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Synthesis and anti-inflammatory evaluation of steroid derivatives of the Lapdesf GL-FT series

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Author(s):
Marcella Gabrielle Mendes Machado
Total Authors: 1
Document type: Doctoral Thesis
Press: Araraquara. 2017-03-20.
Institution: Universidade Estadual Paulista (Unesp). Faculdade de Ciências Farmacêuticas. Araraquara
Defense date:
Advisor: Chung Man Chin
Abstract

Glucocorticoids (GCs) are drugs widely used in therapy due their anti-inflammatory, immunosuppressive and antiangiogenic activities. They have the ability to reduce the transcription of a series of inflammatory enzymes / proteins such as cyclooxygenase-2 (COX-2), lipoxygenases, phospholipase A2, induced nitric oxide synthase (iNOS) and proinflammatory cytokines such as tumor necrosis factor alpha (TNF-alpha), over expressed in several inflammatory diseases. However, its use is limited due to the various adverse reactions. Phthalimide derivatives have also been reported in the literature with important anti-inflammatory activity. Thus, in the present work, new steroid anti-inflammatory derivatives as TNF-alpha cytokine modulators, useful in the treatment of chronic inflammatory diseases, have been designed through the molecular hybridization strategy. In this context, six compounds prednisolone and budesonide derivatives, Lapdesf GL-FT series, were synthesized and characterized. The final compounds were evaluated for anti-inflammatory activity in a model of distal ulcerative colitis, immunosuppressive activity and cell viability assay required for the TNF-alpha assay. In addition, GLFT 2 and 3 compounds were evaluated for anti-inflammatory activity in paw edema model. In the ulcerative colitis test, Lapdesf GL-FT 5 and 6 compounds were statistically equal to the negative control and showed anti-inflammatory activity with regression of the ulceration caused by the induction with acetic acid. Compound 5 also showed improvement in clinical signs such as weight gain and increased survival of animals and total regression of ulceration in 83.3% of treated animals. GLFT 1 and 3 compounds were statistically different from the positive and negative control groups. They presented anti-inflammatory activity with total regression of ulceration in 33.3% of the animals in each group, being superior to the standard drug, prednisolone, which obtained 16.7% of total ulceration regression. Cell viability for all Lapdesf GL-FT compounds at the concentrations of 50, 25, 12.5, 6.25, 3.125 and 1.65 μM was higher than 70% indicating low cytotoxicity. However, GL-FT 2 and 3 compounds showed unexpected cell viability, reaching values of 300 and 400%, respectively, at the concentrations evaluated. Lapdesf GL-FT 1-6 did not present immunosuppressive activity in the in vitro assay. Lapdesf GL-FT 2 and 3 compounds showed anti-inflammatory activity in the paw edema test, and there was no statistical difference with the standard drug, prednisolone. (AU)

FAPESP's process: 14/08728-6 - Design and synthesis of new anti-inflammatory steroids of Lapdesf FT-GL and GL-TAU series with potential anti-VEGF activity
Grantee:Marcella Gabrielle Mendes Machado
Support Opportunities: Scholarships in Brazil - Doctorate