-thiazolo[4,5- d ]pyrimidine-2-thiones ( 3 ) (Becan and Wagner, 2008) with diethyl sulfate and water for the replacement of the 2-thioxo group with 2-oxo. First, compounds 2 were obtained through the reaction of the corresponding, refluxing aromatic aldehyde with 4-amino-5-carboxamido-3-substituted-2,3-dihydrothiazole-2-thiones 1 (Gewald, 1966), in the presence of bases according to the earlier reported procedure (Becan and Wagner, 2008). Pyrimidine ring formation with aryl aldehydes followed by chlorination with a mixture of phosphorus pentachloride and phosphorus oxychloride gave the desired cores 2 and 3 which were further treated in boiling acetonitrile with diethyl sulfate.…”

“…Poland), and Sigma-Aldrich (Steinheim, Germany). Starting compounds are synthesized according to the literature (Gewald et al ., 1966; Becan and Wagner, 2008). …”

“…Compounds with significant GI are evaluated at five different concentrations ranging from 10 −4 to 10 −8  M. The percent growth was evaluated versus controls not treated with tested compounds. Preparation of the tested compounds and the sulforhodamine B (SRB) protein assay which was used to estimate cell viability of growth were described previously (Becan and Wagner, 2008; Monks et al ., 1991; Boyd and Paull, 1995; Shoemaker et al ., 2002). …”

“…These designed thiazolo[4,5- d ]pyrimidine-2-ones are related to thiazolo[4,5- d ]pyrimidine-2-thiones that have been previously reported to be potent antitumor agents (Becan and Wagner, 2008). Thiazolo[4,5- d ]pyrimidine derivatives have been extensively studied as potential drug candidates and also have anticancer activity (Rida et al ., 1996; Fahmy et al ., 2002, 2003).…”

“…The method involved subsequent treatment of the appropriate 3,5-diaryl-2-thioxo-5,6-dihydro-4 H -thiazolo[4,5- d ]pyrimidin-7-ones ( 2 ) and 7-chloro-3,5-diaryl-thiazolo[4,5- d ]pyrimidine-2-thiones ( 3 ) with diethyl sulfate and water for the replacement of the 2-thioxo group by an oxygen function (Scheme 1). Compounds 2 and 3 were obtained from 4-amino-5-carboxamido-3-substituted-2,3-dihydrothiazole-2-thiones ( 1 ) (Gewald, 1966) according to a reported earlier procedure (Becan and Wagner, 2008). Pyrimidine ring formation with appropriate aryl aldehyde, followed by chlorination provided the desired cores 2 and 3 , bearing the respective aromatic substituent at position 3 and 5, which could further be treated with diethyl sulfate and hydrolyzed to yield 2-thiazolones 4a – 4f and 5a – 5f .…”