Terpenoid indole alkaloids vinblastine

Vinblastine is a highly effective anticancer agent currently used clinically against leukemia, Hodgkin s lymphoma, and other cancers. (113, 114). Vinblastine is derived from dimerization of vindoline and another terpenoid indole alkaloid, catharanthine. 

After their discovery, the Vinca alkaloids became the first natural anticancer agents to be clinically used, and they are still an indispensable part of most curative regimens used in cancer chemotherapy nowadays. On the other hand, the plant producing these alkaloids, C. roseus, has become one of the most extensively studied medicinal plants. The levels of vincristine and vinblastine in the plant revealed to be extremely low and, for pharmaceutical production, approximately half a ton of dry leaves is needed to obtain 1 g of vinblastine [4]. This feet stimulated intense investigation in alternative methods for the production of vinblastine and vincristine, namely chemical synthesis and plant cell cultures. However, chemical synthesis showed not to be viable due to the high number of transformations involved, and the anticancer alkaloids were never detected in cell cultures, which express alkaloid metabolism very poorly [5, 6]. The biosynthetic pathway of terpenoid indole alkaloids in C. roseus has also been intensively studied with the objective of developing a manipulation strategy to improve the levels of the anticancer alkaloids in the leaves of the plant [5, 7-10]. 

After the discovery of the anticancer properties of vinblastine and vincristine, the elucidation of their structure, Fig. (1), was a natural step achieved in the early 60s [26, 27], and it was shown that they were dimeric terpenoid indole alkaloids - as already stated above. Simultaneously, further studies of the plant C. roseus revealed that this plant is an amazing chemical factory, producing more than 100 different terpenoid indole alkaloids, including two other with important pharmacological activity ajmalicine, used as an antihypertensive, and serpentine, used as sedative [6, 28]. 

Alkaloids of this class, like reserpine and vinblastine, play an important role in medicine. GC analysis of terpenoid indole alkaloids was shown to be possible by Lloyd et al. (1960). Later, this technique was further applied for various terpenoid indole alkaloids using packed columns (Verpoorte and Baerheim Svendsen 1984). More recently, capillary columns have been applied in the analysis of such alkaloids. 

Yang L, Wang H, Zu Y, Zhao C, Zhang L, Chen X, Zhang Z (2011) Ultrasound-assisted extraction of the three terpenoid indole alkaloids vindoline, catharanthine and vinblastine from Catharanthus roseus using ionic liquid aqueous solutions. Chem Eng J 172 705-712... 

Fig. 3 Biosynthesis pathway for terpenoid indole alkaloids in C. roseus. Unbroken arrows indicate single enzymatic conversions and broken arrows indicate multiple enzymatic conversions. The stmctures of ajmalicine and vinblastine are shown. STR, strictosidine synthase...

Terpenoid indole alkaloid biosynthetic enzymes are associated with at least three different cell types in C. roseus TDC and STR are localized to the epidermis of aerial organs and the apical meristem of roots, D4H and DAT are restricted to the laticifers and idio-blasts of leaves and stems, and GlOH is found in internal parenchyma of aerial organs (St-Pierre et al. 1999 Buriat et al. 2004) thus, vindoline pathway intermediates must be translocated between cell types. Moreover, enzymes involved in terpenoid indole alkaloid biosynthesis in C. roseus are also localized to at least five subcellular compartments TDC, D4H and DAT are in the cytosol, STR and the peroxidase that couples catharanthine to vinblastine are localized to the vacuole indicating transport of tryptamine across the tono-plast, SGD is a soluble enzyme associated with the cytoplasmic face of the endoplasmic reticulum, the P450-dependent monooxygenases are integral endomembrane proteins, and the N-methyltransferase involved in vindoline biosynthesis is localized to thylakoid membranes (De Luca and St-Pierre 2000). 

L-Tryptophan is an indole ring containing aromatic amino acid derived via the shikimate pathway. The tryptophan-derived alkaloids are found in eight families, of which, Apocynaceae, Loganiaceae, Rubiaceae, and Nyssaceae are the best sources. The alkaloids under discussion are the Catharanthus alkaloids, namely, ajmalicine, tabersonine, catharanthine, vindoline, vinblastine, vincristine and vincamine as well as terpenoid alkaloids derived from other families, namely, yohimbine, reserpine, strychnine, brucine, and ellipticine. The above-mentioned alkaloids are pharmacologically very important and hence extremely valuable. This chapter describes various aspects of the tryptophan-derived alkaloids like occurrence, biological activity, phytochemistry, and commercial and biotechnological aspects. 

---