RESUMO
The jerantinine family of Aspidosperma indole alkaloids from Tabernaemontana corymbosa are potent microtubule-targeting agents with broad spectrum anticancer activity. The natural supply of these precious metabolites has been significantly disrupted due to the inclusion of T. corymbosa on the endangered list of threatened species by the International Union for Conservation of Nature. This report describes the asymmetric syntheses of (-)-jerantinines A and E from sustainably sourced (-)-tabersonine, using a straight-forward and robust biomimetic approach. Biological investigations of synthetic (-)-jerantinine A, along with molecular modelling and X-ray crystallography studies of the tubulin-(-)-jerantinine B acetate complex, advocate an anticancer mode of action of the jerantinines operating via microtubule disruption resulting from binding at the colchicine site. This work lays the foundation for accessing useful quantities of enantiomerically pure jerantinine alkaloids for future development.
Assuntos
Antineoplásicos Fitogênicos/farmacologia , Alcaloides Indólicos/farmacologia , Tubulina (Proteína)/metabolismo , Antineoplásicos Fitogênicos/síntese química , Linhagem Celular Tumoral , Colchicina/farmacologia , Cristalografia por Raios X , Ensaios de Seleção de Medicamentos Antitumorais , Espécies em Perigo de Extinção , Química Verde , Humanos , Alcaloides Indólicos/síntese química , Alcaloides Indólicos/química , Alcaloides Indólicos/isolamento & purificação , Microtúbulos/química , Microtúbulos/efeitos dos fármacos , Microtúbulos/metabolismo , Modelos Moleculares , Quinolinas/química , Quinolinas/isolamento & purificação , Sementes/química , Tabernaemontana/química , Tubulina (Proteína)/química , Moduladores de Tubulina/farmacologia , Voacanga/químicaRESUMO
Natural products with anti-cancer activity play a vital role in lead and target discovery. We report here the synthesis and biological evaluation of the plant-derived alkaloid, piperlongumine and analogues. Using a Horner-Wadsworth-Emmons coupling approach, a selection of piperlongumine-like compounds were prepared in good overall yield from a novel phosphonoacetamide reagent. A number of the compounds displayed potent anti-cancer activity against colorectal (HCT 116) and ovarian (IGROV-1) carcinoma cell lines, via a mechanism of action which may involve ROS generation. Contrary to previous reports, no selective action in cancer cell (MRC-5) was observed for piperlongumine analogues.
Assuntos
Antineoplásicos/farmacologia , Dioxolanos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Dioxolanos/síntese química , Dioxolanos/química , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Estrutura Molecular , Espécies Reativas de Oxigênio/metabolismo , Relação Estrutura-AtividadeRESUMO
We present a selection of elegant and diverse biomimetic syntheses of complex natural product dimers. The dimerisation pathways discussed encompass the most prevalent strategies, including: Diels-Alder, Aldol, Mannich, conjugate addition, oxidative, radical and photochemical approaches; each underpinned through rational biosynthetic speculation.
