Rauvolfia, ajmaline alkaloids

N.A. Rauvolfia serpentina (L.) Benth. Indole alkaloids, reserpine, rescinnamine, ajmaline, yohimbine.99 Regulate hearbeat, treat high blood pressure and anxiety. Sedative and depressant effect on sympathetic nervous system. 

Within the natural products field, the investigation of complete biosynthetic pathways at the enzyme level has been especially successful for plant alkaloids of the monoterpenoid indole alkaloid family generated from the monoterpene gluco-side secologanin and decarboxylation product of tryptophan, tryptamine [3-5]. The most comprehensive enzymatic data are now available for the alkaloids ajmalicine (raubasine) from Catharanthus roseus, and for ajmaline from Indian Rauvolfia serpentina [6] the latter alkaloid with a six-membered ring system bearing nine chiral carbon atoms. Entymatic data exsist also for vindoline, the vincaleucoblastin (VLB) precursor for which some studies on enzymatic coupling of vindoline and catharanthine exist in order to get the so-called dimeric Catharanthus indole-alkaloids VLB or vincristine [7-9] with pronounced anti-cancer activity [10, 11]. 

Synthesis of the anti-arrhythmic drug ajmaline from Rauvolfia plants, an efficient source of several alkaloid types used in therapy, represents an even more advanced study of the total enzymatic synthesis of terpenoid indole alkaloids. Ajmaline is a class I anti-arrhythmic alkaloid because of its activity as heart muscle sodium channels antagonist [35],... 

Ruppert, M., Xueyan, M. and Stockigt, J. (2005) Alkaloid biosynthesis in Rauvolfia-cDNA cloning of the major enzymes of the ajmaline pathway. Curr. Org. Chem., 9, 1431-44. 

Gao S, von Schumann G, Stockigt J. A newly detectedreductase from Rauvolfia closes a gap in the biosynthesis of the antiar-rhythmic alkaloid ajmaline. Planta Med. 2002 68 906-911. 

After deglucosylation, the pathway proceeds through a 4,21-Dehydrogeissoschizine derivative to ajmalicine (an a-Blocking spasmolytic agent, used for tinnitus and cranial trauma with an ergot derivative). If cyclization occurs between C-17 and C-18, the yohimbine nucleus is produced, whose derivatives include the Rauvolfia alkaloids reserpine and resdnnamine (antihypertensive activity). Ajmaline, formerly used as an antiarrythmic, also occurs in Rauvolfia species, and several of the enzymes in the pathway have been isolated. Recent considerations suggest that the C-16-C-5 bond may be formed before the N-4-C-21 bond (Fig. 38). 

AJMALINE The alkaloid ajmaline is isolated from the root of Rauvolfia serpentine and other Rauvolfia species, family Apocynaceae (see section C02, Antihypertensives). Ajmaline has a very similar mode of action to quinidine. It works through retardation of the speed of depolarisation and repolarisation as well as a retardation of the reactivation of the sodium-system. Its sedative effect is weak. 

According to their mode of action the Rauvolfia-alkaloids can be divided into two gronps the centrally acting reserpine, rescinnamine, and deserpidine and the peripherally acting yohimbine, raubasine and ajmaline. The blood pressure lowering effect is dne to an inhibition of the sympathomimetic effects in the autonomic nervous system and has a long latency and duration. The effect is dne to depletion of the serotonin and... 

Rauvolfia alkaloids are prepared in 0.5% alcoholic solution, and 10(l1 is applied for TLC, e.g. reserpine, rescinnamine, rauwolscine, ajmaline, serpentine. 

Three alkaloids from Rauvolfia species have industrial interest aj-maline (38), reserpine (39), and rescinnamine. Ajmaline is used for its antiarrhythmic activity, reserpine and rescinnamine for their antihyper-... 

Biosynthesis R. is derived from vomilenine, an intermediate in the biosynthetic pathway to the antiarrhyth-mic ajmaline, by glucosylation. The corresponding glucosyl transferase is membrane-bound, dependent on uridine diphosphate glucose, and has a high substrate specificity. A soluble, substrate-specific glu-cosidase effects the reversal of this reaction see also Rauvolfia alkaloids. 

Figure 1 Chemical structure of ajmaline (1), the typical ajmalan-type alkaloid of Rauvolfia. (The chiral centers are marked with atom numbers).

During the recent decades, attempts were made to detect novel biological and pharmacological activities of alkaloids from the genus Rauvolfia. The results demonstrated that ajmaline and derivatives interact with ion... 

A number of side routes originate from various intermediates of the ajmaline pathway (AP) are shown in Figure 22. They lead to a complex biosynthetic network of sarpagan and ajmalan alkaloids in Rauvolfia. 

The enzyme-catalyzed biosynthesis of the sarpagan-ajmalan-type firni-ihes of monoterpenoid indole alkaloids in the genus Rauvolfia, in particular R. serpentina Benth. ex Kurz, have recendy been delineated in detail. The major pathway leading to the structural intricate antiarrhythmic ajmaline, together with several side routes and bypasses, form a comprehensive and complex anabolic network of which a multitude of single-enzymatic... 

Tissue and cell cultures of Rauvolfia serpentina synthesize a plethora of alkaloids, dominated by yohimbine (5), ajmaline (37), and ajmalidine, which differed from that of any plant part and from undifferentiated cultures (Ellis, 1988). 

Plant Cells. The metabolism of unlabelled alkaloids in plant cell cultures has been followed using heteronuclear multiple quantum coherence NMR. The addition of ajmaline to cell suspension cultures of somatic hybrids of Rauvolfia serpentina Benth. ex Kurz and Rhazya stricta Decaisne (R x R cells) resulted in its conversion to raumacline. When, vinorine, an intermediate of ajmaline metabolism, was added to suspensions on R x R cells, vellosimine was formed and then converted to 10-deoxysarpagine. However, vinorine was apparently metabolised by a second pathway to vomilenine or raucaffricine." ... 

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