Dehydrogeissoschizine from strictosidine

Deglucosylated strictosidine is converted via several unstable intermediates into 4,21-dehydrogeissoschizine from which catharanthine and vindoline are believed to derive, Fig. (5). This part of the pathway has been scarcely characterized - it includes an undetermined number of steps, seems to involve the intermediate stemmadenine, and the branching point for the 2 paths giving rise to catharanthine and vindoline has been proposed to be dehydrosecodine by Blaskd and Cordell [71], and to be stemmadenine by Verpoorte et al. [89]. The 6 last biosynthetic steps leading to the production of vindoline from the intermediate tabersonine have been thoroughly characterized and are represented in Fig. (6) [45, 90]. 

Vincamine, vinblastine and vincristine are very important clinic alkaloids. They are produced naturally by plants vincamine by Vinca minor, and vinblascine and vincristine by Madagascar periwinkle Catharanthus roseus). The vindoline synthesis pathway starts with strictosidine and, via dehydrogeissoschizine, preakuammicine, stemmadenine and tabersonine, is converted to vindoline and vincristine (Figure 42). Conversion from vindoline to vinblastine is based on the NADH enzyme activity. Vinblastine and vincristine are very similar alkaloids. The difference is that vincristine has CHO connected to N, whereas vinblastine in the same situation has only CO3. This synthetic structural differences influence their activity. Vinblastine is used to treat Hodgkin s disease (a form of lymphoid cancer), while vincristine is used clinically in the treatment of children s leukaemia. Vincristine is more neurotoxic than vinblastine. 

The knowledge of the biosynthesis of catharanthine is very limited only some feeding experiments with labeled precursors have been described, quite some years ago. Qureshi and Scott (227-229) reported that catharanthine is formed from tabersonine fed to the plant. However, other groups have not been able to confirm these results (230-232). Corynantheine aldehyde (229) and geissoschizine fed to C. roseus plants were reported to be incorporated into catharanthine (233). From these experiments it is believed that the pathway goes from strictosidine via 4,21-dehydrogeissoschizine, stemmadenine, and dehydrosecodine (Fig. 16). Based on the structures, the involvement of tabersonine in the catharanthine pathway is not likely, despite the reports of its incorporation. So far, nothing is known about the enzymes involved in this pathway. 

Scheme 13.61. A path, involving a Pictet-Spengler ring closure of the imiue formed from the reaction of tyramine with secologanin to strictosidine and thence to dehydrogeissoschizine. The process is supported by a large number of feeding experiments with labelled compounds. (Much of this chemistry has been reviewed and, at any rate, is too extensive to repeat here. See, for example, Scott, A. I. in Hey, D. H. Wiesner, K. F. (eds.), MTP International Review ofScience Vol. 9, Butterworths, London, 1973,pp. 105 ft) The final cyclization and ring closure processes appear to be spontaneous.

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