Alkaloids monomeric precursors

If the C-15, C-16 bond is oxidatively cleaved, the secodine skeleton results (the proposed progenitor of the Aspidosperma and the iboga systems) through alternative Diels-Alder type cyclizations to afford tabersonine and catharanthine. The bisindole alkaloids of Catharanthus roseus reflect the union of vindoline and catharanthine to afford anhydrovinblastine modification affords the clinically significant alkaloids, vinblastine (VLB) and vincristine (VCR Fig. 39). The alkaloids, particularly VCR, are important as anticancer agents and have led to the development of the semisynthetic derivatives vindesine and vinorelbine (Fig. 40). Synthetic approaches are available to join the monomeric precursors. The enzymatically controlled sequence of reactions from tabersonine to vindoline has been elucidated. 

Catharanthine (LIV) and vindoline (Lin) are regarded as the monomeric precursors of the dimeric alkaloids vinblastine and vincristine, via a-3 ,4 -anhydrovinblastine. C. roseus peroxidase catalyzes the coupling reaction of catharanthine and vindoline (Scheme XXVI) to lead to a-3 ,4 -anhydrovinblastine (XLVH) or, more properly, to an iminium intermediate (LVI) from which a-3 ,4 -anhydrovinblastine is directly derivated [52,74,166]. a-3 ,4 -Anhydrovinblastine is then converted to vinblastine (XLIX, R = CH3) and vincristine (XLIX, R = CHO) in C. roseus plants [167-169], a-3 ,4 -Anhydrovinblastine (XLVn), or the unstable iminium intermediate (LVI) formed during the coupling reaction, is then assumed to be the precursor of all dimeric alkaloids in C. roseus. 

Strictosidine is the general precursor of several divergent pathways leading to the multitude of TIAs accumulated by C. rosens. Somewhere, downstream of strictosidine formation, the pathway of TIAs suffers several ramifications mostly uncharacterized. The less ill characterized branches are the ones leading to catharanthine and vindoline, the monomeric precursors of the Vinca alkaloids, Fig. (2). Those branches will be the ones discussed here. 

Vindoline and catharanthine are the last monomeric precursors of the dimeric anticancer alkaloids of C. roseus, and they are also the two major alkaloids accumulated in the leaves of the plant [106, 107], The study of the dimerization biosynthetic step stems in early work on the chemical synthesis of the dimeric alkaloids and it has involved much discussion. Moreover, the chemical dimerization reaction has industrial application in the synthesis of vinorelbine and vinflunine. Due to its potential regulatory importance for the production of the dimeric Vinca alkaloids in the plant, and to the much that is known about the chemical and biosynthetic reactions, the dimerization step will be presented in particular detail here. 

In face of the structural similarities unraveled during the 1960s of vindoline and catharanthine with the dimeric alkaloids, and due to their great abundance in the plant, these two compounds were immediately considered the most likely monomeric precursors of the Vinca alkaloids, although the cleavamine moiety of vinblastine presented some differences from catharanthine, namely a fragmentation of the C5-C18 bond, Fig. (2). 

A key intermediate in the biosynthesis of all iridoid indole alkaloids is the glu-coside strictosidine (isovincoside. Fig. 260). Strictosidine is transformed to aj-malicine, which is a precursor of stemmadenine, tabersonine, vindoline and catharanthine (Fig. 261). The dimeric alkaloids, like vinblastine (vincaleuco-blastine) and vincristine (Fig. 259) are derived from monomeric precursors, e.g. catharanthine and vindoline. 

Finally, the monomeric precursors vindoline and catharanthine are coupled in a reaction thought to be catalyzed by a class III Prx, namely, CrPrxl, to yield the dimeric alkaloid 3, 4 -anhydrovinblastine, which is converted into vinblastine and then into vincristine (Scheme 4.7) [35, 36]. 

When LEE is used, it is advisable to do either very quickly or from only a moderately alkaline aqueous solution, which was basified by sodium carbonate or ammonia. The Catharanthus alkaloids was prepared by LEE from the 75 % ethanol extract at pH 3.5, then adjusted the basic to pH 12 and finally extracted by chloroform [7]. Three major alkaloids, vinblastine and its monomeric precursors (vindoline and catharanthine), were monitored in transformed root cultures of Catharanthus roseus, after rapid sample preparation by LEE in our previous work [8]. The extraction method was the same as above. Other Catharanthus alkaloids, such as vindoline, catharanthine, and anhydrovinblastine, were prepared by LEE from the methanol extraction [9]. 

As artefacts, dimers that are readily formed from monomeric precursors under mild conditions are obvious candidates, and the presence of acid during work-up can have far-reaching effects. In the bis-tertiary series, with ordinary methods of alkaloid extraction using acid, it is usually not possible to isolate bisnordihydrotoxiferine (4c), since it is highly labile and under such conditions rapidly isomerized and oxidized. However, Delle Monache et al. 

A partial synthesis101 of alstonerine (178) from macroline (179) (shown in Scheme 17) is of considerable interest, in view of the strategic position occupied by macroline as a possible precursor of both the monomeric Alstonia alkaloids (e.g. alstonerine) and the dimeric alkaloids (e.g. villalstonine and macralstonine). 

Feeding radioactive [8] as [3H-CO2CH3] and [10] as [14c-OCOCH3] into apical cutting of 3-4 month-old C. roseus plants afforded low but definite incorporations of both alkaloids into vinblastine [12] demonstrating that these monomeric alkaloids are the precursors of [12](90). Feeding both [acetyl-14C] vindoline and [OC3h3] catharanthine to 6 week-old differentiated C. roseus plants for 6 days, labelled anhydrovinblastine [11] was isolated (91). This was incorporated into vinblastine by cell-free preparations of Catharanthus roseus (92,93 ). 

Recently however, a basic peroxidase, anhydrovinblastine synthase, which couples eatharanthine and vindoline to yield anhydrovinblastine, the putative precursor to vinblastine and vincristine, has been purified and characterized from C. roseus leaves 421,422). The enzyme showed a specifie anhydrovinblastine synthase activity of l.Snkatmg and a molecular weight of 45.40kDa. It was shown to be a high-spin ferrie heme protein belonging to the plant peroxidases superfamily (class HI peroxidases), and eytochemical studies showed that the enzyme is localized in the mesophyll vacuoles, in individual spots at the inner surface of the tonoplast. On the basis of the ability of the monomeric alkaloid substrates to reduce the C. roseus basic... 

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