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Bioactive terpenoids from Euphorbia pubescens: isolation and derivatization
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Abstract(s)
As espécies do género Euphorbia têm sido utilizadas na medicina tradicional, desde a Antiguidade, para o tratamento de verrugas, tumores, cancros e infeções intestinais, entre outras patologias.
Nas últimas décadas, o estudo fitoquímico destas espécies tem merecido uma especial atenção, devido ao isolamento de um enorme número de compostos biologicamente ativos, dos quais se destacam os diterpenos policíclicos e macrocíclicos, com esqueletos do tipo jatrofano e latirano, triterpenos tetracíclicos e pentacíclicos e esteroides. Das diversas atividades biológicas demonstradas por estes compostos, são de salientar os resultados obtidos com os diterpenos macrocíclicos, que revelaram uma importante atividade moduladora da glicoproteína-P, uma das principais proteínas transmembranares envolvidas na multirresistência das células tumorais aos fármacos anti-neoplásicos.
Esta dissertação teve como principal objetivo a pesquisa de novos compostos bioativos a partir de Euphorbia pubescens. Para tal, foram utilizadas duas abordagens: i) o isolamento de compostos a partir três frações do extrato metanólico; ii) derivatização molecular de compostos isolados em maior quantidade. O estudo fitoquímico foi realizado recorrendo a técnicas cromatográficas, nomeadamente cromatografia em coluna ou cromatografia preparativa em camada fina.
Foram isolados e identificados onze compostos, incluindo cinco triterpenos pentacíclicos (taraxerona, taraxerol, acetato de taraxerol, isomultiflorenol e acetato de isomultiflorenol), um diterpeno macrocíclico do tipo jatrofano (euphopubescenol), três lactonas diterpénicas do tipo ent-abietano (helioscopinolidos A, B e E), um esteroide (β-sitosterol) e um composto fenólico (coniferaldeído).
A taraxerona foi isolada em maiores quantidades, pelo que se procedeu à derivatização da função cetona em C-3 por condensação com a hidrazina, fenil-hidrazina e a 2,4-dinitrofenilhidrazina, obtendo-se três novos derivados.
As estruturas químicas dos compostos foram deduzidas com base nas suas características físicas e espectroscópicas (IV, espectrometria de massa, ressonância magnética nuclear unidimensional - 1H-RMN e 13C-RMN - e bidimensional - 1H-1H-COSY, HMQC, HMBC) e por comparação com dados descritos na literatura.
Futuramente, serão realizados estudos adicionais que permitirão avaliar a capacidade dos compostos obtidos como moduladores da glicoproteína-P em células tumorais resistentes.
Euphorbia species have been used in traditional medicine to treat cancer, tumors and warts. In the last decades, considerable attention has been focused on plants from this genus as a source of biologically active compounds (e.g. antitumor, cytotoxic, antibacterial and antiviral). These plants are characterized for biosynthesizing macrocyclic and polycyclic diterpenes, as well as triterpenes, steroids and phenols. In particular, the discovery of macrocyclic jatrophane- and lathyrane-type diterpenes as a new class of potent modulators of the transmembrane protein P-gp (P-glycoprotein), the main ABC transporter involved in multidrug resistance in cancer, has fostered an increasing interest in the research of this genus. To find out new bioactive compounds, the phytochemical study of three fractions of Euphorbia pubescens methanol extract was performed using chromatographic techniques, such as column chromatography or preparative thin layer chromatography. Overall, eleven compounds were isolated, including euphopubescenol, a jatrophanetype macrocyclic diterpene, three ent-abietane diterpenic lactones (helioscopinolides A, B and E) five pentacyclic triterpenes (taraxerone, taraxerol, taraxerol acetate; isomultiflorenol and isomultiflorenyl acetate), one steroid (β-sitosterol), and one phenolic compound (coniferaldehyde). Taraxerone was isolated in major amounts. Therefore, taking advantage of the ketone function at C-3, molecular derivatization reactions were attempted, namely condensation of taraxerone with hydrazine monohydrate, phenylhydrazine and 2,4- dinitrophenylhydrazine to obtain three new hydrazone derivatives. The structures of all compounds, including stereochemical features, were deduced from their physical and spectroscopic data, which included: infrared spectroscopy, mass spectrometry (MS), and extensive one- and two- dimensional nuclear magnetic resonance studies (COSY, HMQC and HMBC), and by comparison of these data with those reported in the literature. Further studies will be performed in order access their ability as P-gp modulators.
Euphorbia species have been used in traditional medicine to treat cancer, tumors and warts. In the last decades, considerable attention has been focused on plants from this genus as a source of biologically active compounds (e.g. antitumor, cytotoxic, antibacterial and antiviral). These plants are characterized for biosynthesizing macrocyclic and polycyclic diterpenes, as well as triterpenes, steroids and phenols. In particular, the discovery of macrocyclic jatrophane- and lathyrane-type diterpenes as a new class of potent modulators of the transmembrane protein P-gp (P-glycoprotein), the main ABC transporter involved in multidrug resistance in cancer, has fostered an increasing interest in the research of this genus. To find out new bioactive compounds, the phytochemical study of three fractions of Euphorbia pubescens methanol extract was performed using chromatographic techniques, such as column chromatography or preparative thin layer chromatography. Overall, eleven compounds were isolated, including euphopubescenol, a jatrophanetype macrocyclic diterpene, three ent-abietane diterpenic lactones (helioscopinolides A, B and E) five pentacyclic triterpenes (taraxerone, taraxerol, taraxerol acetate; isomultiflorenol and isomultiflorenyl acetate), one steroid (β-sitosterol), and one phenolic compound (coniferaldehyde). Taraxerone was isolated in major amounts. Therefore, taking advantage of the ketone function at C-3, molecular derivatization reactions were attempted, namely condensation of taraxerone with hydrazine monohydrate, phenylhydrazine and 2,4- dinitrophenylhydrazine to obtain three new hydrazone derivatives. The structures of all compounds, including stereochemical features, were deduced from their physical and spectroscopic data, which included: infrared spectroscopy, mass spectrometry (MS), and extensive one- and two- dimensional nuclear magnetic resonance studies (COSY, HMQC and HMBC), and by comparison of these data with those reported in the literature. Further studies will be performed in order access their ability as P-gp modulators.
Description
Tese de mestrado, Química Farmacêutica e Terapêutica, 2020, Universidade de Lisboa, Faculdade de Farmácia.
Keywords
Euphorbia pubescens Multidrug resistance Pentacyclic triterpenes Diterpenes Teses de mestrado -2020