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Assessment of the In Vivo Genotoxicity of New Lead Compounds to Treat Sickle Cell Disease
Laboratório de Pesquisa e Desenvolvimento de Fármacos (Lapdesf), Departamento de Fármacos e Medicamentos, Faculdade de Ciências Farmacêuticas, Univ Estadual Paulista (UNESP), Rodovia Araraquara Jaú Km. 01, 14801-902, Araraquara, SP, Brazil
Departamento de Ciências Biológicas, Faculdade de Ciências Farmacêuticas, Univ Estadual Paulista (UNESP), Rodovia Araraquara Jaú Km. 01, 14801-902, Araraquara, SP, Brazil
Laboratório de Avaliação e Síntese de Substâncias Bioativas (LASSBio), Faculdade de Farmácia, Univ Federal do Rio de Janeiro (UFRJ), Centro de Ciências da Saúde, Cidade Universitária, Ilha do Fundão, 21.944-190–Rio de Janeiro, RJ, Brazil
* Author to whom correspondence should be addressed.
Received: 8 February 2011; in revised form: 31 March 2011 / Accepted: 2 April 2011 / Published: 6 April 2011
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.
Keywords: genotoxicity assay; micronucleus; sickle cell; phthalimide derivatives
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Dos Santos, J.L.; Longhin Bosquesi, P.; Varanda, E.A.; Moreira Lima, L.; Chung, M.C. Assessment of the In Vivo Genotoxicity of New Lead Compounds to Treat Sickle Cell Disease. Molecules 2011, 16, 2982-2989.
Dos Santos JL, Longhin Bosquesi P, Varanda EA, Moreira Lima L, Chung MC. Assessment of the In Vivo Genotoxicity of New Lead Compounds to Treat Sickle Cell Disease. Molecules. 2011; 16(4):2982-2989.
Dos Santos, Jean Leandro; Longhin Bosquesi, Priscila; Varanda, Eliana Aparecida; Moreira Lima, Lídia; Chung, Man Chin. 2011. "Assessment of the In Vivo Genotoxicity of New Lead Compounds to Treat Sickle Cell Disease." Molecules 16, no. 4: 2982-2989.