Syntheses and Antitumor Evaluation of C(6)‐Isobutyl‐ and C(6)‐Isobutenyl‐Substituted Pyrimidines, and Dihydropyrrolo[1,2‐c]pyrimidine‐1,3‐diones

Abstract

A growing body of evidence supports that pyrimidine derivatives, in which the sugar residues have been replaced by acyclic side chains, might be developed as promising anticancer agents that interfere with tumor cell proliferation, survival, and metastatic formation. In this work, we prepared novel pyrimidines bearing i-Bu (i.e., 3, 4, and 7 -9) and isobutenyl (i.e., 5 and 10) side chains at C(6) and examined their in vitro effects on tumor cell lines. The dihydropyrrolo[1,2-c]pyrimidine-1,3-diones 6 and 11 were obtained as products of intramolecular cyclization, which occurred during the removal of Bn in 5 or MeO protecting groups in 10. Fluorination of 3 with diethylaminosulfur trifluoride (DAST) and then dehydrohalogenation of the resulting fluorinated derivative 4 afforded 6-isobut-2'-enyl pyrimidine derivative 5 with a C(2')¼C(3') bond. For the preparation of 6-isobut-1'-en-1-yl pyrimidine 10, a synthetic strategy involving acetylation of the 1,3-diols was applied. 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. Additionally, it was shown that the mechanism 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.

Synthesis, structural and conformational studies of Z- and E-isomers of fluorinated C-6 isobutenyl N-methyl thymine derivatives

“…Chemistry 6-(1,3-Dihydroxyisobutenyl) N-methyl pyrimidine derivative (1) [19] was synthesized according to a multistep procedure, which included lithiation reaction of appropriate pyrimidine derivative and nucleophilic addition to 1,3-dibenzyloxy-2-propanone [20,21], followed by various transformations both of the acyclic side-chain at C-6 and of the heterocyclic base. In the next step, one primary hydroxyl group in 1 was selectively converted to methoxytritylated group (Scheme 1).…”

Methoxymethyl (MOM) Group Nitrogen Protection of Pyrimidines Bearing C-6 Acyclic Side-Chains

“…Synthesis of the pyrimidine scaffold 2 was achieved according to the previously reported procedure ( Scheme 1 ) [ 38 ]. Treatment of 2,4-dimethoxy-5,6-dimethylpyrimidine with lithium diispropylamide (LDA) in THF at −55 °C afforded the corresponding lithiated precursor, which reacted in situ with 1,3-dibenzyloxy-2-propanone to give 6-(1,3-dibenzyloxy-2-hydroxyisobutyl)thymine ( 1 ) [ 35 ].…”

“…Demethoxylation of 2 with acetyl chloride (AcCl) and water gave the same product 3 in improved yield (68%). To avoid intramolecular cyclization and formation of a conformationally constrained carbon-bridged pyrrolido[1,2- c ]pyrimidine, formed by N -1 linkage to the acyclic moiety at C-6 position [ 35 , 38 ], a strategy involving N- methoxymethylation of 3 was applied with methoxymethyl chloride (MOMCl) as alkylating reagent.…”

“…High performance liquid chromatography was performed on an Agilent 1100 series system with UV detection (photodiode array detector) using Zorbax C18 reverse-phase analytical column (2.1 × 30 mm, 3.5 µm). 6-[(3-Benzyloxy-2-benzyloxymethyl-2-hydroxy)propyl]-5-methyl-2,4-dimethoxypyrimidine ( 1 ) and 6 -[(3-benzyloxy-2-benzyloxymethyl)propyl]-5-methyl-2,4-dimethoxypyrimidine ( 2 ) were synthesized using analogous procedures as described previously [ 35 , 38 ].…”