Design, Synthesis, and Pharmacological Evaluation of Novel Hybrid Compounds To Treat Sickle Cell Disease Symptoms

Author(s):Show less -

dos Santos, Jean Leandro ^[1] ; Lanaro, Carolina ^[2] ; Lima, Lidia Moreira ^[3] ; Gambero, Sheley ^[2] ; Franco-Penteado, Carla Fernanda ^[2] ; Aexandre-Moreira, Magna Suzana ^[4] ; Wade, Marlene ^[5] ; Yerigenahally, Shobha ^[5] ; Kutlar, Abdullah ^[6] ; Meiler, Steffen E. ^[5] ; Costa, Fernando Ferreira ^[2] ; Chung, ManChin ^[1]

Affiliation

^[1] Univ Estadual Paulista UNESP, Fac Ciencias Farmaceut, Dept Farmacos & Med, Lab Pesquisa & Desenvolvimento Farmacos Lapdesf, 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, Lab Avaliacao & Sintese Subst Bioat, BR-21944971 Rio De Janeiro - Brazil

^[4] Univ Fed Alagoas, Inst Ciencias Biol & Saude, Lab Farmacol & Imunidale LaFI, Maceio, AL - Brazil

^[5] Med Coll Georgia, Dept Anesthesiol & Perioperat Med, Augusta, GA 30912 - USA

^[6] Med Coll Georgia, Sickle Cell Ctr, Augusta, GA 30912 - USA

• Document type: Journal article
• Source: Journal of Medicinal Chemistry; v. 54, n. 16, p. 5811-5819, AUG 25 2011.
• Web of Science Citations: 27

Abstract

A novel series of thalidomide derivatives (4a-f) designed by molecular hybridization were synthesized and evaluated in vitro and in vivo for their potential use in the oral treatment of sickle cell disease symptoms. Compounds 4a-f demonstrated analgesic, anti-inflammatory, and NO-donor properties. Compounds 4c and 4d were considered promising candidate drugs and were further evaluated in transgenic sickle cell mice to determine their capacity to reduce the levels of the proinflammatory cytokine tumor necrosis factor alpha (TNF alpha). Unlike hydroxyurea, the compounds reduced the concentrations of TNF alpha to levels similar to those induced with the control dexamethasone (300 mu mol/kg). These compounds are novel lead drug candidates with multiple beneficial actions in the treatment of sickle cell disease symptoms and offer an alternative to hydroxyurea treatment. (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
• FAPESP's process: 10/12495-6 - Optimization, synthesis and pharmacological evaluation of new drug candidates to treat the symptoms of sickle cell disease
• Grantee: Jean Leandro dos Santos
• Support Opportunities: Regular Research Grants