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 acyclonucleosides, 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 substituent 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-substituted uracil derivative 6 (5-[bis-(2-p-methoxybenzylthioethyl)amine]acetylaminouracil) exhibited high antiproliferative activity against HeLa and MiaPaCa-2 cell lines, by an as yet unknown mechanism.
Noll
Steffi
S
Institut für Radiopharmazie, Forschungszentrum Dresden-Rossendorf, Postfach 510119, 01314 Dresden, Germany.
Kralj
Marijeta
M
Suman
Lidija
L
Stephan
Holger
H
Piantanida
Ivo
I
D002453:Cell Cycle / Q000187:drug effects; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects*; D006801:Humans; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship
D011743:Pyrimidines