engleski

Synthesis, Structural Characterization and Biological Activity of Novel N-Sulfonyl and Sulfonamido Derivatives of Nucleobases and Nucleosides

In continuation of our preliminary work directed towards the synthesis and characterization of biologically active nucleobase derivatives, we presented the synthesis of structurally novel N-sulfonyl N-sulfonylamidino and sulfonamido pyrimidine and purine derivatives and evaluate their biological activity. The N-9 sulfonyl products of 6-chloropurine 36-39 were synthesized by the condensation reaction of the 6-chloro-9H-purine (33) with 4-methylbenzenesulfonyl chloride, 4-bromobenzenesulfonyl chloride, 4-chloro-3-nitrobenzenesulfonyl chloride and 2-naphtalenesulfonyl chloride in acetone and in the presence of aqueous KOH at 0 oC. To solve the problem of instability in solutions, the chlorine at the C-6 position in 37 was substituted with morpholine yielding much more stable 6-morpholino N-9 sulfonyl products 40. The condensation reactions of guanine 41 with different sulfonyl chlorides were carried out using 2 equivalents KOH/H2O in DMF at room temperature and N-9-sulfonyl guanine derivatives: 9-(p-toluenesulfonyl)guanine (42), 9-(4-acetamidobenzenesulfonyl)guanine (43), and 9-(2-nitrobenzenesulfonyl)guanine (44) were isolated in 76%, 58% and 60%, respectively. The Cu(I)-catalyzed three-component coupling reaction of 1-propargyl thymine 50 with 4-acetamidobenzenesulfonyl and diisopropylamine gave the N-sulfonylamidino product 52 in 78 % yield. However, in the same conditions three-component reaction of 1-propargyl guanine 48 was not successful. The series of C-5 sulfonamido pyrimidines 54-61 were prepared by heating 5-aminouracil with the selected sulfonyl chlorides in pyridine. The reaction was regioselective and only isolated products were the C-5 substituted pyrimidine. The cytotoxicity of compounds 41-44 and 54-61 were tested against normal cells (MDCK1), carcinoma cell lines (CaCo, NCI-H358, HeLa) and human leukemia (Raji, K562, Jurkat) and lymphoma (HuT78) cell lines by the MTT assay. Depending on the dose applied compounds showed moderate to high antiproliferative activity against a panel of hematological malignancies in vitro.

synthesis; 9-sulfonyl-6-chloropurines; 6-morpholino-9-sulfonylpurines; C-5-sulfonamido pyrimidines; antiproliferative effects; leukemia cells; solid tumors cells

nije evidentirano