Design, Synthesis, and Pharmacological Evaluation of Novel Hybrid Compounds to Treat Sickle Cell Disease Symptoms. Part II: Furoxan Derivatives

Autor(es):Mostrar menos -

Dos Santos, Jean Leandro ^[1] ; Lanaro, Carolina ^[2] ; Chelucci, Rafael Consolin ^[1] ; Gambero, Sheley ^[2] ; Bosquesi, Priscila Longhin ^[1] ; Reis, Juliana Santana ^[1] ; Lima, Lidia Moreira ^[3] ; Cerecetto, Hugo ^[4] ; Gonzalez, Mercedes ^[4] ; Costa, Fernando Ferreira ^[2] ; Chung, Man Chin ^[1]

Afiliação do(s) autor(es)

^[1] Univ Estadual Paulista UNESP, Lapdesf Lab Pesquisa & Desenvolvimento Farmacos, Dept Farmacos & Medicamentos, Fac Ciencias Farmaceut, BR-14801902 Araraquara, SP - Brazil

^[2] Univ Campinas UNICAMP, Haematol & Haemotherapy Ctr, Hemoctr, BR-13083970 Campinas, SP - Brazil

^[3] Univ Fed Rio de Janeiro, Fac Farm, LASSBio Lab Avaliacao & Sintese Subst Bioat, BR-21944971 Rio De Janeiro, RJ - Brazil

^[4] Univ Republica, Fac Ciencias, Fac Quim, Grp Quim Med, Lab Quim Organ, Montevideo 11400 - Uruguay

• Tipo de documento: Artigo Científico
• Fonte: Journal of Medicinal Chemistry; v. 55, n. 17, p. 7583-7592, SEP 13 2012.
• Citações Web of Science: 34

Resumo

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 gamma-globin expression. After 96 h at 5 mu M, compound 3b was able to induce gamma-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. (AU)

• Processo FAPESP: 07/56115-0 - Otimização, síntese e avaliação farmacológica de compostos híbridos duais úteis para o tratamento dos sintomas da anemia falciforme
• Beneficiário: Jean Leandro dos Santos
• Modalidade de apoio: Bolsas no Brasil - Doutorado
• Processo FAPESP: 10/12495-6 - Otimização, síntese e avaliação farmacológica de novos candidatos a fármacos para tratamento dos sintomas da anemia falciforme
• Beneficiário: Jean Leandro dos Santos
• Modalidade de apoio: Auxílio à Pesquisa - Regular