Assessment of the in vivo genotoxicity of new lead compounds to treat sickle cell disease

Abstract

The compounds 1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl nitrate (C1), (1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl nitrate (C2), 3-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)benzyl nitrate (C3), 4-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-N-hydroxy-benzenesulfonamide (C4), 4-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)benzyl nitrate (C5), and 2-[4-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)phenyl]ethyl nitrate (C6) were evaluated with a micronucleus test using mouse peripheral blood to identify new candidate drugs for the treatment of sickle cell disease (SCD) that are safer than hydroxyurea. The compounds induced an average frequency of micronucleated reticulocytes (MNRET) of less than six per 1,000 cells at 12.5, 25, 50, and 100 mg/kg, whereas hydroxyurea induced an average MNRET frequency of 7.8, 9.8, 15, and 33.7 per 1000 cells respectively, at the same concentrations. Compounds C1-C6 are new non-genotoxic in vivo candidate drugs for the treatment of SCD symptoms.

Figure 1

Chemical structures of compounds C1-C6.

Figure 2

Average frequency of micronucleated reticulocytes (MNRET) and standard deviation of 1,000 cells from mice treated with the drug hydroxyurea (HU) and all the synthesized compounds C1-C6 at different concentrations. *P < 0.05.

Figure 3

Average frequency of micronucleated reticulocytes (MNRET) and standard deviation of 1000 cells from mice treated with the positive control cyclophosphamide (100 mg/Kg), CMC / Tween (negative control) and water (control white). * P < 0.05.