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

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• 作者：Jean Leandro Dos Santos ; Carolina Lanaro ; Rafael Consolin Chelucci ; Sheley Gambero ; Priscila Longhin Bosquesi ; Juliana Santana Reis ; L铆dia Moreira Lima ; Hugo Cerecetto ; Mercedes Gonz谩lez ; Fernando Ferreira Costa ; Man Chin Chung
• 刊名：Journal of Medicinal Chemistry
• 出版年：2012
• 出版时间：September 13, 2012
• 年：2012
• 卷：55
• 期：17
• 页码：7583-7592
• 全文大小：459K
• 年卷期：v.55,no.17(September 13, 2012)
• ISSN：1520-4804

文摘

Phthalimide derivatives containing furoxanyl subunits as nitric oxide (NO)-donors (3a鈥?b>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鈥?b>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 纬-globin expression. After 96 h at 5 渭M, compound 3b was able to induce 纬-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.