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.
Antineoplastic Agents, Phytogenic/pharmacology , Indole Alkaloids/pharmacology , Tubulin/metabolism , Antineoplastic Agents, Phytogenic/chemical synthesis , Cell Line, Tumor , Colchicine/pharmacology , Crystallography, X-Ray , Drug Screening Assays, Antitumor , Endangered Species , Green Chemistry Technology , Humans , Indole Alkaloids/chemical synthesis , Indole Alkaloids/chemistry , Indole Alkaloids/isolation & purification , Microtubules/chemistry , Microtubules/drug effects , Microtubules/metabolism , Models, Molecular , Quinolines/chemistry , Quinolines/isolation & purification , Seeds/chemistry , Tabernaemontana/chemistry , Tubulin/chemistry , Tubulin Modulators/pharmacology , Voacanga/chemistry
The roots of the endangered medicinal plant Croton megalocarpoides collected in Kenya were investigated and twenty-two compounds isolated. Among them were twelve new ent-clerodane (1-12) and a new abietane (13) diterpenoids, alongside the known crotocorylifuran (4 a), two known abietane and four known ent-trachylobane diterpenoids, and the triterpenoids, lupeol and acetyl aleurotolic acid. The structures of the compounds were determined using NMR, HRMS and ECD. The isolated compounds were evaluated against a series of microorganisms (fungal and bacteria) and also against Plasmodium falciparum, however no activity was observed.
Abietanes/isolation & purification , Croton/chemistry , Diterpenes, Clerodane/isolation & purification , Abietanes/chemistry , Diterpenes, Clerodane/chemistry , Endangered Species , Kenya , Molecular Structure , Plant Roots/chemistry , Plants, Medicinal/chemistry
