RESUMO
Rotigotine (RTG) is a dopamine agonist used in the treatment of Parkinson's disease. As it is susceptible to oxidation, stability studies must be carefully designed for the identification and characterization of all possible degradation products. Here, RTG degradation was evaluated according to the International Conference on Harmonization guidelines under various stress conditions, including acidic and basic hydrolysis, oxidative, metallic, photolytic, and thermal conditions. Additionally, more severe stress conditions were applied to induce RTG degradation. Significant degradation was only observed under oxidative and photolytic conditions. The samples were analyzed by high performance liquid chromatography coupled to photodiode array detectors, charged aerosol, and high-resolution mass spectrometry. Chromatographic analyses revealed the presence of eight substances related to RTG, four of which were already described and were qualified impurities (impurities B, C, K and E) and four new degradation products (DP-1 - DP-4), whose structures were characterized by high-resolution mass spectrometry through Q-Orbitrap and electrospray ionization. In the stress testing of the active pharmaceutical ingredient in solid form, significant RTG degradation was observed in the presence of the oxidative matrix. The results corroborate the literature that confirm the high susceptibility of RTG to oxidation and the importance of using different detectors to detect degradation products in forced degradation studies.
Assuntos
Estabilidade de Medicamentos , Espectrometria de Massas por Ionização por Electrospray , Tetra-Hidronaftalenos , Tiofenos , Cromatografia Líquida de Alta Pressão/métodos , Tiofenos/química , Tiofenos/análise , Espectrometria de Massas por Ionização por Electrospray/métodos , Tetra-Hidronaftalenos/química , Tetra-Hidronaftalenos/análise , Oxirredução , Agonistas de Dopamina/análise , Agonistas de Dopamina/química , Hidrólise , Contaminação de Medicamentos/prevenção & controle , FotóliseRESUMO
The cubane phenyl ring bioisostere paradigm was further explored in an extensive study covering a wide range of pharmaceutical and agrochemical templates, which included antibiotics (cefaclor, penicillin G) and antihistamine (diphenhydramine), a smooth muscle relaxant (alverine), an anaesthetic (ketamine), an agrochemical instecticide (triflumuron), an antiparasitic (benznidazole) and an anticancer agent (tamibarotene). This investigation highlights the scope and limitations of incorporating cubane into bioactive molecule discovery, both in terms of synthetic compatibility and physical property matching. Cubane maintained bioisosterism in the case of the Chagas disease antiparasitic benznidazole, although it was less active in the case of the anticancer agent (tamibarotenne). Application of the cyclooctatetraene (COT) (bio)motif complement was found to optimize benznidazole relative to the benzene parent, and augmented anticancer activity relative to the cubane analogue in the case of tamibarotene. Like all bioisosteres, scaffolds and biomotifs, however, there are limitations (e.g. synthetic implementation), and these have been specifically highlighted herein using failed examples. A summary of all templates prepared to date by our group that were biologically evaluated strongly supports the concept that cubane is a valuable tool in bioactive molecule discovery and COT is a viable complement.
Assuntos
Benzeno/química , Ciclo-Octanos/química , Nitroimidazóis/química , Antineoplásicos/química , Benzoatos/química , Estrutura Molecular , Tetra-Hidronaftalenos/químicaRESUMO
Plumbago scandens L. is a Brazilian tropical/subtropical species that occurs along the coast. Chemically it is mainly represented by naphthoquinones, flavonoids, terpenoids and steroids. The aim of the present work is to study quantitative changes in the root metabolic production of Plumbago scandens during different physiologic developmental stages relative to floration. The results indicated the presence of four substances in the extracts: plumbagin, epi-isoshinanolone, palmitic acid and sitosterol, independent on developmental stage. The naphthoquinone plumbagin has always showed to be the major component of all extracts. Naphthoquinones exhibited their highest content during floration, while the content of the two others components decreased during this stage, revealing an inverse profile. The chemical composition changed depending on the plant requirements.
Assuntos
Naftoquinonas/química , Ácido Palmítico/química , Raízes de Plantas/química , Plumbaginaceae/química , Sitosteroides/química , Tetra-Hidronaftalenos/química , Cromatografia Gasosa , Naftoquinonas/metabolismo , Ácido Palmítico/metabolismo , Raízes de Plantas/crescimento & desenvolvimento , Raízes de Plantas/metabolismo , Plumbaginaceae/crescimento & desenvolvimento , Plumbaginaceae/metabolismo , Sitosteroides/metabolismo , Tetra-Hidronaftalenos/metabolismoRESUMO
Plumbago scandens L. is a Brazilian tropical/subtropical species that occurs along the coast. Chemically it is mainly represented by naphthoquinones, flavonoids, terpenoids and steroids. The aim of the present work is to study quantitative changes in the root metabolic production of Plumbago scandens during different physiologic developmental stages relative to floration. The results indicated the presence of four substances in the extracts: plumbagin, epi-isoshinanolone, palmitic acid and sitosterol, independent on developmental stage. The naphthoquinone plumbagin has always showed to be the major component of all extracts. Naphthoquinones exhibited their highest content during floration, while the content of the two others components decreased during this stage, revealing an inverse profile. The chemical composition changed depending on the plant requirements.
Plumbago scandens L. é uma espécie brasileira tropical/subtropical que ocorre ao longo da costa. Quimicamente, é principalmente representada por naftoquinonas, flavonóides, terpenóides e esteróides. objetivo do presente trabalho é estudar mudanças quantitativas da produção metabólica nas raízes de Plumbago scandens durante diferentes estágios de desenvolvimento fisiológico, relativos à floração. Os resultados indicaram a presença de quatro substâncias nos extratos: plumbagina, epi-isoshinanolona, ácido palmítico e sitosterol, independente do estágio de desenvolvimento. A naftoquinona plumbagina tem sempre mostrado ser o componente majoritário de todos os extratos. Naftoquinonas exibiram seus maiores conteúdos durante a floração, enquanto o conteúdo dos dois outros componentes decresceu durante este estágio, revelando um perfil inverso. A composição química modificou dependendo das necessidades da planta.
Assuntos
Naftoquinonas/química , Ácido Palmítico/química , Raízes de Plantas/química , Plumbaginaceae/química , Sitosteroides/química , Tetra-Hidronaftalenos/química , Cromatografia Gasosa , Naftoquinonas/metabolismo , Ácido Palmítico/metabolismo , Raízes de Plantas/crescimento & desenvolvimento , Raízes de Plantas/metabolismo , Plumbaginaceae/crescimento & desenvolvimento , Plumbaginaceae/metabolismo , Sitosteroides/metabolismo , Tetra-Hidronaftalenos/metabolismoRESUMO
The compound 1,c-3-diphenyltetran-r-1-ol (systematic name: 1,c-3-diphenyl-1,2,3,4-tetrahydro-r-1-naphthol), C(22)H(20)O, which possesses the tetrahydronaphthalene core that is found in a large number of natural products, crystallizes with Z' = 4 and with the four molecules forming a hydrogen-bonded cyclic aggregate. The aliphatic six-membered rings are present with two different conformations in the molecules of the asymmetric unit. A comparison with similar fragments reveals their conformational flexibility. In addition, the structure demonstrates the relative stereochemistries of the chiral centers, which are important since the title compound is used in the stereoselective synthesis of compounds with therapeutic activity.
Assuntos
Naftóis/química , Tetra-Hidronaftalenos/química , Cristalografia por Raios X , Ligação de Hidrogênio , Modelos Moleculares , Estereoisomerismo , Difração de Raios XRESUMO
Isocatalpanol and tecomaquinone I were obtained from roots of Lippia sidoides, a medicinal plant from northeast Brazil. Reduction of tecomaquinone I with NaBH4 yielded a new derivative. Structural elucidation was done on the basis of spectral data, mainly by high-field NMR and electron ionization mass spectrometry.
Assuntos
Compostos Heterocíclicos de 4 ou mais Anéis/análise , Compostos Heterocíclicos de 4 ou mais Anéis/química , Lippia/metabolismo , Espectroscopia de Ressonância Magnética/métodos , Tetra-Hidronaftalenos/análise , Tetra-Hidronaftalenos/química , Isótopos de Carbono , Compostos Heterocíclicos de 4 ou mais Anéis/normas , Espectroscopia de Ressonância Magnética/normas , Conformação Molecular , Prótons , Padrões de Referência , Tetra-Hidronaftalenos/normasRESUMO
A new 4alpha-aryltetralin-type lignan called burseranin (1) and a known analogous lignan picropolygamain (2) were isolated along with known triterpenes, lupeol and epi-lupeol from the methanol extract of stems of Bursera graveolens, which showed a remarkable inhibitory activity against human HT1080 fibrosarcoma cells. The whole structure of 1 was established based on combined spectral studies and the absolute structure for 2 was first confirmed by CD spectral evidence. In addition, cytotoxic activities of the stem (methanol) extract and its components are evaluated in this paper.
Assuntos
Antineoplásicos Fitogênicos/química , Bursera/química , Lignanas/química , Tetra-Hidronaftalenos/química , Antineoplásicos Fitogênicos/isolamento & purificação , Antineoplásicos Fitogênicos/farmacologia , Linhagem Celular Tumoral , Dicroísmo Circular , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , México , Extratos Vegetais/química , Caules de Planta/química , Tetra-Hidronaftalenos/isolamento & purificação , Tetra-Hidronaftalenos/farmacologiaRESUMO
HIV-1 integrase is a critical enzyme for replication of HIV, and its inhibition has the potential to lead to an anti-retroviral therapy that has advantages over existing therapies. Cytosporic acid (1) is a polyketide-derived novel natural product that was isolated from a fermentation broth of the filamentous fungus Cytospora sp. collected from Puerto Rico. It inhibited strand transfer reaction of HIV-1 integrase with an IC(50) of 20 microM. The isolation, structure elucidation, relative stereochemistry, and activity of 1 are described.