Abstract
New thiopurines with the propargylthio, pyrrolidinobutynylthio, sulfenamide, and sulfonamide groups in the pyrimidine ring were synthesized. The anticancer activity of these compounds and previously obtained 2- or 6-substituted azathioprine analogs and dialkylaminoalkylthiopurines were tested in vitro against three cell lines: glioblastoma SNB-19, melanoma C-32, and human ductal breast epithelial tumor T47D. 2-Chloro-7-methyl-6-pyrrolidinobutynylthiopurine (5b) was the most potent compound against SBN-19 and C-32 cell lines with the activity similar to cisplatin (EC50 = 5.00 and 7.58 μg/ml, respectively). The dialkylaminoalkylthio derivatives (4b, 4c, 4e, and 4f) showed good activity against SBN-19 cell line (EC50 < 10 μg/ml). The azathioprine analogs (2a, 2b, and 3a) were more active than azathioprine against SBN-19 and C-32 cell lines. The sulfenamide and sulfonamide derivatives of purine were very weak active against tested cell lines. All studied thiopurines were less toxic than cisplatin.Electronic supplementary materialThe online version of this article (doi:10.1007/s00044-015-1364-2) contains supplementary material, which is available to authorized users.
Highlights
All studied thiopurines were less toxic than cisplatin
In search for novel thiopurine derivatives, we described synthesis of 2-chloro-6-alkynylthio-7-methylpurines 5a, 5b from 2-chloro derivative and propargyl bromide and further via Mannich reaction with pyrrolidine
Other types of thiopurines bearing the sulfenamide 10a–e and sulfonamide 8a–d groups were obtained through S-amination of purinethiones 1a–d and oxidation with 3-chloroperoxybenzoic acid
Summary
The sulfur-containing purines: 6-mercaptopurine, 6-thioguanine, and azathioprine, have been considered as important and effective drugs used in cancer chemotherapy, for immunosuppression in kidney or heart transplantation and autoimmune diseases (Steurer et al, 2006; Hawwa et al, 2008; Relling et al, 2013; Rao et al, 2013). 6-Mercaptopurine is widely used as an antileukemic agent in the lymphoproliferative disorders, including lymphoma, childhood acute lymphoblastic leukemia, and other neoplastic conditions (Hawwa et al, 2008; Prima et al, 2013; Miron et al, 2009). The use of thiopurines is limited by their toxicities, which include hepatotoxicity, myelosuppression, pancreatitis, and allergic reactions (Prima et al, 2013). For this reason, many thiopurine derivatives and analogs have been synthesized for evaluation of their biological activities and reduced toxicity. 9-substituted derivatives of 6-(t-butoxycarbamylaminohexyl)thiopurine were obtained which showed moderate antibacterial activity (Rao et al, 2013); a series of 6-mercaptopurine analogs with 1,2,3-triazole or steroid rings exhibited
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