Orbitídeos de Euphorbiaceae, caracterização química e síntese: prospecção racional de peptídeos cíclicos com potencial antitumoral
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Data
2019-04-02
Autores
Nastri, Jhennifer Priscila
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Editor
Universidade Estadual Paulista (Unesp)
Resumo
Peptídeos cíclicos compreendem uma classe de substâncias que ocorrem em algumas plantas superiores e que exibem uma ampla quantidade de atividades biológicas. Estes compostos bioativos vem despertando o interesse de setores estratégicos no desenvolvimento de fármacos e cosméticos devido sua característica cíclica, o que gera maior afinidade e seletividade para determinado alvo, isso ocorre pela restrição de rotação de suas ligações químicas. O estudo de orbitídeos presentes em Jatropha ribifolia e Croton sphaerogynus (Euphorbiaceae) foi dividido nas seguintes etapas: identificação e caracterização química dos compostos, síntese dos orbitídeos e atividade antitumoral. Neste estudo foi isolado e caracterizado o peptídeo ribifolina oriunda de J. ribifolia. Visando avaliar a polaridade e a carga da extremidade amino-terminal foi planejada a síntese de três peptídeos análogos, visto que substâncias com maior hidrofobicidade possuem maior atividade antitumoral de acordo com a literatura. Para tanto, o aminoácido serina foi substituído por alanina (não possui grupo hidroxila), treonina (possui um grupo metila adicional) e lisina (possui uma carga positiva na sua cadeia lateral). Os peptídeos foram sintetizados, purificados e avaliados em função anticâncer. Contudo, apenas o análogo da lisina cíclica gerou uma boa inibição de crescimento para as linhagens celulares de HCT-116 e MCF-7. Paralelamente, foi realizada a coleta da espécie C. sphaerogynus (caule e folhas) na cidade do Rio de Janeiro-RJ, o material vegetal foi extraído em etanol e fracionado em sílica de fase-reversa, o que permitiu obter uma fração enriquecida de peptídeos. A partir dessa fração foi possível assinalar, pela técnica de LC-MS, possíveis poli-Leu/Ile orbitídeos nas folhas e caules de C. sphaerogynus. Os espectros de MS2 permitiram observar perdas de massas de 113 Da, as quais foram atribuídas aos peptídeos tetraleucil (ou tetraisoleucil), pentaleucil (ou pentaisoleucil), hexaleucil (ou hexaisoleucil) e heptaleucil (ou heptaisoleucil). A análise por HPLC preparativo das folhas desta espécie, permitiu ainda isolar dois flavonoides que foram caracterizados como sendo campferol triglicosilado e rutina. Os estudos apresentados mostraram que a C. sphaerogynus possui uma baixa diversidade de peptídeos. Somado a isso, os nossos resultados mostraram, que ao contrário da literatura, a presença de uma carga positiva em orbitídeos é importante para sua atividade anticâncer, como observado para a ribifolina.
Cyclic peptides comprise a class of naturally occurring compoundsin some higher plants and exhibit a wide range of biological activities. These bioactive compounds have aroused the interest from strategic sectors fordrugs and cosmetics development due to their cyclic characteristic, which generates greater affinity and selectivity used todetermine target,due the restriction of rotation of their chemical bonds. The study onorbitides present in Jatropha ribifoliaand Croton sphaerogynus(Euphorbiaceae) wasdivided into the following stages:identification and chemical characterization of compounds, synthesis of orbitidesand antitumor activity.In this study, ribifoline peptidefrom J. ribifoliawas isolated and characterized. In order to evaluate the polarity and the charged at the aminoterminus, the synthesis of three analogous peptides was planned, since substances with higher hydrophobicity have higher antitumor activity according to the literature. Therefore, the serine amino acid has been replaced by alanine (no hydroxyl group), threonine (has an additional methyl group) and lysine (has a positive charge on its side chain). The peptides were synthesized, purified and evaluated in anticancer activity. However, only the cyclic lysine analog generated good growth inhibition for the HCT-116 and MCF-7 cell lines. At the same time, the specie C. sphaerogynus(stem and leaves) was collected in the city Rio de Janeiro-RJ, the vegetal material was extracted in ethanol and fractionated in phase-reversed silica, which allowed toobtain an enriched peptides fraction.From this fraction, it was identify, by the LC-MS technique,possible poly-Leu / Ileorbitides in the leaves and stems of C. sphaerogynus. The spectra MS2allowed to observe mass losses of 113 Da, which allowed to indicate the peptides tetraleucil (or tetraisoleucil), pentaleucil (or pentaisoleucil), hexaleucil (or hexaisoleucil) and heptaleucil (or heptaisoleucil). Preparative HPLC analysis ofthe leaves from this specie also allowed to isolate two flavonoids that were characterized as triglycosylated campperol and rutin.The studies presented showed that C. sphaerogynus has a low diversity of peptides. Added to this, our results showed that unlike the literature, the presence of a positive charge in orbitids is important for its anticancer activity, as observed for ribifoline.
Cyclic peptides comprise a class of naturally occurring compoundsin some higher plants and exhibit a wide range of biological activities. These bioactive compounds have aroused the interest from strategic sectors fordrugs and cosmetics development due to their cyclic characteristic, which generates greater affinity and selectivity used todetermine target,due the restriction of rotation of their chemical bonds. The study onorbitides present in Jatropha ribifoliaand Croton sphaerogynus(Euphorbiaceae) wasdivided into the following stages:identification and chemical characterization of compounds, synthesis of orbitidesand antitumor activity.In this study, ribifoline peptidefrom J. ribifoliawas isolated and characterized. In order to evaluate the polarity and the charged at the aminoterminus, the synthesis of three analogous peptides was planned, since substances with higher hydrophobicity have higher antitumor activity according to the literature. Therefore, the serine amino acid has been replaced by alanine (no hydroxyl group), threonine (has an additional methyl group) and lysine (has a positive charge on its side chain). The peptides were synthesized, purified and evaluated in anticancer activity. However, only the cyclic lysine analog generated good growth inhibition for the HCT-116 and MCF-7 cell lines. At the same time, the specie C. sphaerogynus(stem and leaves) was collected in the city Rio de Janeiro-RJ, the vegetal material was extracted in ethanol and fractionated in phase-reversed silica, which allowed toobtain an enriched peptides fraction.From this fraction, it was identify, by the LC-MS technique,possible poly-Leu / Ileorbitides in the leaves and stems of C. sphaerogynus. The spectra MS2allowed to observe mass losses of 113 Da, which allowed to indicate the peptides tetraleucil (or tetraisoleucil), pentaleucil (or pentaisoleucil), hexaleucil (or hexaisoleucil) and heptaleucil (or heptaisoleucil). Preparative HPLC analysis ofthe leaves from this specie also allowed to isolate two flavonoids that were characterized as triglycosylated campperol and rutin.The studies presented showed that C. sphaerogynus has a low diversity of peptides. Added to this, our results showed that unlike the literature, the presence of a positive charge in orbitids is important for its anticancer activity, as observed for ribifoline.
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Palavras-chave
Croton sphaerogynus, Orbitídeos, Orbitides, Jatropha ribifolia