Raghav N, Garg S
Department of Chemistry, Kurukshetra University, Kurukshetra 136119, India.
Department of Chemistry, Kurukshetra University, Kurukshetra 136119, India.
Eur J Pharm Sci. 2014 Aug 18;60:55-63. doi: 10.1016/j.ejps.2014.04.006. Epub 2014 Apr 26.
Cathepsins have emerged as a potential target for anti-cancer drug development. In the present study, we have synthesized three structurally related series of flavanoids i.e., 2'-hydroxychalcones, flavanones and flavones and assayed in vitro to study their inhibitory potency against cathepsin B and H, promising drug candidate for cancer therapy. Enzyme kinetics studies were carried out in presence of these compounds after preliminary proteolytic studies on endogenous protein substrates. SAR studies suggested that open chain flavanoids were better inhibitors as compared to their cyclized analogs. The most potent inhibitors among the three series were nitro substituted compounds 1g, 2g and 3g with Ki values of ∼6.18×10(-8) M, 4.8×10(-7) M and 7.85×10(-7) M for cathepsin B and Ki values of ∼2.8×10(-7) M, 31.8×10(-6) M and 33.7×10(-6) M for cathepsin H, respectively. The relationship between chalcone, flavanones and flavone structures interpreted by docking studies on cathepsin B and H also provided useful insights.
组织蛋白酶已成为抗癌药物开发的一个潜在靶点。在本研究中，我们合成了三个结构相关的类黄酮系列，即2'-羟基查耳酮、黄烷酮和黄酮，并进行了体外测定，以研究它们对组织蛋白酶B和H的抑制效力，这两种酶是癌症治疗中有前景的候选药物。在对内源蛋白质底物进行初步蛋白水解研究后，在这些化合物存在的情况下进行了酶动力学研究。构效关系研究表明，与环化类似物相比，开链类黄酮是更好的抑制剂。这三个系列中最有效的抑制剂是硝基取代化合物1g、2g和3g，对组织蛋白酶B的Ki值分别约为6.18×10(-8) M、4.8×10(-7) M和7.85×10(-7) M，对组织蛋白酶H的Ki值分别约为2.8×10(-7) M、31.8×10(-6) M和33.7×10(-6) M。通过对组织蛋白酶B和H的对接研究解释的查耳酮、黄烷酮和黄酮结构之间的关系也提供了有用的见解。
