Intensive efforts in anticanver drug discovery are still needed to develop more effective antitumor agents. Thiazolo[4,5-d]pyrimidines are important class of fused heterocycles. Variety of biological activities have been reported earlier. In our previous research, we found that they possess cytotoxic activity [1]. As a 7-thio guanine analogues, thiazolo[4,5-d]pyrimide derivatives may  interfere with the synthesis of guanine. Recently we have synthesized and evaluated in vitro a series of the new derivatives of thiazolo[4,5-d]pyrimidines, which exhibited anticancer activity (Scheme). Treatment of a starting 4-amino-5-carbamoyl-3-phenyl-2-thioxo-2,3-dihydrothiazole 1 with triflouroacetic anhydride gave directly 5-trifluoromethyl-3-phenyl-2-thioxo-thiazolo[4,5-d]pyrimidine-7-on 2, while with benzoyl chloride acylation of the 4-amino group was occurred. Intramolecular cyclization of intermediate diamides 3 was affected by base and underwent in the presence of sodium ethoxylate. The subsequent chlorination of  obtained compound 4  with phosphorus oxychloride  afforded the 7-chloro derivatives 5 in good yield . Nucleophilic substitution  of the chlorine atom by reaction of 5 with the appropriate amine in boiling 1-propanol gave the target 7-substituted amino-thiazolo- [4,5-d]pyrimidines 6. Thiazolo[4,5-d]pyrimidin-2-ones 7 were obtained by the replacement of the 2-thioxo group with 2-oxo. To evaluate the cytotoxic effect, newly synthesized compounds were submitted for testing at the National Cancer Institute (Bethesda, USA), against 60 human tumor cell lines. Most effective 7-(4-chlorobenzyl)-3,5-diphenyl-thiazolo-  [4,5-d]pyrimidin-2-on 7 turned out to be active against 40 cell lines (highest activity parameter for U0-31 renal cancer, GI₅₀= -7.37). Interesting was the fact that, although in varying degrees, all active compounds inhibited the growth of ovarian carcinoma cell line IGROV1, even if it was the only line across the 60 cell panel (in the case of 7-4-methylpiperazi-1-yl 6 derivative). IGROV1cell line expresses   high-affinity IL-4 and IL-13 receptors shared by both cytokines that regulate proliferation and apoptosis. Inhibition of the interaction between interleukin and receptor, by inhibiting the synthesis or by blocking the receptor is a way to influence on biological processes. It is important to search for small synthetic molecules that maintain a high binding affinity for the receptor [2,3].

References: 

1. L.Becan, E.Wagner, Arzneim-Forsch/Drug Res. 2008, 58, 521

2. T. Murata, N.I. Obiri, R.K. Puri, Int. J. Cancer, 1997, 70, 230

3. T.D. Mueller, J.Zhang et.al,  Biochimica and Biophysica Acta, 2002, 1592, 237

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