title: Design, synthesis, and pharmacological evaluation of novel hybrid compounds to treat sickle cell disease symptoms.
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 α (TNFα). Unlike hydroxyurea, the compounds reduced the concentrations of TNFα to levels similar to those induced with the control dexamethasone (300 μmol/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.
authors.affiliation: Laboratório de Pesquisa e Desenvolvimento de Fármacos (Lapdesf), Departamento de Fármacos e Medicamentos, Faculdade de Ciências Farmacêuticas, Universidade Estadual Paulista (UNESP), Rodovia Araraquara Jaú Km. 01, 14801-902, Araraquara, SP, Brazil. santosjl@fcfar.unesp.br
authors.forename: Jean Leandro
authors.initials: JL
authors.lastname: dos Santos
authors.forename: Carolina
authors.initials: C
authors.lastname: Lanaro
authors.forename: Lídia Moreira
authors.initials: LM
authors.lastname: Lima
authors.forename: Sheley
authors.initials: S
authors.lastname: Gambero
authors.forename: Carla Fernanda
authors.initials: CF
authors.lastname: Franco-Penteado
authors.forename: Magna Suzana
authors.initials: MS
authors.lastname: Alexandre-Moreira
authors.forename: Marlene
authors.initials: M
authors.lastname: Wade
authors.forename: Shobha
authors.initials: S
authors.lastname: Yerigenahally
authors.forename: Abdullah
authors.initials: A
authors.lastname: Kutlar
authors.forename: Steffen E
authors.initials: SE
authors.lastname: Meiler
authors.forename: Fernando Ferreira
authors.initials: FF
authors.lastname: Costa
authors.forename: ManChin
authors.initials: M
authors.lastname: Chung
mesh_terms: D019342:Acetic Acid; D000700:Analgesics / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000755:Anemia, Sickle Cell / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000986:Antisickling Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D002211:Capsaicin; D003085:Colic / Q000139:chemically induced / Q000378:metabolism / Q000517:prevention & control; D015195:Drug Design; D004423:Ear / Q000473:pathology; D004487:Edema / Q000139:chemically induced / Q000378:metabolism / Q000517:prevention & control; D005260:Female; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008956:Models, Chemical; D015394:Molecular Structure; D010538:Peritonitis / Q000139:chemically induced / Q000378:metabolism / Q000517:prevention & control; D013792:Thalidomide / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D013864:Thioglycolates; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D000700:Analgesics; D000893:Anti-Inflammatory Agents; D000986:Antisickling Agents; D013864:Thioglycolates; D014409:Tumor Necrosis Factor-alpha; D013792:Thalidomide; D019342:Acetic Acid; D002211:Capsaicin