Katsori A-M, Chatzopoulou M, Dimas K, Kontogiorgis C, Patsilinakos A, Trangas T, Hadjipavlou-Litina D
Department of Pharmaceutical Chemistry, School of Pharmacy, Aristotle University of Thessaloniki, Thessaloniki 54124, Greece.
Eur J Med Chem. 2011 Jul;46(7):2722-35. doi: 10.1016/j.ejmech.2011.03.060. Epub 2011 Apr 5.
A series of novel curcumin analogues has been designed, synthesized and tested in vitro/in vivo as potential multi-target agents. Their anti-proliferative and anti-inflammatory activities were studied. Compounds 1b and 2b were stronger inhibitors of soybean lipoxygenase (LOX) than curcumin. Analogue 1b was also the most potent aldose reductase (ALR2) inhibitor. Two compounds, (1a and 1f) exhibited in vivo anti-inflammatory activity comparable to that of indomethacin, whereas derivative 1i exhibited even higher activity. The derivatives were also tested for their anti-proliferative activity using three different human cancer cell lines. Compounds 1a, 1b, 1d and 2b exhibited significant growth inhibitory activity as compared to curcumin, against all three cancer cell lines. Lipophilicity was determined as R(M) values using RPTLC and theoretically. The results are discussed in terms of the structural characteristics of the compounds. Docking simulations were performed on LOX and ALR2 inhibitor 1b and curcumin. Compound 1b is well fitted in the active site of ALR2, binding to the ALR2 enzyme in a similar way to curcumin. Allosteric interactions may govern the LOX-inhibitor binding.
设计、合成了一系列新型姜黄素类似物，并在体外/体内作为潜在的多靶点药物进行了测试。研究了它们的抗增殖和抗炎活性。化合物1b和2b对大豆脂氧合酶（LOX）的抑制作用比姜黄素更强。类似物1b也是最有效的醛糖还原酶（ALR2）抑制剂。两种化合物（1a和1f）表现出与吲哚美辛相当的体内抗炎活性，而衍生物1i表现出更高的活性。还使用三种不同的人类癌细胞系测试了这些衍生物的抗增殖活性。与姜黄素相比，化合物1a、1b、1d和2b对所有三种癌细胞系均表现出显著的生长抑制活性。通过反相薄层色谱法（RPTLC）并从理论上测定了亲脂性，以R（M）值表示。根据化合物的结构特征对结果进行了讨论。对LOX和ALR2抑制剂1b以及姜黄素进行了对接模拟。化合物1b很好地拟合在ALR2的活性位点，以与姜黄素相似的方式与ALR2酶结合。变构相互作用可能决定了LOX与抑制剂的结合。
