RESUMO
Germacranolides, secondary metabolites produced by plants, have garnered academic and industrial interest due to their diverse and complex topology as well as a wide array of pharmacological activities. Molephantin, a highly oxygenated germacranolide isolated from medicinal plants, Elephantopus mollis and Elephantopus tomentosus, has exhibited antitumor, inflammatory, and leishmanicidal activities. Its chemical structure is based on a highly strained ten-membered macrocyclic backbone with an (E,Z)-dienone moiety, which is fused with an α-methylene-γ-butyrolactone and adorned with four successive stereogenic centers. Herein, we report the first synthesis of molephantin in 12 steps starting from readily available building blocks. The synthesis features the highly diastereoselective intermolecular Barbier allylation of the ß,γ-unsaturated aldehyde with optically active 3-bromomethyl-5H-furan-2-one intermediate and ensuing Nozaki-Hiyama-Kishi (NHK) macrocyclization for the construction of the highly oxygenated ten-membered macrocyclic framework. This synthetic route enabled access to another germacranolide congener, tomenphantopin F. Furthermore, cycloisomerization of molephantin into 2-deethoxy-2ß-hydroxyphantomolin could be facilitated by irradiation with ultraviolet A light (λmax=370â nm), which opened a versatile and concise access to the related furanogermacranolides such as EM-2, phantomolin, 2-O-demethyltomenphantopin C, and tomenphantopin C.
Assuntos
Oxigênio , Oxigênio/química , Asteraceae/química , Estereoisomerismo , Sesquiterpenos de Germacrano/química , Sesquiterpenos de Germacrano/síntese química , Furanos/química , Furanos/síntese química , Estrutura MolecularRESUMO
Acid-catalyzed transannular cyclization of the germacrene-type sesquiterpene lactone nobilin 1 was investigated with the aim of obtaining new anti-trypanosomal cadinane derivatives. The reaction was regiospecific in all tested reaction conditions. Compounds were fully characterized by spectroscopic and computational methods, and the anti-trypanosomal activity was evaluated and compared to nobilin (IC50 3.19±1.69µM). The tricyclic derivative 11 showed most potent in vitro activity against Trypanosoma brucei rhodesiense bloodstream forms (IC50 0.46±0.01µM). Acid-catalyzed transannular cyclization of natural cyclodecadienes is an efficient strategy to generate new natural product derivatives with anti-protozoal activity.
Assuntos
Bibenzilas/síntese química , Lactonas/síntese química , Sesquiterpenos de Germacrano/síntese química , Sesquiterpenos/síntese química , Tripanossomicidas/síntese química , Trypanosoma brucei rhodesiense/efeitos dos fármacos , Bibenzilas/farmacologia , Chamaemelum , Ciclização , Humanos , Lactonas/farmacologia , Sesquiterpenos Policíclicos , Sesquiterpenos/farmacologia , Sesquiterpenos de Germacrano/farmacologia , Tripanossomicidas/farmacologiaRESUMO
4,5- and 1,10-Epoxygermacrones were isolated from the essential oil of aerial parts of Geranium macrorrhizum L. (Geraniaceae). The structures of the epoxy derivatives were deduced from their 1D- and 2D-NMR spectra, molecular modeling, and confirmed by synthesis starting from germacrone. The epoxy compounds were screened for their antimicrobial activities by a microdilution assay, which revealed high activities of both compounds against Bacillus subtilis (minimum inhibitory concentrations (M/Cs) determined were 4.3 and 43â nmol/ml for 1,10- and 4,5-epoxygermacrone, resp.) and Pseudomonas aeruginosa (0.043 and 0.855â µmol/ml for 1,10- and 4,5-epoxygermacrone, resp.). The discovery and observed activity of the two epoxides fills the gap in our knowledge of the active principles in this highly renowned ethnomedicinal plant species.
Assuntos
Antibacterianos/química , Antibacterianos/farmacologia , Geranium/química , Sesquiterpenos de Germacrano/química , Bacillus subtilis/efeitos dos fármacos , Técnicas de Química Sintética , Compostos de Epóxi/química , Compostos de Epóxi/farmacologia , Geranium/metabolismo , Espectroscopia de Ressonância Magnética , Testes de Sensibilidade Microbiana , Estrutura Molecular , Óleos Voláteis/química , Plantas Medicinais/química , Pseudomonas aeruginosa/efeitos dos fármacos , Sesquiterpenos de Germacrano/síntese química , Sesquiterpenos de Germacrano/farmacologia , Relação Estrutura-AtividadeRESUMO
Enantiomerically pure (+)-vemolepin was semi-synthesized for the first time using the synthon (6S,7R,8S)-8,14-diacetoxy-15-hydroxygermacra-1(10),4,11(13)-trien-6, 12-olide [(+)-minimolide], the major sesquiterpene lactone of the Argentinean vine Mikania minima. After performing four consecutive reactions (Cope rearrangement, two oxidations, and selective hydrolysis of the acetate groups) on the synthon (+)-minimolide, a (+)-vernolepin yield of ca. 40% was achieved, proving to be a suitable semi-synthetic strategy for the production of quantities between 0.5-1.0 g of (+)-vernolepin. The transformations described here mimetize the biogenetic pathway for the production of (+)-vernolepin in the genus Vernonia. The synthesized (+)-vernolepin, but not its precursors, shows antifungal activity similar to amphotericin B. The semi-synthesis reported here combines affordable and easily available chemical reagents with classical organic methodologies.