Radiomodulatory effect of a non-electrophilic NQO1 inducer identified in a screen of new 6, 8-diiodoquinazolin-4(3H)-ones carrying a sulfonamide moiety

Aiten M Soliman,Heba M Karam,Mai H Mekkawy,Maureen Higgins,Albena T Dinkova-Kostova,Mostafa M Ghorab

doi:10.1016/j.ejmech.2020.112467

Aiten M Soliman, Heba M Karam + Show 4 more

Open Access

https://doi.org/10.1016/j.ejmech.2020.112467

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Abstract

Fifteen new quinazolinone derivatives bearing benzenesulfonamide moiety with variable acetamide tail were synthesized. The structures assigned to the products were concordant with the microanalytical and spectral data. Compounds 4–18 were screened for their ability to induce the antioxidant enzyme NAD(P)H: quinone oxidoreductase 1 (NQO1) in cells, a classical target for transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2). The 2-((6,8-diiodo-4-oxo-3-(4-sulfamoylphenyl)-3,4-dihydroquinazolin-2-yl)thio)-N-(3,4,5-trimethoxyphenyl) acetamide 15 showed the most potent NQO1 inducer activity in vitro. Compound 15 had low toxicity in mice (LD50 = 500 mg/kg). It also reduced the damaging effects of gamma radiation, as assessed by the levels of Nrf2, NQO1, reactive oxygen species (ROS) and malondialdehyde (MDA) in liver tissues. In addition, compound 15 showed amelioration in the complete blood count of irradiated mice and enhanced survival over a period of 30 days following irradiation. Molecular docking of 15 inside the Nrf2-binding site of Kelch-like ECH associated protein 1 (Keap1), the main negative regulator of Nrf2, showed the same binding interactions as that of the co-crystallized ligand considering the binding possibilities and energy scores. These findings suggest that compound 15 could be considered as a promising antioxidant and radiomodulatory agent.

Highlights

The extensive use of radiotherapy and the damage caused to the surrounding normal organs have provoked researchers to find new strategies to protect normal tissues from radiation hazards [1, 2]
Scheme 1 shows the synthesis of thioacetamide quinazolinone benzenesulfonamide derivatives 5-18
The present results indicate that compound 15 has an antioxidant capacity as the treatment of irradiated mice with 15 prevents oxidative stress, reducing the increase in lipid peroxidation markers and maintaining the expression of nuclear factor erythroid 2related factor 2 (Nrf2) compared with the irradiated group suggesting improved hepatic antioxidant capacity

Summary

Introduction

The extensive use of radiotherapy and the damage caused to the surrounding normal organs have provoked researchers to find new strategies to protect normal tissues from radiation hazards [1, 2]. Excessive production of ROS and RNS promotes oxidative stress, which can affect all cellular components, including single or double DNA strand breaks [6]. This ROS-mediated toxicity can lead to mutations and cause cardiovascular, neurological toxicities and sexual dysfunction as well as cancer [7,8,9,10]. The use of multitarget antioxidants that act as radioprotectors can help limit normal tissue damage caused by ionizing radiation [12,13,14]

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