Unnatural spirocyclic oxindole alkaloids biosynthesis in Uncaria guianensis

Lopes, Adriana A.; Chioca, Bianca; Musquiari, Bruno; Crevelin, Eduardo José; França, Suzelei de Castro; Silva, Maria Fátima das Graças Fernandes da; Pereira, Ana Maria Soares

doi:10.1038/s41598-019-47706-3

Cited by 23 publications

(15 citation statements)

References 30 publications

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“…It is important to highlight that all plants have grown healthy, without visible physiological change, which means that the unnatural precursor was not toxic for the plantlets. A methanolic extract from fresh shoots of T. catharinensis was prepared after 30 Our results showed that PDB strategies using analogue precursor successfully produced unnatural alkaloids in T. catharinensis.…”

Section: Resultsmentioning

confidence: 91%

“…Due to the importance of natural product analogues, many strategies for modifying natural products have been explored in order to obtain "new-to-nature" molecules [29]. Recently, we have demonstrated that the biosynthesis of fluorinated and methylated analogues of oxindole alkaloids in Uncaria guianensis plantlets by precursor-directed biosynthesis (PDB) is a viable and efficient bioprocess, and this approach is unusual using plants [30]. The successful incorporation of unnatural precursors in the biosynthetic route of a given natural product can lead to the formation of an analogue that can be more biologically important than the natural product itself.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2020

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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.

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Section: Resultsmentioning

confidence: 91%

Section: Introductionmentioning

confidence: 99%

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

et al. 2020

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“…J.F.Gmel. It was determined that the formation of the oxindole moiety proceeds along a pinacol-pinacolone rearrangement reaction from an indole precursor [57]. The oxindole moiety is comprised of a benzene ring fused with a pyrrole ring, substituted at C-2 with a carbonyl [55].…”

Section: Oxindole Alkaloidsmentioning

confidence: 99%

Comprehensive Review of the Components in Cat’s Claw (Uncaria tomentosa) and Their Antibacterial Activity

Blanck¹,

Huebner²,

Rolls³

et al. 2022

AppliedChem

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Cat’s claw (Uncaria tomentosa (Willd. ex Schults) DC.), a plant that is exceptionally rich in phytochemicals, has been used for centuries by the indigenous people of South and Central America as a therapeutic and is currently widely exported for medicinal purposes. Extracts and individual components have shown considerable potential as antibacterials in the literature. The purpose of this review is twofold: first, to provide a substantiated, comprehensive collection of the known chemical constituents of U. tomentosa, including their detailed structures; second, to identify those components that offer some promise as antibacterials based on the research to date. Bacterial resistance to currently available antibiotics continues to increase and is widely recognized as an impending, potentially catastrophic, problem. There is research to suggest that U. tomentosa components may have antibacterial potential individually or synergistically with established antibiotics against microbes, including Borrelia burgdorferi, the causative agent of Lyme disease. It is our intention that this review will provide a valuable resource to investigators in search of new antimicrobials to meet the daunting challenge of antibiotic resistance.

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“…The biosynthesis as well as synthesis of other representatives of this compound class is well studied (see e.g. Lopes et al 2019;Martin et al 1991). Therefore, similar work is necessary to investigate the proposed javaniside biosynthesis in Palicourea in the context of the general 2-oxindole alkaloids biosynthetic pathways.…”

Section: Javanisidementioning

confidence: 99%

Alkaloid diversification in the genus Palicourea (Rubiaceae: Palicoureeae) viewed from a (retro-)biogenetic perspective

et al. 2021

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The species-rich genus Palicourea (Rubiaceae: Palicoureeae) is source of an intriguing diversity of alkaloids derived from tryptamine and its precursor tryptophan. So far simple tryptamine analogues, polypyrroloindoline, β-carboline, and, most importantly, monoterpene-indole, i.e., tryptamine-iridoid alkaloids of various structural types including javaniside, alstrostine and strictosidine derivatives have been identified. Here the diverse alkaloids that numerous studies have found in the genus are examined and organized according to their structures and biosynthetic groups. Using a parsimony-based approach that follows the concept of retro-biogenesis usually applied in synthetic chemistry, possible biosynthetic pathways are proposed and important steps and relationships between these alkaloids are highlighted. Understanding alkaloid diversification is of importance in studying the ecological significance and evolution of biosynthetic capabilities of the genus Palicourea, and should stimulate future investigations on the biochemical and genetic background.

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Unnatural spirocyclic oxindole alkaloids biosynthesis in Uncaria guianensis

Cited by 23 publications

References 30 publications

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

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

Comprehensive Review of the Components in Cat’s Claw (Uncaria tomentosa) and Their Antibacterial Activity

Alkaloid diversification in the genus Palicourea (Rubiaceae: Palicoureeae) viewed from a (retro-)biogenetic perspective

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