El-Said M S, El-Gazzar M G, Al-Dosari M S, Ghorab M M
Medicinal, Aromatic and Poisonous Plants Research Center (MAPPRC), College of Pharmacy, King Saud University, Riyadh, Saudi Arabia.
Arzneimittelforschung. 2012 Mar;62(3):149-56. doi: 10.1055/s-0031-1299695. Epub 2012 Jan 23.
Based on the reported anticancer activity of 2-pyridone, a new series of 6-amino-5-cyano-1-(3-ethylphenyl)-2-oxo-4-substituted-1,2-dihydropyridine-3-carbo-nitriles 4a-p were synthesized and tested for in-vitro anticancer activity against Ehrlich Ascites Carcinoma (EAC) cell line and liver human tumor cell line (HEPG2). Radiosensitizing activity was also evaluated. The starting material 2-cyano-N-(3-ethylphenyl)-acetamide 3 was obtained via reaction of 3-ethyl aniline 1 with ethyl cyanoacetate under condition of fusion. Upon treatment of compound 3 with aromatic aldehyde and malononitrile in the presence of catalytic amount of piperidine yielded the corresponding 1,2-dihydropyridine derivative 4a-p. Also chromenes 5 and 6 were obtained in good yield via reaction of compound 3 with salicyladehyde under different condition. The chromene derivatives 5 and 6 were further reacted with malononitrile in NH4OAc, afford the corresponding chromenopyridones 7 and 8. The structures of the synthesized compounds 3-8 were confirmed by analytical and spectral data. Compounds 4d, 4e, 5 and 6 showed higher anticancer activity against EAC cell line with IC50 values (75.32, 20.77, 73.1 and 67.05 µM) compared to doxorubicin as positive control with IC50 value (68.13 µM), moreover, these compounds showed potent activity on HEPG2 cell line with IC50 values (26.5, 19.2, 39.3, 44.9 µM), respectively, compared to doxorubicin (CAS 29042-30-6) (38.46 µM) and their activity increased synergistically when combined with γ-radiation.
基于已报道的2-吡啶酮的抗癌活性，合成了一系列新的6-氨基-5-氰基-1-(3-乙基苯基)-2-氧代-4-取代-1,2-二氢吡啶-3-甲腈4a-p，并对其针对艾氏腹水癌（EAC）细胞系和人肝癌细胞系（HEPG2）进行了体外抗癌活性测试。还评估了其放射增敏活性。起始原料2-氰基-N-(3-乙基苯基)乙酰胺3是通过3-乙基苯胺1与氰基乙酸乙酯在熔融条件下反应制得的。在催化量的哌啶存在下，用芳香醛和丙二腈处理化合物3，得到相应的1,2-二氢吡啶衍生物4a-p。同样，在不同条件下，化合物3与水杨醛反应，以良好的产率得到色烯5和6。色烯衍生物5和6在醋酸铵中与丙二腈进一步反应，得到相应的色烯并吡啶酮7和8。通过分析和光谱数据确认了合成化合物3-8的结构。与作为阳性对照的阿霉素（IC50值为68.13 μM）相比，化合物4d、4e、5和6对EAC细胞系显示出更高的抗癌活性，IC50值分别为（75.32、20.77、73.1和67.05 μM），此外，与阿霉素（CAS 29042-30-6）（38.46 μM）相比，这些化合物对HEPG2细胞系也显示出较强的活性，IC50值分别为（26.5、19.2、39.3、44.9 μM），并且当与γ射线联合使用时，它们的活性协同增加。
