Anhydrovinblastine biosynthesis

Additionally, there had, for many years, been a vast synthetic effort underway aimed at the synthesis of the two monomeric units, where it was anticipated that the two units could be joined to form the vinblastine-type bisindole alkaloids. Coincidentally, as it transpired, 20 years of effort in the areas of synthesis and biosynthesis converged, at almost the same time, on the compound 3, 4 -anhydrovinblastine (8). 

The extremely low yield of vincristine (2) from intact plants has made pursuit of its biosynthesis a very challenging problem, which at this point in time remains unsolved. Kutney et al. have used both anhydrovinblastine (8) (227) and catharanthine N-oxide (107) (233) as precursors to vincristine (2) in a cell-free preparation, but incorporation levels were extremely low. Therefore, the question of whether vinblastine (1) is an in vivo, as well as an in vitro, precursor remains to be answered. Several possibilities exist for the overall oxidation of vinblastine (1) to vincristine (2), including a direct oxidation of the A-methyl group or oxidative loss of the N-methyl group followed by N-formylation. 

Further information is available on the biosynthesis of vinblastine-type alkaloids (cf. Vol. 11, p. 19 Vol. 10, p. 19). Anhydrovinblastine (61) was found to be metabolized to leurosine (63) and Catharine (64) in cultures of a C. roseus cell-line that do not normally produce these alkaloids.55 Ring-opening in the conversion of the skeleton of anhydrovinblastine (61) into that of Catharine (64) has been suggested to occur by Baeyer-Villiger-type oxidation of an imine las (62). The alternative 21 -imine could give catharinine.56... 

Scott AI, Gueritte F, Lee SL. Role of anhydrovinblastine in file biosynthesis of file antitumor dimeric indole alkaloids. J. Am. 

Baxster RI, Dorschel CA, Lee SL, Scott AI. Biosynthesis of the antitumor cafiiaranfiius alkaloids. Conversion of anhydrovinblastine into vinblastine. J. Chem. Soc. Chem. Comm. 1979 257-259. Gueritte F, Bac NV, Langlois Y, Potier P. Biosynthesis of antitumour alkaloids from Cafiiaranfiius roseus. Conversion of 20 deoxyleurosidine into vinblastine. J. Chem. Soc. Chem. Comm. 1980 452-453. 

There are, however, a few examples in which the exclusive participation of peroxidase in the synthesis of natural bioactive alkaloids has been reported. These mainly concern the biosynthesis of some monoterpenoid indole alkaloids, especially the synthesis of a-3 ,4 -anhydrovinblastine (XLVII) [76],... 

Fig. (2). Biosynthesis of vinblastine from the monomeric precursors catharanthine and vindoline. Anhydrovinblastine is the direct product of the dimerization reaction and the precursor of the anticancer drugs. Shaded areas indicate the structural differences between the precursor catharanthine and the deavamine part of...

The search of the enzyme responsible for the dimerization reaction, i.e. for the biosynthesis of anhydrovinblastine, resulted in the finding that peroxidase-like activities extracted from cell suspension cultures were capable of performing the coupling of catharanthine and vindoline into anhydrovinblastine [125-127]. Horseradish peroxidase, a commercial plant peroxidase, was also capable of performing the coupling reaction [128]. 

Sottomayor M, Ros Barcelo A (2003) Peroxidase from Catharanthus roseus (L.) G. Don and the biosynthesis of a-3, 4 -anhydrovinblastine a specific role for a multifunctional enzyme. Protoplasma 222 97-105. doi 10.1007/s00709-003-0003-9... 

---