Planta Med 2021; 87(01/02): 136-147
DOI: 10.1055/a-1315-2282
Biological and Pharmacological Activities
Original Papers

Precursor-directed Biosynthesis in Tabernaemontana catharinensis as a New Avenue for Alzheimerʼs Disease-modifying Agents

Bruno Musquiari
1  Biotechnology Unit, University of Ribeirão Preto (UNAERP), Ribeirão Preto, SP, Brazil
,
Eduardo J. Crevelin
2  Faculty of Philosophy, Sciences and Letters at Ribeirão Preto, Universidade de São Paulo (USP), Ribeirão Preto, SP, Brazil
,
Bianca W. Bertoni
1  Biotechnology Unit, University of Ribeirão Preto (UNAERP), Ribeirão Preto, SP, Brazil
5  Botanic Garden of Medicinal Plant Ordem e Progresso (BOP), Jardinópolis, SP, Brazil
,
Suzelei de C. França
1  Biotechnology Unit, University of Ribeirão Preto (UNAERP), Ribeirão Preto, SP, Brazil
,
1  Biotechnology Unit, University of Ribeirão Preto (UNAERP), Ribeirão Preto, SP, Brazil
5  Botanic Garden of Medicinal Plant Ordem e Progresso (BOP), Jardinópolis, SP, Brazil
,
Ana Carolina Devides Castello
6  State University of Campinas (UNICAMP), Institute of Biology, Department of Botany, Campinas, SP, Brazil
,
Willian O. Castillo-Ordoñez
3  Department of Biology, Faculty of Natural Sciences, Exacts and Education, University of Cauca, Popayán Colombia
,
Silvana Giuliatti
4  Department of Genetics, Ribeirão Preto Medical School, University of São Paulo (USP), Ribeirão Preto, SP, Brazil
,
Adriana A. Lopes
1  Biotechnology Unit, University of Ribeirão Preto (UNAERP), Ribeirão Preto, SP, Brazil
› Author Affiliations
Supported by: Coordenação de Aperfeiçoamento de Pessoal de Nível Superior Grant #88882.365148/2019-01

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.

Supporting Information



Publication History

Received: 02 September 2020

Accepted after revision: 19 November 2020

Publication Date:
15 December 2020 (online)

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