engleski

Synthesis of modified pyrimidine bases and positive impact of chemically reactive substituents on their in vitro antiproliferative activity

The antiproliferative activity screening on human tumor cell lines of a series of modified uracil and cytosine bases as well as some corresponding acyclonucleotides, and comparison of structure-activity relationship revealed the importance of chemical reactivity of the substituent attached to the C5-position of uracil for the activity of studied compounds. Namely, the results obtained for the most active compounds, 5-(Chloroacetylamino)uracil (2) and its acyclic sugar analogue 18, suggest that formation of a covalent bond between reactive substitutent and several possible targets within the thymidylate synthase mechanism (sulphur of the cysteine residue, basic part of the enzyme, N, N-methylene tetrahydrofolate or its reactive iminium forms) is the most probable mode of action. In addition, novel C5-substitued uracil derivative 6 (5-[bis-(2-p-methoxybenzylthioethyl)amine]acetylamino-uracil) exhibited high antiproliferative activity against HeLa and MiaPaCa-2 cell lines, by an as yet unknown mechanism.

modified pyrimidine bases ; antiproliferative activity ; human tumor cell lines

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