RESUMO
We describe enantioselective syntheses of strychnos and chelidonium alkaloids. In the first case, indole acetic acid esters were established as excellent partner nucleophiles for enantioselective cooperative isothiourea/Pd catalyzed α-alkylation. This provides products containing indole-bearing stereocenters in high yield and with excellent levels of enantioinduction in a manner that is notably independent of the N-substituent. This led to concise syntheses of (-)-akuammicine and (-)-strychnine. In the second case, the poor performance of ortho-substituted cinnamyl electrophiles in the enantioselective cooperative isothiourea/Ir catalyzed α-alkylation was overcome by appropriate substituent choice, leading to enantioselective syntheses of (+)-chelidonine, (+)-norchelidonine, and (+)-chelamine.
Assuntos
Alcaloides/química , Chelidonium/química , Strychnos/química , Alcaloides/síntese química , Alquilação , Benzofenantridinas/síntese química , Benzofenantridinas/química , Alcaloides de Berberina/síntese química , Alcaloides de Berberina/química , Catálise , Chelidonium/metabolismo , Humanos , Indóis/síntese química , Indóis/química , Irídio/química , Paládio/química , Sirtuína 1/antagonistas & inibidores , Sirtuína 1/metabolismo , Estereoisomerismo , Estricnina/síntese química , Estricnina/química , Strychnos/metabolismo , Tioureia/químicaRESUMO
Monoterpenoid indole alkaloids (MIAs) possess a diversity of alkaloid skeletons whose biosynthesis is poorly understood. A bioinformatic search of candidate genes, combined with their virus-induced gene silencing, targeted MIA profiling and in vitro/in vivo pathway reconstitution identified and functionally characterized six genes as well as a seventh enzyme reaction required for the conversion of 19E-geissoschizine to tabersonine and catharanthine. The involvement of pathway intermediates in the formation of four MIA skeletons is described, and the role of stemmadenine-O-acetylation in providing necessary reactive substrates for the formation of iboga and aspidosperma MIAs is described. The results enable the assembly of complex dimeric MIAs used in cancer chemotherapy and open the way to production of many other biologically active MIAs that are not easily available from nature.
Assuntos
Carbolinas/metabolismo , Catharanthus/metabolismo , Alcaloides Indólicos/metabolismo , Proteínas de Plantas/genética , Aspidosperma/genética , Aspidosperma/metabolismo , Catharanthus/genética , Enzimas/genética , Enzimas/metabolismo , Regulação da Expressão Gênica de Plantas , Inativação Gênica , NADP/metabolismo , Proteínas de Plantas/metabolismo , Quinolinas/metabolismo , Strychnos/metabolismo , Tabernaemontana/metabolismo , Alcaloides de Vinca/metabolismoRESUMO
Monoterpene indole alkaloids comprise a diverse family of over 2000 plant-produced natural products. This pathway provides an outstanding example of how nature creates chemical diversity from a single precursor, in this case from the intermediate strictosidine. The enzymes that elicit these seemingly disparate products from strictosidine have hitherto been elusive. Here we show that the concerted action of two enzymes commonly involved in natural product metabolism-an alcohol dehydrogenase and a cytochrome P450-produces unexpected rearrangements in strictosidine when assayed simultaneously. The tetrahydro-ß-carboline of strictosidine aglycone is converted into akuammicine, a Strychnos alkaloid, an elusive biosynthetic transformation that has been investigated for decades. Importantly, akuammicine arises from deformylation of preakuammicine, which is the central biosynthetic precursor for the anti-cancer agents vinblastine and vincristine, as well as other biologically active compounds. This discovery of how these enzymes can function in combination opens a gateway into a rich family of natural products.The biosynthetic pathway of preakuammicine, a monoterpene precursor of the anti-cancer agent vinblastine, has remained largely unexplored. Here, the authors provide transcriptomic and biochemical data to identify two enzymes that, in tandem, convert strictosidine to akuammicine, the stable shunt product of preakuammicine.
Assuntos
Alcaloides/metabolismo , Indóis/metabolismo , Proteínas de Plantas/metabolismo , Strychnos/metabolismo , Alcaloides de Vinca/metabolismo , Álcool Desidrogenase/genética , Álcool Desidrogenase/metabolismo , Alcaloides/química , Sequência de Bases , Produtos Biológicos/química , Produtos Biológicos/metabolismo , Vias Biossintéticas/genética , Sistema Enzimático do Citocromo P-450/genética , Sistema Enzimático do Citocromo P-450/metabolismo , Indóis/química , Isoenzimas/genética , Isoenzimas/metabolismo , Modelos Químicos , Estrutura Molecular , Proteínas de Plantas/genética , Strychnos/enzimologia , Strychnos/genética , Alcaloides de Vinca/químicaRESUMO
An in vivo study of Strychnos alkaloids metabolites in rats by ultra high performance liquid chromatography with linear ion trap Orbitrap MS is reported for the first time. Two major Strychnos alkaloids compounds including strychnine and brucine were investigated. To obtain optimal extraction efficiency, samples were pretreated by using an SPE plate. The structures of metabolites and their fragment ions were characterized based on the accurate mass and MSn data. Forty-seven metabolites were identified in rat urine, of which 25 were reported for the first time. Four new metabolism pathways were proposed on the basis of the identified metabolites. This study provides a practical approach for rapidly identifying complicated metabolites, a methodology that could be widely applied not only in forensic and clinically toxicological relevant cases, but also for the structural characterization of metabolites of other compounds.
Assuntos
Alcaloides/análise , Strychnos/química , Alcaloides/metabolismo , Animais , Cromatografia Líquida de Alta Pressão , Masculino , Espectrometria de Massas , Ratos , Ratos Sprague-Dawley , Strychnos/metabolismoRESUMO
Gardovatine (1), the first Strychnos-Strychnos alkaloid with a C3/C7 cleaved backbone, was isolated from twigs and leaves of Gardneria ovate, together with an analogue divarine (2). The structure was established by extensive spectroscopic methods. Both compounds showed potential cytotoxicities against five human cancer cell lines.
Assuntos
Alcaloides/química , Alcaloides Indólicos/química , Indóis/química , Loganiaceae/química , Strychnos/química , Alcaloides/isolamento & purificação , Alcaloides/toxicidade , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Alcaloides Indólicos/isolamento & purificação , Alcaloides Indólicos/toxicidade , Loganiaceae/metabolismo , Espectroscopia de Ressonância Magnética , Conformação Molecular , Folhas de Planta/química , Folhas de Planta/metabolismo , Strychnos/metabolismoRESUMO
In the present study, Pb(II) removal efficiency of Strychnos potatorum seed powder (SPSP) from aqueous solution has been investigated. Batch mode adsorption experiments have been conducted by varying pH, contact time, adsorbent dose and Pb(II) concentration. Pb(II) removal was pH dependent and found to be maximum at pH 5.0. The maximum removal of Pb(II) was achieved within 360 min. The Lagergren first-order model was less applicable than pseudo-second-order reaction model. The equilibrium adsorption data was fitted to Langmuir and Freundlich adsorption isotherm models to evaluate the model parameters. Both models represented the experimental data satisfactorily. The monolayer adsorption capacities of SPSP as obtained from Langmuir isotherm was found to be 16.420 mg/g. The FTIR study revealed the presence of various functional groups which are responsible for the adsorption process.