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

Autori
Ismaili, Hamit

Vrsta, podvrsta i kategorija rada
Ocjenski radovi, doktorska disertacija

Fakultet
Faculty of Mathematics and Natural Sciences

Mjesto
Pristina, Kosovo

Datum
24.05

Godina
2013

Stranica
101

Mentor
Žinić, Biserka

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

Sažetak
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.

Izvorni jezik
Engleski

Znanstvena područja
Kemija

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