Antioxidant activity of erlotinib and gefitinib: theoretical and experimental insights

Abstract

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 IC₅₀ for erlotinib and gefitinib were 0.584 and 0.696 mM, respectively, while IC₅₀ 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.

Keywords:

• Erlotinib and gefitinib
• DFT study
• antioxidant mechanism
• hydrogen atom transfer (HAT)
• single electron transfer–proton transfer (SET–PT)
• sequential proton-loss electron-transfer
• molecular docking study
• frontier molecular orbitals

Acknowledgments

The authors thankfully acknowledge fruitful discussions with Dr. Achuthan C Raghavan, Department of Biochemistry, Amala Cancer Research Center. The authors thankfully acknowledge the Central Sophisticated Instrument Facility (CSIF) of the University of Calicut for providing Schrodinger Maestro software and hardware support. KPSH acknowledges the Council of Scientific & Industrial Research (CSIR) for the RA fellowship with file no: 09/0869/(1169)/EMR-1-2021 in Amala Cancer Research Center.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Additional information

Funding

This work was supported by Council of Scientific and Industrial Research.