Publicação
Development of a small library of bioactive compounds through isolation and molecular derivatization
| Resumo: | The present dissertation focuses on the phytochemical study of Euphorbia boetica Boiss. and Euphorbia pubescens Vahl (Euphorbiaceae) aerial parts in an attempt to find effective modulators for P-glycoprotein (P-gp) mediated multidrug resistance (MDR) in tumour cells. The methanol extracts of both plants were fractioned by chromatographic techniques such as column chromatography, preparative thin layer chromatography and high-performance liquid chromatography (HPLC). From the methanol extract of E. boetica, one new premyrsinane-type diterpene with the unusual 5:7:6:3 fused ring system and a new acylation pattern, named euphomyrsinane A, two new tigliane-type diterpenes with new acylation patterns, named phorboboetirane A and phorboboetirane B along with four known macrocyclic diterpenes, premyrsinol-3-propanoate-5-benzoate-7,13,17-triacetate, euphoboetirane A, epoxyboetirane A and epoxyboetirane K were isolated. A known triterpene with the cycloartane skeleton, 24-methylenecycloartanol, and a phenolic compound, methyl gallate were also isolated. From the methanol extracts of E. pubescens, were obtained a known macrocyclic diterpene, euphopubescenol, and a known diterpenic lactone, helioscopinolide A. Due to its biological activity and simple structure paired with the fact that it was isolated in large amounts, methyl gallate was derivatized, aiming at generating a small set of bioactive derivatives. In this way, taking into account that lipophilicity and the presence of nitrogen atoms are described to improve the ability to reverse MDR, three main steps were considered: i) methylation of the hydroxyl groups on the aromatic ring by reaction with dimethylsulfate, yielding methyl 3,4,5-trimethoxebenzoate; ii) reaction of methyl 3,4,5-trimethoxybenzoate with hydrazine yielding 3,4,5-trimethoxybenzohydrazide; iii) condensation of 3,4,5-trimethoxybenzohydrazide with aromatic aldehydes to obtain three derivatives bearing an imine moiety. The chemical structures of the compounds were deduced from their physical and spectroscopic data, which included infrared spectroscopy, mass spectrometry and extensive one- (1H-NMR, 13C-NMR, DEPT) and two-dimensional (1H-1H-COSY, HMQC, HMBC, and NOESY) Nuclear Magnetic Resonance studies and by comparison with literature data. |
|---|---|
| Autores principais: | Gomes, João Nuno da Silva |
| Assunto: | Euphorbia boetica Euphorbia pubescens macrocyclic diterpenes lathyrane multidrug resistance P-glycoprotein |
| Ano: | 2017 |
| País: | Portugal |
| Tipo de documento: | dissertação de mestrado |
| Tipo de acesso: | acesso aberto |
| Instituição associada: | Universidade de Lisboa |
| Idioma: | inglês |
| Origem: | Repositório da Universidade de Lisboa |
| Resumo: | The present dissertation focuses on the phytochemical study of Euphorbia boetica Boiss. and Euphorbia pubescens Vahl (Euphorbiaceae) aerial parts in an attempt to find effective modulators for P-glycoprotein (P-gp) mediated multidrug resistance (MDR) in tumour cells. The methanol extracts of both plants were fractioned by chromatographic techniques such as column chromatography, preparative thin layer chromatography and high-performance liquid chromatography (HPLC). From the methanol extract of E. boetica, one new premyrsinane-type diterpene with the unusual 5:7:6:3 fused ring system and a new acylation pattern, named euphomyrsinane A, two new tigliane-type diterpenes with new acylation patterns, named phorboboetirane A and phorboboetirane B along with four known macrocyclic diterpenes, premyrsinol-3-propanoate-5-benzoate-7,13,17-triacetate, euphoboetirane A, epoxyboetirane A and epoxyboetirane K were isolated. A known triterpene with the cycloartane skeleton, 24-methylenecycloartanol, and a phenolic compound, methyl gallate were also isolated. From the methanol extracts of E. pubescens, were obtained a known macrocyclic diterpene, euphopubescenol, and a known diterpenic lactone, helioscopinolide A. Due to its biological activity and simple structure paired with the fact that it was isolated in large amounts, methyl gallate was derivatized, aiming at generating a small set of bioactive derivatives. In this way, taking into account that lipophilicity and the presence of nitrogen atoms are described to improve the ability to reverse MDR, three main steps were considered: i) methylation of the hydroxyl groups on the aromatic ring by reaction with dimethylsulfate, yielding methyl 3,4,5-trimethoxebenzoate; ii) reaction of methyl 3,4,5-trimethoxybenzoate with hydrazine yielding 3,4,5-trimethoxybenzohydrazide; iii) condensation of 3,4,5-trimethoxybenzohydrazide with aromatic aldehydes to obtain three derivatives bearing an imine moiety. The chemical structures of the compounds were deduced from their physical and spectroscopic data, which included infrared spectroscopy, mass spectrometry and extensive one- (1H-NMR, 13C-NMR, DEPT) and two-dimensional (1H-1H-COSY, HMQC, HMBC, and NOESY) Nuclear Magnetic Resonance studies and by comparison with literature data. |
|---|