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Synthesis and pharmacological evaluation of pomalidomide derivatives for the treatment of sickle cell anemia

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Author(s):
Thais Regina Ferreira de Melo
Total Authors: 1
Document type: Doctoral Thesis
Press: Araraquara. 2018-02-26.
Institution: Universidade Estadual Paulista (Unesp). Faculdade de Ciências Farmacêuticas. Araraquara
Defense date:
Advisor: Jean Leandro dos Santos
Abstract

Sickle cell anemia (SCA) is a inherited hemolitical anemia characterized by a mutation in the β-globin gene. In addition to the vaso-occlusive condition, there is a chronic inflammatory process in the patients characterized by the increase of several pro-inflammatory cytokines, such as TNF-α. Currently, hydroxyurea (HU) is the only drug available for treatment and its beneficial effects are associated with nitric oxide (NO), generated after biotransformation. NO has beneficial effects on the disease such as vasodilatation, inhibition of platelet aggregation and fetal hemoglobin (HbF) production. In this context, the compounds 3 (a-b), 4(a-b) and 5(a-b) were synthesized using molecular hybridization approach of the pomalidomide TNF-α inhibitor subunit with the furoxan ring (1,2,5-oxadiazol-2-N-oxide) as NO donor. Compounds were synthesized in yields ranging from 13 to 30%. The compounds demonstrated ability to release NO at levels ranging from 1 to 30%. In CD34+ cellular cultures, compound 4b at 2.5 μM concentration was able to induce γ-globin, while HU was active only at 4-fold higher concentrations (10 μM). Preliminary studies of the mechanism of action have shown that compound 4b does not interfere with transcription factors such as BCL11A, IKAROS, LRF and histone H3 acetylation levels. Our results indicate that, the mechanism of action of this compound differs from the parental drug pomalidomide. Compound 4b also increased cGMP levels in HUVEC and CD34 + cells. For CD34 + cells, cGMP levels were comparable to that of HU. These results sugest that compound 4b is a promising lead candidate for the development of drug candidates for treatment of SCA. (AU)

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