Badr Mona Hany, Rostom Sherif Ahmed Fawzi, Radwan Mohammed Fouad
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, King Abdulaziz University.
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Alexandria University.
Chem Pharm Bull (Tokyo). 2017;65(5):442-454. doi: 10.1248/cpb.c16-00761.
Two series of novel alkoxylated 2-oxo(imino)-3-pyridinecarbonitriles (structurally-relevant to some reported anticancer pyridines with phosphodiesterase 3A (PDE3A) inhibitory activity) were synthesized and evaluated for their in vitro differential tumor cell growth inhibitory potential against the breast MCF7, hepatocellular Hep-G2, colon CACO-2 cell lines, and a normal human foreskin fibroblast Hs27 cell line. Compounds 8, 16 and 19 displayed recognizable growth inhibitory ability and selectivity towards the breast MCF7 (LC 19.15, 17.34 and 14.70 µM, respectively) as compared with doxorubicin (LC 3.94 µM). Meanwhile, compounds 8, 15, 16, and 19 revealed a marginal inhibitory effect on the growth of the normal human foreskin fibroblast Hs27 cell line, beside a distinctive antioxidant potential in the 2,2-diphenyl-1-picrylhydrazyl (DPPH) assay. These four compounds were further assessed for their in vitro inhibition of PDE3A (a current antitumor therapeutic target), where 16 and 19 showed moderate to weak PDE3A inhibitory as compared with milrinone, the positive control. No clear straightforward liaison between the anticancer potential and PDE3A inhibitory activity could be deduced. Computations of the predicted pharmacokinetic properties, toxicity effects (ADME-T), drug-likeness and drug scores for the newly developed compounds showed non-violations of Lipinski's RO5 and Veber's criteria for good bioavailability, with a predicted high safety profile.
合成了两个系列的新型烷氧基化2-氧代（亚氨基）-3-吡啶甲腈（其结构与一些已报道的具有磷酸二酯酶3A（PDE3A）抑制活性的抗癌吡啶相关），并评估了它们对乳腺癌MCF7、肝癌Hep-G2、结肠癌CACO-2细胞系以及正常人包皮成纤维细胞Hs27细胞系的体外肿瘤细胞生长抑制差异潜力。与阿霉素（LC 3.94 μM）相比，化合物8、16和19对乳腺癌MCF7表现出明显的生长抑制能力和选择性（分别为LC 19.15、17.34和14.70 μM）。同时，化合物8、15、16和19除了在2,2-二苯基-1-苦基肼（DPPH）测定中具有独特的抗氧化潜力外，对正常人包皮成纤维细胞Hs27细胞系的生长也显示出微弱的抑制作用。进一步评估了这四种化合物对PDE3A（当前的抗肿瘤治疗靶点）的体外抑制作用，与阳性对照米力农相比，16和19表现出中度至弱的PDE3A抑制作用。无法推断出抗癌潜力与PDE3A抑制活性之间存在明确直接的联系。对新开发化合物的预测药代动力学性质、毒性作用（ADME-T）、药物相似性和药物评分的计算表明，它们未违反利平斯基的RO5规则和韦伯的良好生物利用度标准，预测具有较高的安全性。
