RESUMEN
Phthalimide derivatives containing furoxanyl subunits as nitric oxide (NO)-donors (3a-g) were designed, synthesized, and evaluated in vitro and in vivo for their potential uses in the oral treatment of sickle cell disease symptoms. All compounds (3a-g) demonstrated NO-donor properties at different levels. Moreover, compounds 3b and 3c demonstrated analgesic activity. Compound 3b was determined to be a promising drug candidate for the aforementioned uses, and it was further evaluated in K562 culture cells to determine its ability to increase levels of γ-globin expression. After 96 h at 5 µM, compound 3b was able to induce γ-globin expression by nearly three times. Mutagenic studies using micronucleus tests in peripheral blood cells of mice demonstrated that compound 3b reduces the mutagenic profile as compared with hydroxyurea. Compound 3b has emerged as a new leading drug candidate with multiple beneficial effects for the treatment of sickle cell disease symptoms and provides an alternative to hydroxyurea treatment.
Asunto(s)
Anemia de Células Falciformes/tratamiento farmacológico , Oxadiazoles/química , Oxadiazoles/farmacología , Diseño de Fármacos , Evaluación Preclínica de Medicamentos , Humanos , Donantes de Óxido Nítrico/síntesis química , Donantes de Óxido Nítrico/química , Donantes de Óxido Nítrico/farmacología , Donantes de Óxido Nítrico/uso terapéutico , Oxadiazoles/síntesis química , Oxadiazoles/uso terapéutico , Reacción en Cadena de la PolimerasaRESUMEN
Sickle cell disease (SCD) is one of the most prevalent hematological diseases in the world. Despite the immense progress in molecular knowledge about SCD in last years few therapeutical sources are currently available. Nowadays the treatment is performed mainly with drugs such as hydroxyurea or other fetal hemoglobin inducers and chelating agents. This review summarizes current knowledge about the treatment and the advancements in drug design in order to discover more effective and safe drugs. Patient monitoring methods in SCD are also discussed.