Leurosine biotransformations: an unusual ring-fission reaction catalyzed by peroxidase

Abstract

The dimeric Vinca alkaloid leurosine undergoes an unusual fission of the piperidine ring of the Iboga substructure when reacted with horseradish peroxidase and hydrogen peroxide. A preparative-scale oxidation of leurosine provided 15'-hydroxycatharinine, which was identified by infrared and proton and carbon-13 NMR spectroscopies and high-resolution mass spectrometry. A proposed pathway for the formation of 15'-hydroxycatharinine involves radical and iminium intermediates and cleavages of a putative diol. The enzymatic transformation product is 3 orders of magnitude less active than leurosine or vinblastine in vitro, in inhibiting the polymerization of tubulin.

Selective Metabolism of Vincristine in Vitro by Cyp3a5

“…5A). An analogous oxidative biotransformation pathway has also been reported for leurosine, another dimeric Vinca alkaloid, when it was catalyzed by horseradish peroxidase (Goswami et al, 1988). Furthermore, a similar compound, catharinine, has been reported as a natural product from several Catharanthus species (Andriamialisoa et al, 1978) as a result of the C-13 and C-14 bond fission of the piperidine ring, probably following the same metabolic reaction from an appropriate precursor in plants.…”

Structure elucidation of indole–indoline type alkaloids: A retrospective account from the point of view of current NMR and MS technology

“…In addition to the works discussed above in some detail, in many studies mass spectrometry was used only to provide an elemental composition for the given molecular weight derived from HR-EI-MS measurements or to list the main fragments as a fingerprint pattern without giving any structural explanation [29][30][31][32][33][34].…”

“…In many of these studies no spectroscopic discussion was reported, only an enumeration of some characteristic 1 H peaks of the biosynthetic products [69], or partial 1 H and 13 C assignments were given [34]. In some other cases NMR spectroscopy served as an indispensable tool to understand the reaction mechanisms.…”

“…Since several bisindoles are used as active pharmaceutical ingredients, some attempts were made to characterize their metabolites [32][33][34]41], degradation products, and process-related impurities [51,[91][92][93] using NMR spectroscopy in some cases.…”

“…The structure elucidation of oxidative in vitro metabolites was reported in references [32][33][34]41]. Due to the structural complexity of these compounds, and because of the low sensitivity of the applied instruments, preparative-scale incubation was necessary in all cases starting from more than a hundred mg of the bisindole derivative and a large amount of enzymes.…”