Strictosidine derivatives

It is reasonable to assume that the unique precursor of angustine bases is strictosidine lactam (16), the intramolecular cyclization product of strictosidine (17). The prerequisite for cyclization is the presence of a secondary amino group in the C ring of strictosidine, that is to say, the presence of a hydrogen atom on N-4. Indeed, compound 18, the AT-benzyl-substituted aglycone of strictosidine, is not subject to cyclization, but is rather in equilibrium with the open form (19) (27). Similarly, replacement of a tetrahydro-(3-carboline unit, such as one finds in strictosidine, by a P-carboline moiety inhibits the cyclization step and thus leads to tetracyclic derivatives, typical of the alkaloids of the genus Pauridiantha. 

As far as biosynthesis is concerned, it is clear that lyaloside (23) and pauridianthoside (26) readily derive from strictosidine (17). These three molecules display identical stereochemistry at the three chiral centers, namely, a,a,(3 for the hydrogen atoms at the 15, 20, 21 positions, respectively. They are closely related to a number of glucoalkaloids identified in Pertusadina euryncha (= Adina rubescens), e.g., rubenine (31) and desoxycordifoline (34, R = H) (49), and in Adina cordifolia, e.g., cordifoline (34, R = OH) (50). Palinine (35),... 

In the course of this chapter devoted to the alkaloids of Pauridiantha, their biosynthesis has been mentioned and some chemotaxonomic correlations have been proposed. As all glucoalkaloids described here derive from strictosidine, a more systematic analysis of its metabolic evolution in plants seems of interest. 

In the state of the art, Scheme 1 shows that the number of Rubiaceae containing glucoalkaloids derived from strictosidine is limited to members of the... 

Terpenoid Indole Alkaloids.—Important recent work has defined strictosidine (97) as a key intermediate in the biosynthesis of terpenoid indole alkaloids with both 3a- and 3/3-configurations. Some of this work, published earlier in preliminary form (cf. Vol. 9, p. 18), is now available in a full paper.26 In addition to those alkaloids examined earlier, strychnine, gelsemine, vincadifformine, isoreserpiline, aricine, isoreserpinine, and ajmaline have been shown to derive from strictosidine (data are also included for ajmalicine, for catharanthine, and for vindoline which had been reported earlier). 

Strictosidine synthetase catalyzes the stereospecific condensation of trypt-amine and the iridoid glucoside secologanin to form strictosidine. The product is the precursor of the monoterpenoid-derived indole and quinoline alkaloids. 

Figure 1.3 Several pathways of secondary metabolites derive from precursors in the shikimate pathway. Abbreviation NPAAs, non-protein amino acids PAL, phenylalanine ammonia lyase TDC, tryptophan decarboxylase STS, strictosidine synthase CHS, chalcone synthase. (See Plate 2 in colour plate section.)...

Stereospecific condensation between tiyptamine and seco-loganin in a Mannich-like reaction is carried out by the enz)une (S)-strictosidine s)m-thase and results in the formation of the glucoalkaloid, (S)-strictosidine, from which most monoterpene indole alkaloids are derived (Figs. 2.1 and 2.9). 

All terpenoid indole alkaloids are derived from tryptophan and the iridoid terpene secologanin (Fig. 2b). Tryptophan decarboxylase, a pyridoxal-dependent enzyme, converts tryptophan to tryptamine (62, 63). The enzyme strictosidine synthase catalyzes a stereoselective Pictet-Spengler condensation between tryptamine and secologanin to yield strictosidine. Strictosidine synthase (64) has been cloned from the plants C. roseus (65), Rauwolfla serpentine (66), and, recently, Ophiorrhiza pumila (67). A crystal structure of strictosidine synthase from R. serpentina has been reported (68, 69), and the substrate specificity of the enzyme can be modulated (70). 

The biosynthetic pathway for ajmaline in R. serpentina is one of the best-characterized terpenoid indole alkaloid pathways. Much of this progress has been detailed in a recent extensive review (78). Like all other terpenoid indole alkaloids, ajmaline, an antiarrhythmic drug with potent sodium channel-blocking properties (79), is derived from deglycosylated strictosidine (Fig. 2c). 

Rubiaceae and Loganiaceae. The molecular acrobatics of the various systems derived from deglucosylation of the primordial alkaloid strictosidine accounts for this stunning structural diversity. 

Cinchona species (Rubiaceae) are sources of quinine and quinidine, containing a quinoline nucleus and derived through the extensive elaboration of strictosidine (Fig. 42). The intriguing history of the antimalarial quinine and its role in world politics over the past 350 years are legendary. It is frequently the only antimalarial drug to which patients are not resistant. Its widest use, however, is in the beverage industry in tonic water. Quinidine, an isomer of quinine, is used to treat cardiac arrythmias. 

The basic stmcture of monoterpenoid indole alkaloids includes an indole nucleus derived from tryptophan via tryptamine (L) and a versatile C9 or CIO unit arising from the monoterpenoid secologanin (LI). Strictosidine synthase catalyzes the synthesis of strictosidine (LII) from tryptamine and secologanin (Scheme XXIV) [76],... 

Rauvolfia, Vinca, and Strychnos species. Strictosidine (79) and 5a-carboxy-strictosidine (78) have been isolated from R. serpentina and S. nux-vomica and were characterized as the pentaacetate and the methoxycarbonyl pentaacetate derivatives, respectively. 

The initial preparation of dihydromancunine (Scheme 13) used an N -blocking group to avoid formation of vallesiachotamine derivatives (i.e. cyclization of C-17 onto iVb). Subsequently" it was found that a blocking group is unnecessary if more acidic media are used, but the yield is lower owing to denaturing of the enzyme used. In an extension of these studies to the 3a-H series strictosidine, treated with... 

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]. 

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