Department of Chemistry of Drugs, Faculty of Pharmacy, Wroclaw Medical University, Borowska 211, 50-556 Wroclaw, Poland.
Department of Basic Medical Science, Wrocław Medical University Borowska 211, 50-556 Wrocław, Poland.
Molecules. 2019 Mar 20;24(6):1093. doi: 10.3390/molecules24061093.
Cyclooxygenase inhibitors as anti-inflammatory agents can be used in chemoprevention. Many in vitro and in vivo studies on human and animal models have explained the mechanisms of the chemopreventive effect of COX inhibitors such as: induction of apoptosis, inhibition of neoplasia, angiogenesis suppression, induction of cell cycle inhibition and inhibition of the expression of peroxisome proliferator-activated receptors. Here, biological evaluation of twelve different Schiff base derivatives of -(2-hydrazine-2-oxoethyl)-4,6-dimethyl-2-sulfanylpyridine- 3-carboxamide are presented. Their in vitro anti-COX-1/COX-2, antioxidant and anticancer activities were studied. The molecular docking study was performed in order to understand the binding interaction of compounds in the active site of cyclooxygenases. Compounds PS18 and PS33 showed a significant inhibitory activity on COX-1 at lower concentrations compared to meloxicam and piroxicam. The IC of COX-1 of these compounds was 57.3 µM for PS18 and 51.8 µM for PS33. Out of the tested compounds, the highest therapeutic index was demonstrated by PS18, PS19, PS33, PS40 and PS41. Lower molar concentrations of these compounds inhibit the growth of cancer cells while not inhibiting the healthy cells. Compounds PS18, PS19 and PS33 simultaneously demonstrated a statistically-significant inhibition of COX-1 or COX-2. This opens up the possibility of applying these compounds in the chemoprevention of cancer.
环氧化酶抑制剂作为抗炎药物可用于化学预防。许多体外和体内研究已经解释了 COX 抑制剂（如诱导细胞凋亡、抑制肿瘤发生、抑制血管生成、诱导细胞周期抑制和抑制过氧化物酶体增殖物激活受体表达）的化学预防作用的机制。在这里，我们介绍了 12 种不同的 -(2-肼基-2-氧代乙基）-4,6-二甲基-2-巯基吡啶-3-甲酰胺的席夫碱衍生物的生物学评估。研究了它们体外抗 COX-1/COX-2、抗氧化和抗癌活性。为了了解化合物在环氧化酶活性部位的结合相互作用，进行了分子对接研究。与美洛昔康和吡罗昔康相比，化合物 PS18 和 PS33 在较低浓度下对 COX-1 表现出显著的抑制活性。这些化合物对 COX-1 的 IC 为 57.3 µM（PS18）和 51.8 µM（PS33）。在测试的化合物中，PS18、PS19、PS33、PS40 和 PS41 表现出最高的治疗指数。这些化合物的摩尔浓度较低，可抑制癌细胞的生长，而不抑制健康细胞。化合物 PS18、PS19 和 PS33 同时对 COX-1 或 COX-2 表现出统计学意义上的抑制作用。这为这些化合物在癌症的化学预防中的应用提供了可能性。
