Antiviral and Cytostatic Evaluation of the Novel 6-acyclic Chain Substituted Thymine Derivatives

Abstract

A series of the novel 5-methyl pyrimidine derivatives with an acyclic side chain at the C-6 position were synthesized using lithiation of a 2,4-dimethoxy-5,6-dimethyl pyrimidine and subsequent nucleophilic addition or substitution reactions of the organolithium intermediate thus obtained with acetaldehyde, epichlorhydrine, fluorinated ketones and fluorinated ester. The novel compounds were evaluated for their cytostatic and antiviral activities. Among all the compounds evaluated, two fluorinated acyclic pyrimidine derivatives showed the highest cytostatic activities. The compound containing a 2-hydroxy-3,3,3-trifluoro-1-propenyl side chain exhibited a pronounced effect against breast carcinoma (MCF-7, IC50=8.38 micorg/ml), while the compound with a 2-fluoromethyl-2-acetoxypropyl chain exhibited moderate effect against cervical carcinoma (HeLa, IC50=19.73 microg/ml).

Synthesis and structural studies of C-5 aryl- and C-6 alkyl-substituted pyrimidine derivatives

“…Moreover, NOE between 2 0 -OH and 2-OCH 3 proved that 2-OCH 3 protons are more deshielded than 4-OCH 3 . The chemical shifts pattern of C-5 and C-6 disubstituted pyrimidine derivatives in 13 C NMR spectra are consistent with those observed for related compounds [7][8][9][10]18]. Moreover, the magnitudes of one-, two-, three-and fourbond C-F couplings in 7 at C-6 0 , C-5 0 , C-4 0 and C-3 0 , respectively, are in accord once with the literature data for fluorinated pyrimidine derivatives [7][8][9][10].…”

“…Recently, we have reported that fluorinated propyl and propenyl acyclic pyrimidine derivatives exhibited rather pronounced cytostatic activities against breast carcinoma (MCF-7) and cervical carcinoma (HeLa) [7]. Moreover, some nonconventional C-6 fluoroalkylated and fluorophenylalkylated pyrimidine nucleoside mimetics showed to be good model compounds for development of tracer molecules in positron-emission tomography (PET) [8][9][10].…”

A theoretical study on 2-chloro-5-(2-hydroxyethyl)-4-methoxy-6-methylpyrimidine by DFT/ab initio calculations

“…The biological activities shown by 6-substituted uracil derivatives provide a new motivation to explore the chemical and biological activities of these pyrimidine derivatives [2][3][4][5][6][7][8]. Uracil derivatives as well as their nucleosides which have significant status in the field of chemotherapy, are substituted either at C5 or C6 positions.…”

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

“…In addition, we have reported that fluorinated pyrimidine derivatives containing the 3,3,3-trifluoro-2-hydroxyprop-1-enyl side chain at C(6) exhibited a pronounced effect against breast carcinoma (MCF-7), while the compound with the 2-(fluoromethyl)-2-acetoxypropyl chain exhibited moderate effect against cervical carcinoma (HeLa) [20]. C(6)-Substituted pyrimidines containing the 4-fluorophenyl moiety in the side chain showed pronounced antiproliferative effect on colon (SW620 and HCT116) and lung carcinoma (H460) [21].…”

“…1) crystallizes with two independent molecules in the asymmetric unit in the orthorhombic space group Pca2 1 . These two independent molecules, denoted as A and B, differ in the conformation of one of two BnOCH 2 groups, and thus, C (20) Table 1), join two independent molecules of 3, so forming finite D(2) motifs [32]. The H-donor atoms are exclusively atoms of molecule B, whereas the O-atoms of molecule A are exclusively H-acceptors.…”