Mutagenicity of New Lead Compounds to Treat Sickle Cell Disease Symptoms in a Salmonella/Microsome Assay

Author(s)

dos Santos, Jean Leandro ^[1] ; Varanda, Eliana A. ^[2] ; Lima, Lidia Moreira ^[3] ; Chin, Chung Man ^[1]

Affiliation

^[1] UNESP, Fac Ciencias Farmaceut, Dept Farmacos & Medicamentos, Lapdesf, BR-14801902 Araraquara, SP - Brazil

^[2] UNESP, Fac Ciencias Farmaceut, Dept Ciencias Biol, BR-14801902 Araraquara, SP - Brazil

^[3] UFRJ, Fac Farm, LASSBio, Ctr Ciencias Saude, BR-21944190 Rio De Janeiro - Brazil

• Document type: Journal article
• Source: INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES; v. 11, n. 2, p. 779-788, FEB 2010.
• Web of Science Citations: 8

Abstract

A series of phthalimide derivatives planned as drugs candidates to treat the symptoms of sickle cell anemia were evaluated in a mutagenicity test using strains of Salmonella typhimurium TA100 and TA102, without and with addition of S9 mixture, with the aim to identify the best structural requirements for a drug candidate without genotoxic activity. The compounds (1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl nitrate (1); (1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl nitrate (2); 3-(1,3-dioxo-1,3-dihydro-2H-iso-indol-2-yl)benzyl nitrate (3); 4-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-N-hydroxy-benzenesulfonamide (4); 4-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl) benzyl nitrate (5) and 2-{[}4-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)phenyl]ethyl nitrate (6) presented mutagenic potency ranging between 0-4,803 revertants/mu mol. These results allowed us to propose that a methyl spacer linked to a nitrate ester subunit associated to meta aromatic substitution decreases mutagenicity. (AU)

• FAPESP's process: 07/56115-0 - Optimization, synthesis and pharmacological evaluation of dual hybrid compounds useful to treat the symptoms of sickle cell disease
• Grantee: Jean Leandro dos Santos
• Support Opportunities: Scholarships in Brazil - Doctorate