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Syntheses and Antitumor Evaluation of C-6 Isobutyl and Isobutenyl Substituted Pyrimidines and Pyrrolopyrimidines

Syntheses of pyrimidine derivatives with isobutyl (3, 4 and 7-9) and isobutenyl (5 and 10) side chain at position C-6 are described. The dihydropyrrolo[1, 2-c]pyrimidin-1, 3-diones (6 and 11) are also obtained as the products of an intramolecular cyclization, which occurs during the removal of benzyl (in 5) or methoxy protecting groups (in 10). The synthetic strategy for 6-(2-hydroxymethyl-3-hydroxypropen-1-yl)-2, 4-dimethoxy-5-methylpyrimdine (10) involved the debenzylation of 3, followed by acetylation of resulting triol 7 and fluorination of diacetylated 8. Dehydrohalogenation reaction of derivative 9 with acetyl protecting groups yielded the desired 10, which side chain double bond is in conjugation with heterocyclic ring, unlike for 5 in which elimination orientation is favored by the influence of benzyl protecting groups. The structures of compounds 3 and 6 are determined by single crystal X-ray structure analysis. Antitumor evaluation of compounds 3-11 showed that 2, 4-dimethoxypyrimidine containing 6-[(1, 3-dibenzyloxy)-2-hydroxy]methyl side-chain (3) exerted a strong antiproliferative effect on the studied tumor cell lines. It was also shown that the machanism of antiproliferative effect of 3 in HeLa cells include early G2/M arrest and apoptosis as well as a p53-independent S-phase arrest upon prolonged treatment

C-6 isobutyl and isobutenyl substituted pyrimidines; pyrrolopyrimidines; PET; antitumor evaluations

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