Department of Organic Chemistry, Faculty of Chemical Engineering and Technology, University of Zagreb, Marulićev trg 20, PO Box 177, HR-10000 Zagreb, Croatia.
Bioorg Med Chem. 2010 Apr 1;18(7):2704-12. doi: 10.1016/j.bmc.2010.02.023. Epub 2010 Feb 18.
5,6-Disubstituted pyrimidine derivatives (3-20) were prepared by intramolecular cyclization reaction of alpha-(1-carbamyliminomethylene)-gamma-butyrolactone (2) with sodium ethoxide and subsequent chemical transformation of 2-hydroxy group in C-5 side chain as well as lithiation reaction for introduction of acyclic side chain at C-6. All compounds were characterized by (1)H NMR, (13)C NMR and mass spectra. Structures of compounds 4, 7 and 14 were unambiguously confirmed by X-ray crystal structural analysis. Supramolecular structures of these three compounds differ significantly. Two N-H...O and one C-H...O hydrogen bonds in 4 form three-dimensional network. One O-H...N hydrogen bond and one pi...pi interaction self-assemble the molecules of 7 into sheets. In supramolecular aggregation of 14, only pi...pi stacking interactions participate, so forming chains. The compounds were evaluated for their cytostatic activities against human malignant cell lines. Of all tested compounds, 2,4-dimethoxy-5-methoxytritylethylpyrimidine (9) and 2,4-dichloro-5-chloroethylpyrimidine (14) exhibited the most prominent inhibitory effects. Furthermore, compound 14 showed marked activity against human colon carcinoma (IC(50)=0.4microM).
5,6-二取代嘧啶衍生物（3-20）是通过α-（1-氨甲酰亚氨基亚甲基）-γ-丁内酯（2）与乙醇钠的分子内环化反应以及 C-5 侧链 2-羟基的后续化学转化和 C-6 无环侧链的锂化反应制备的。所有化合物均通过（1）H NMR、（13）C NMR 和质谱进行了表征。化合物 4、7 和 14 的结构通过 X 射线晶体结构分析得到了明确的证实。这三种化合物的超分子结构差异显著。在 4 中，两个 N-H···O 和一个 C-H···O 氢键形成了三维网络。在 7 中，一个 O-H···N 氢键和一个π···π相互作用将分子组装成薄片。在 14 的超分子聚集中，只有π···π堆积相互作用参与，因此形成了链。对这些化合物进行了人恶性细胞系的细胞抑制活性评估。在所有测试的化合物中，2,4-二甲氧基-5-甲氧基三苯乙基嘧啶（9）和 2,4-二氯-5-氯乙基嘧啶（14）表现出最显著的抑制作用。此外，化合物 14 对人结肠癌细胞表现出显著的活性（IC（50）=0.4μM）。
