Abstract
Plants produce a high diversity of metabolites that can act as regulators of cholinergic
dysfunction. Among plants, the potential of species of the genus Tabernaemontana to treat neurological disorders has been linked to iboga-type alkaloids that are
biosynthesized by those species. In this context, precursor-directed biosynthesis
approaches were carried out using T. catharinensis plantlets to achieve new-to-nature molecules as promising agents against Alzheimerʼs
disease. Aerial parts of T. catharinensis, cultured in vitro, produced 7 unnatural alkaloids (5-fluoro-ibogamine, 5-fluoro-voachalotine,
5-fluoro-12-methoxy-Nb-methyl-voachalotine, 5-fluoro-isovoacangine, 5-fluoro-catharanthine,
5-fluoro-19-(S)-hydroxy-ibogamine, and 5-fluoro-coronaridine), while root extracts
showed the presence of the same unnatural iboga-type alkaloids and 2 additional ones:
5-fluoro-voafinine and 5-fluoro-affinisine. Moreover, molecular docking approaches
were carried
out to evaluate the potential inhibition activity of T. catharinensis’ natural and unnatural alkaloids against AChE and BChE enzymes. Fluorinated iboga
alkaloids (5-fluoro-catharanthine, 5-fluoro-voachalotine, 5-fluoro-affinisine, 5-fluoro-isovoacangine,
5-fluoro-corinaridine) were more active than natural ones and controls against AchE,
while 5-fluoro-19-(S)-hydroxy-ibogamine, 5-fluoro-catharanthine, 5-fluoro-isovoacangine,
and 5-fluoro-corinaridine showed better activity than natural ones and controls against
BChE. Our findings showed that precursor-directed biosynthesis strategies generated
“new-to-nature” alkaloids that are promising Alzheimerʼs disease drug candidates.
Furthermore, the isotopic experiments also allowed us to elucidate the initial steps
of the biosynthetic pathway for iboga-type alkaloids, which are derived from the MEP
and shikimate pathways.
Key words
Tabernaemontana catharinensis
- Apocynaceae - iboga-alkaloids - Alzheimerʼs - fluorinated analogues - molecular
docking - cholinergic dysfunction - cholinesterase inhibitors
