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/μmol. These results allowed us to propose that a methyl spacer linked to a nitrate ester subunit associated to meta aromatic substitution decreases mutagenicity.
Highlights
Sickle cell disease is a hematological genetic disease that results from a single point mutation of βGlu6 in Hb to βVal6 in HbS
HbF concentration decreases after birth but there is an association between increasing this kind of hemoglobin with reduction of painful episodes in patients with sickle cell disease [3]
1.1 revertants/μmol in the presence and absence of metabolic activation for TA100, respectively. These results indicate that HU has a mutagenic potential at high concentrations above 234 μmol/plate using TA100 e TA102 Salmonella strain, a previous study had showed the absence of mutagenicity of HU tested up 0.5 mg per plate in TA100, TA98 and TA1537 [11]
Summary
Sickle cell disease is a hematological genetic disease that results from a single point mutation of βGlu in Hb to βVal in HbS. In the deoxygenated state there is an interaction between the mutation region of one HbS molecule and a region defined by βPhe and βLeu in the heme pocket of another HbS. This interaction leads to polymerization that causes the normally flexible red blood cells (RBC) to adopt rigid, sickle like shapes that block small capillaries initiating the vaso-oclusive process, and causing local tissue damage and severe pain [1,2]. HbF concentration decreases after birth but there is an association between increasing this kind of hemoglobin with reduction of painful episodes in patients with sickle cell disease [3]. HU is known as a ribonucleotide reductase inhibitor and as an antineoplasic drug that provokes DNA alterations (genotoxic activity), inducing gene and chromosome mutations [4,5]
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