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.
Highlights
Sickle cell disease (SCD), one of the most prevalent haematological diseases in the World, is an autosomal recessive disorder characterized by a point mutation (GTG to GAG) in the sixth codon of the β-globin gene, which leads to the substitution of a glutamic acid for a valine residue in the β-globin chain
Our results show that HU exhibited genotoxic potential in mammalian cells at all the concentrations tested
Is essential to combine both types of experiments to characterize the genotoxicity of compounds. These mutagenicity and genotoxicity evaluations of compounds C1–C6 allow us to characterize them as candidate drugs that are safer than HU in the treatment of SCD symptoms
Summary
Sickle cell disease (SCD), one of the most prevalent haematological diseases in the World, is an autosomal recessive disorder characterized by a point mutation (GTG to GAG) in the sixth codon of the β-globin gene, which leads to the substitution of a glutamic acid for a valine residue in the β-globin chain. This substitution has profound consequences for the structure of haemoglobin (Hb). Hydroxyurea (HU) is the main drug available for the treatment of sickle cell anaemia that is authorized by the U.S Food and Drug Administration. The beneficial effects of HU in the treatment of SCD are associated, in part, with its ability to be bioconvert in vivo to nitric oxide (NO)
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