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(Reference retrieved automatically from Web of Science through information on FAPESP grant and its corresponding number as mentioned in the publication by the authors.)

Synthesis and pharmacological evaluation of pomalidomide derivatives useful for sickle cell disease treatment

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Author(s):
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Ferreira de Melo, Thais Regina [1] ; Dulmovits, Brian M. [2, 3] ; dos Santos Fernandes, Guilherme Felipe [1] ; de Souza, Cristiane M. [4] ; Lanaro, Carolina [4] ; He, Minghzu [2, 3] ; Al Abed, Yousef [2, 3] ; Chung, Man Chin [1] ; Blanc, Lionel [2] ; Costa, Fernando Ferreira [4] ; dos Santos, Jean Leandro [1]
Total Authors: 11
Affiliation:
[1] Sao Paulo State Univ, Sch Pharmaceut Sci, UNESP, BR-14800903 Araraquara, SP - Brazil
[2] Zucker Sch Med Hofstra Northwell, Dept Mol Med & Pediat, Hempstead, NY 11549 - USA
[3] Feinstein Inst Med Res, Lab Dev Erythropoiesis, Les Nelkin Mem Pediat Oncol Lab, Manhasset, NY 11030 - USA
[4] Univ Estadual Campinas, Fac Med Sci, UNICAMP, BR-13083970 Campinas, SP - Brazil
Total Affiliations: 4
Document type: Journal article
Source: BIOORGANIC CHEMISTRY; v. 114, SEP 2021.
Web of Science Citations: 0
Abstract

Fetal hemoglobin (HbF) induction constitutes a valuable and validated approach to treat the symptoms of sickle cell disease (SCD). Here, we synthesized pomalidomide-nitric oxide (NO) donor derivatives (3a-f) and evaluated their suitability as novel HbF inducers. All compounds demonstrated different capacities of releasing NO, ranging 0.3-30.3%. Compound 3d was the most effective HbF inducer for CD34+ cells, exhibiting an effect similar to that of hydroxyurea. We investigated the mode of action of compound 3d for HbF induction by studying the in vitro alterations in the levels of transcription factors (BCL11A, IKAROS, and LRF), inhibition of histone deacetylase enzymes (HDAC-1 and HDAC-2), and measurement of cGMP levels. Additionally, compound 3d exhibited a potent anti-inflammatory effect similar to that of pomalidomide by reducing the TNF-alpha levels in human mononuclear cells treated with lipopolysaccharides up to 58.6%. Chemical hydrolysis studies revealed that compound 3d was stable at pH 7.4 up to 24 h. These results suggest that compound 3d is a novel HbF inducer prototype with the potential to treat SCD symptoms. (AU)

FAPESP's process: 16/09502-7 - Design, synthesis and antitubercular activity of new oxazolidinones useful for the treatment of multidrug-resistant tuberculosis
Grantee:Guilherme Felipe dos Santos Fernandes
Support Opportunities: Scholarships in Brazil - Doctorate
FAPESP's process: 15/19531-1 - Targeting histone deacetylase (HDAC-1 and HDAC-2) as mechanisms to induce fetal hemoglobin in sickle cell disease
Grantee:Jean Leandro dos Santos
Support Opportunities: Regular Research Grants
FAPESP's process: 13/04244-1 - Synthesis, structural characterization and NO-donor evaluation of hybrid compounds useful to treat sickle cell disease symptoms
Grantee:Thaís Regina Ferreira de Melo
Support Opportunities: Scholarships abroad - Research Internship - Master's degree
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
FAPESP's process: 14/00984-3 - Red blood cell disorders: pathophysiology and new therapeutic approaches
Grantee:Fernando Ferreira Costa
Support Opportunities: Research Projects - Thematic Grants
FAPESP's process: 14/06755-6 - Synthesis and pharmacological evaluation of new pomalidomide derivatives to treat sickle cell disease symptoms
Grantee:Thaís Regina Ferreira de Melo
Support Opportunities: Scholarships in Brazil - Doctorate