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Doctoral Thesis
DOI
https://doi.org/10.11606/T.60.2022.tde-21062022-105657
Document
Author
Full name
Debora Munhoz Rodrigues
E-mail
Institute/School/College
Knowledge Area
Date of Defense
Published
Ribeirão Preto, 2022
Supervisor
Committee
Campo, Vanessa Leiria (President)
Crotti, Antonio Eduardo Miller
Forim, Moacir Rossi
Sairre, Mirela Ines de
Title in Portuguese
Obtenção de derivados semissintéticos de artepelin C e bacarina oriundos da própolis verde e avaliação de suas atividades biológicas
Keywords in Portuguese
Derivados prenilados
Efeitos antitumorais
Própolis verde
Semissíntese de produtos naturais
Abstract in Portuguese
Baccharis dracunculifolia, planta nativa brasileira conhecida popularmente como "alecrim do campo", é a principal fonte botânica para a produção de própolis verde, a qual possui composição química complexa, rica em derivados prenilados do ácido-p-cumárico, como a drupanina, o artepillin C e a bacarina. Importantes atividades biológicas têm sido atribuídas a estes derivados, despertando, portanto, tanto o interesse nacional quanto internacional. Assim, com objetivo de aumentar as possibilidades no desenvolvimento de novos fármacos de origem natural, propôs-se a obtenção de derivados semissintéticos da drupanina, artepelin C e da bacarina, visando potencializar as atividades biológicas relatadas para estes compostos, com destaque para as seguintes atividades: antiproliferativa, inibidora da enzima AKR1C3, antimicrobiana e antiparasitária Os compostos fenólicos prenilados da própolis verde foram obtidos a partir de extratos hidroalcóolicos, utilizando-se cromatografia em coluna aberta (CLV) e cromatografia de contracorrente de alta velocidade (HSCCC). Posteriormente, foram obtidos derivados semissintéticos multivalentes da drupanina, artepelin C e bacarina, assim como derivados amídicos, via acoplamento com cinco aminoácidos diferentes. Foram obtidos ao todo vinte oito estruturas químicas derivadas dos produtos naturais, as quais foram purificadas e elucidadas por análises de Ressonância Magnética Nuclear de 1H e 13C, bem como de Espectrometria de Massas (ESI-MS). Os testes antitumorais indicaram que os compostos derivados de aminoácidos (4, 14, 16, 17, 18, 24 e 26) foram considerados os derivados mais promissores com atividade antiproliferativa contra a linhagem tumoral de mama hormônio dependente MCF-7. O derivado da drupanina 18 forneceu a melhor concentração inibitória em linhagens de carcinoma (IC50= 9,6 ± 3,2 µM) e índice de seletividade de 5,5 nos ensaios com MCF-7, indicando baixa toxicidade e alta seletividade. Além disso, as simulações de docking revelaram que o composto 18 apresentou interações de docking coerentes, bem como fortes interações dentro do sitio ativo da AKR1C3.
Title in English
Development and biological evaluation of artepillin C and baccharin semisynthetic derivatives from Brazilian green propolis
Keywords in English
Antitumor activities
Green propolis
Prenylated derivatives
Semisynthesis from natural products
Abstract in English
Baccharis dracunculifolia, a Brazilian native plant popularly known as "alecrim do campo", is the primary botanical source in green propolis production, which has a complex chemical composition rich in prenylated p-coumaric acid derivatives, such as drupanin, artepillin C, and baccharin. Twenty-eight chemical structures derived from natural products were obtained, purified and elucidated by Nuclear Magnetic Resonance analyses (1H e 13C NMR) as well as Mass Spectrometry (ESI-MS). Important biological activities have been attributed to these derivatives, arousing national and international interest. It was obtained semisynthetic derivatives of drupanin, artepillin C, and baccharin, aiming to potentiate the biological activities reported for these compounds, mainly antiproliferative, AKR1C3 enzyme inhibitor, antimicrobial and antiparasitic. Prenylated phenolic compounds of green propolis were obtained from propolis hydroalcoholic extract using open-column chromatography and high-speed countercurrent chromatography (HSCCC), as well as high-performance preparative liquid chromatography (HPLC-DAD). Subsequently, multivalent semisynthetic derivatives of artepillin C, baccharin, and amide derivatives were synthesized via coupling with five different amino acids. The antiproliferative assays showed that the amino acid derivatives (4, 14, 16, 17, 18, 24, and 26) were the most promising compounds against the hormone-dependent breast tumor cell lines, MCF7. The drupanin derivative 18 was the most active compound with the best halfmaximal inhibitory concentration (IC50= 9.6 ± 3.2 µM) and selectivity index (5.5) against MCF-7 cells, indicating low toxicity and high selectivity. Furthermore, docking simulations revealed that compound 18 showed coherent docking interactions and strong interactions within the active site of AKR1C3.
 
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Release Date
2024-04-08
Publishing Date
2022-06-22
 
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