Formation of the Indole Alkaloids Serpentine and Ajmalicine in Cell Suspension Cultures of Catharanthus roseus

Abstract

The Rauwolfia alkaloid, ajmalicine, has been found to have broad application in the treatment of circulatory diseases, especially in the relief of obstruction of normal cerebral blood flow. In combination with other Rauwolfia alkaloids it has been used to lower high blood pressure. Annually an estimated 3500 kg of ajmalicine are isolated from natural sources, by pharmaceutical industries worldwide, for therapeutic use in the treatment of these diseases. To date, ajmalicine has been found to occur as a natural product in 20 species of the genus Rauwolfia, four of Catharanthus, two of Mitragyne and in Paus-inystalia yohirribe, and Stemmadenia obovata (13). For industrial purposes ajmalicine is extracted from dried Rauwolfia roots. However, it can also be prepared from the alkaloid serpentine by reduction with BH-4. Since there is an overall shortage of Rauwolfia drugs, increasing use is being made of the serpentine reduction method. In roots of the fast growing Catharanthus roseus low amounts of ajmalicine, but relatively large amounts of serpentine are produced. This latter compound is first isolated then converted to ajmalicine. The biosynthesis of ajmalicine and serpentine has been clarified by isotope incorporation studies using differentiated plants of C. roseus (11, 4, 24). The biosynthetic sequence is shown in Figure 1 and involves the condensation of tryptamine with the iridoid glycoside, secologanin to give vincoside (19) which is subsequently, in several unknown steps, transformed to ajmalicine and finally oxidized to serpentine.