Síntese de derivados glicosídicos de produtos naturais bioativos como candidatos a novos fármacos

• Ano de defesa: 2018
• Autor(a) principal: Flaviano Melo Ottoni
• Tipo de documento: Tese
• Tipo de acesso: Acesso aberto
• Idioma: por
• Instituição de defesa: Universidade Federal de Minas Gerais; Brasil; FARMACIA - FACULDADE DE FARMACIA; Programa de Pós-Graduação em Ciências Farmacêuticas; UFMG
• Palavras-chave em Português: Lausona; Digitoxigenina; Glicolsiltriazóis; Triazóis O-glicosídicos; Citotoxicidade; Antitumoral; Anti-herpética
• Link de acesso: http://hdl.handle.net/1843/33808; https://orcid.org/0000-0003-4307-4336

We describe herein the synhtesis and evaluation of glycoside derivatives of lawsone (1) and digitoxigenin (2), natural compounds that show mainly antimicrobial and antitumoral activity. The aim was to obtain glycosides with potent activity, more selectives and with lower toxicity. For lawsone two serie of derivatives were obtained, classical glycosides, by a method of glycosylation in alkaline medium using phase-transfer catalyst, and glycosyl triazoles via “click” chemistry. The saccharidic moieties were D-glucose, D-galactose, D-N-acetylglucosamine or L-fucose. Both α and β anomers were obtained from each carbohydrate for classical glycosides of lawsone. In regard to digitoxigenin (2) the compounds correspond to O-glycosyl triazoles derived from D-glucose, D-galactose, D-mannose, D-cellobiose, N-phthaloyl-D-glucosamine, L-rhamnose and L-fucose. The glycosides of lawsone were assayed against three breast cancer cell lines (SKBR-3, MCF-7 and MDA-231). In general, the α-glycosides were more active than β anomers, whose α-glycoside from peracetylated D-glucose (44) showed IC50 = 2.11 µM against SKBR-3. However, the glycosyl triazole from peracetylated D-glucose 11 showed IC50 = 0.78 µM against the same tumor cell line. We also evaluated the leishmanicidal potential of glycosides of lawsone against promastigote forms of L. infantum e L. amazonensis, wherein the β-fucoside showed IC50 = 1.64 µM against both species and higher selectivity index (SI) against murine macrophages (SI>25). The glycosides of digitoxigenin were evaluated for antiherpetic activity against different lineages of herpes virus 1 (HSV-1-KOS e HSV-29-R) and against the lineage HSV-2-333 of herpe virus 2. The deacetylated O-glycosyl triazole derived from deacetylated D-mannose (38) presented a higher antiherpetic activity against HSV-1-29-R (acyclovir resistant) and HSV-2-333 with IC50 = 0.37 µM and SI>800 for both lineages. The O-glycosyl triazoles of digitoxigenin were also evaluated against five cancer cell lines (A549, H460, LNCAp, PC3 e HCT-8) with relevant results for compound 38, which showed IC50 = 0.24 µM against H460 and IC50 = 0.58 µM against A549 and PC3. From results we concluded that the glycosides synthesized are promising, because several presented higher activity than the aglycone, indicating that saccharidic moiety improves the biological activity. Moreover, some compounds showed low cytotoxicity against non-tumoral or uninfected cells, suggesting increase of selectivity of action.