K P Safna Hussan, Babu Thekkekara D, C M Pareeth, Joshy Greena, Mathew Deepu, Thayyil M Shahin
Department of Biochemistry, Amala Cancer Research Center, Amala Nagar, Thrissur, India.
College of Horticulture, Center for Plant Biotechnology and Molecular Biology, Kerala Agriculture University, Thrissur, India.
Free Radic Res. 2022 Feb;56(2):196-208. doi: 10.1080/10715762.2022.2065990. Epub 2022 May 5.
Erlotinib and gefitinib are quinazoline derivatives with antineoplastic properties. Usually, intake of antineoplastic agents results in much a greater degree of oxidative stress, i.e. the production of free radicals, than induced by cancer itself. Hence, anticancerous drugs must also exhibit antioxidant activity but this has not been studied thus far. In this study, the antioxidant activity of erlotinib and gefitinib was examined by experimental and computational studies. It was found that erlotinib and gefitinib exhibit good 2,2-dipheny l-1-picrylhydrazyl (DPPH) radical and hydroxyl radical scavenging (HRS) activities. In DPPH assay, the IC for erlotinib and gefitinib were 0.584 and 0.696 mM, respectively, while IC for HRS assay were 0.843 and 1.03 mM for erlotinib and gefitinib, respectively. Structural characteristics such as frontier molecular orbitals (FMOs), molecular electrostatic potential maps (MESPs), and global descriptive parameters were calculated at DFT/B3LYP/6-311++G (d,p) on the optimized geometries of erlotinib and gefitinib. UV-visible spectroscopy revealed the possible electronic transitions between the FMOs and their associated excitation energies of both drugs and found that erlotinib has π to π* transitions while gefitinib has π to π* and σ to π* transitions. To elucidate the antioxidant activity of erlotinib and gefitinib, three mechanisms namely hydrogen atom transfer (HAT), single electron transfer proton transfer (SETPT), and sequential proton-loss electron-transfer (SPLET) were employed and articulated the results in arithmetic parameters like bond dissociation energy (BDE), proton affinity (PA), ionization potential (IP), electron transfer enthalpy (ETE), and proton dissociation enthalpy (PDE). Further, molecular docking studies have been carried out to have a better understanding of binding sites and modes of interaction with a well-known antioxidant target protein monoamine oxidase-B (MAO-B) employing docking scores and types of interactions. All the calculated parameters point out that though gefitinib and erlotinib were interchangeable, erlotinib requires a lesser amount of energy for proton transfer and electron transfer, moreover it scavenges radicals easily.
厄洛替尼和吉非替尼是具有抗肿瘤特性的喹唑啉衍生物。通常，与癌症本身所诱导的相比，摄入抗肿瘤药物会导致更大程度的氧化应激，即自由基的产生。因此，抗癌药物也必须表现出抗氧化活性，但迄今为止尚未对此进行研究。在本研究中，通过实验和计算研究考察了厄洛替尼和吉非替尼的抗氧化活性。发现厄洛替尼和吉非替尼表现出良好的2,2 - 二苯基 - 1 - 苦基肼（DPPH）自由基清除和羟基自由基清除（HRS）活性。在DPPH测定中，厄洛替尼和吉非替尼的IC50分别为0.584和0.696 mM，而在HRS测定中，厄洛替尼和吉非替尼的IC50分别为0.843和1.03 mM。在厄洛替尼和吉非替尼的优化几何结构上，采用DFT/B3LYP/6 - 311++G(d,p)计算了诸如前沿分子轨道（FMO）、分子静电势图（MESP）和全局描述参数等结构特征。紫外 - 可见光谱揭示了两种药物的FMO之间可能的电子跃迁及其相关的激发能，发现厄洛替尼有π到π跃迁，而吉非替尼有π到π和σ到π*跃迁。为了阐明厄洛替尼和吉非替尼的抗氧化活性，采用了氢原子转移（HAT）、单电子转移质子转移（SETPT）和顺序质子损失电子转移（SPLET）三种机制，并以诸如键解离能（BDE）、质子亲和力（PA）、电离势（IP）、电子转移焓（ETE）和质子解离焓（PDE）等算术参数来阐述结果。此外，进行了分子对接研究，以更好地了解与著名的抗氧化靶蛋白单胺氧化酶 - B（MAO - B）的结合位点和相互作用模式，采用对接分数和相互作用类型。所有计算参数都指出，尽管吉非替尼和厄洛替尼可相互替代，但厄洛替尼在质子转移和电子转移方面所需能量较少，而且它更容易清除自由基。
