Monoterpenoid indole alkaloid

Mitragyna alkaloids. Alkaloids ( monoterpenoid indole alkaloids) from the genus Mitragyna (Rubiaceae), containing more than 10 species of trees found in the tropical and subtropical regions of Africa and Asia. Use The leaves, the bark and roots are used in traditional medicine in West Africa for the treatment of leprosy wounds, blood poisonings, colics, and as an emetic and diuretic also as yellow dye (bark, M. af-ricana). In India the dried leaves are smoked (like opium) and are supposed to be a substitute for opium... 

J. E. Saxton, ed.. Indoles, Part Four, The Monoterpenoid Indole Alkaloids, Wdey-Interscience, New York, 1983. 

The in vivo transformation of [6-14C]strictosidine (19) to gelsemine in Gelsemium sempervirens was claimed with an incorporation of 0.47% (33). This provides another experimental support to the proposal that strictosidine appears to be the original precursor in the biosynthesis of monoterpenoid indole alkaloids, although the detailed pathway of this biosynthetic process still remains obscure. 

The alkaloidal glucoside strictosidine was recognized in 1968 as the biosynthetic precursor of monoterpenoid indole alkaloids.3 The enzyme that... 

Fig. 10.1 Reaction catalyzed by strictosidine synthase (Str) in monoterpenoid indole alkaloid formation.

Salutaridinol 7-0-acetyltransferase catalyzes the conversion of the phenanthrene alkaloid salutaridinol to salutaridinol-7-Oacetate, the immediate precursor of thebaine along the morphine biosynthetic pathway in P. somniferum (Fig. 10.7).26 Acetyl CoA-dependent acetyltransferases have an important role in plant alkaloid metabolism. They are involved in the synthesis of monoterpenoid indole alkaloids in medicinal plant species such as Rauwolfia serpentina. In this plant, the enzyme vinorine synthase transfers an acetyl group from acetyl CoA to 16-epi-vellosimine to form vinorine. This acetyl transfer is accompanied by a concomitant skeletal rearrangement from the sarpagan- to the ajmalan-type (reviewed in2). An acetyl CoA-dependent acetyltransferase also participates in vindoline biosynthesis in Catharanthus roseus, the source of the chemotherapeutic dimeric indole alkaloid vinblastine (reviewed in2). Acetyl CoA deacetylvindoline 4-O-acetyltransferase catalyzes the last step in vindoline biosynthesis. A cDNA encoding acetyl CoA deacetylvindoline 4-0-acetyltransferase was recently successfully isolated.27... 

Since the last major review of the biosynthesis of the monoterpenoid indole alkaloids (97), there have been several full and partial 98-104) reviews of various aspects of the work that has been conducted since 1974. Two major developments have dominated the field in this period, namely, the demonstrations that (i) strictosidine (33) is the universal precursor of the monoterpenoid indole alkaloids and (ii) selected cell-free systems of C. roseus have the ability to produce the full range of alkaloid structure types, including the bisindoles. This section traces some aspects of these developments, paying particular attention to work been carried out with C. roseus, and omitting work, important though it may be, on other monoterpenoid indole alkaloid-producing plants, e.g., Rauwolfia, Campto-theca, and Cinchona. 

Kreuger and Carew (141) examined the effects of a number of alkaloid precursors on alkaloid production in suspension cultures and found that at 100 mg/liter tryptamine hydrochloride enhanced alkaloid production. The alkaloids produced, however, were A-acetyltryptamine and N,N-dimethyltryptamine, rather than the monoterpenoid indole alkaloids. Added geraniol and mevalonic acid had no effect on alkaloid production. 

Ihara, M. Fukumoto, K. (1997) Recent progress in the chemistry of non-monoterpenoid indole alkaloids. Nat. Prod. Rep., 14,413-29,... 

Stockigt J and Ruppert M (1999) Strictosidine - the biosynthetic key to monoterpenoid indole alkaloids. Comprehensive Natural Products Chemistry, Vol 4. Elsevier, Amsterdam, pp 109-138. 

Abstract The multi-step enzyme catalysed biosyntheses of monoterpenoid indole and isoquinoline alkaloids are described. Special emphasis is placed on those pathways leading to alkaloids of pharmacological and medicinal significance which have been fully elucidated at the enzyme level. The successful identification and cloning of cDNAs of single enzymes and their application provides great opportunities to develop novel strategies for both in vitro and in vivo alkaloid production in whole plants or tissue cultures, as well as in microbial systems such as Escherichia coli and yeast. 

Chemo-Enzymatic Synthesis of Monoterpenoid Indole Alkaloids. 78... 

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]. 

Enzymatic Formation of Monoterpenoid Indole Alkaloids 2.1 Heteroyohimbine /Sarpagine /Ajmaline Type Alkaloids... 

Chemo-enzymatic approaches to monoterpenoid indole alkaloids have attracted much interest since the beginning of the 1990s. At that time, synthetically early ... 

It became apparent early on that compounds of the 1,2-disubstituted cyclohexenes allow exploitation of a wide range of synthetic opportunities, leading to their frequent use in natural product synthesis the application of chemo-synthetic routes for selected monoterpenoid indole alkaloid alone are summarised here [86]. 

Fig. 10 Enzyme-catalysed formation of chiral monoacetate synthons from meso-diacetate or meso-diol for chemo-enzymatic synthesis of monoterpenoid indole alkaloids...

Fig. 12 First enantio-selective, chemo-enzymatic synthesis of the monoterpenoid indole alkaloid (-)-akagerine, member of the family of Strychnos alkaloids...

The monoterpenoid indole alkaloids constitute one of the largest and most complex groups of secondary metabolites produced by plants. They have been shown to occur mainly in the Apocynaceae, the Loganiaceae, and the Rubiaceae plant families, but are also found more sporadically in a few other families. Of the several thousand indole alkaloids that have been characterized, a number have been developed into valuable medicines for the treatment of neurological disorders (reserpine), cancer (vinblastine and vincristine), and as vasodilators (yohimbine).1 3... 

A large amount of structural information is available that describes the variety of indole alkaloids produced in plants. This has recently been followed by significant increases in our knowledge of the biosynthetic pathways that lead to their production and of the genes involved. Several reviews have appeared recently that describe the chemistry, biochemistry, cell and molecular biology of alkaloid biosynthesis.1 3 This chapter will selectively review recently characterized genes that appear to be responsible for the diversity and complexity of monoterpenoid indole alkaloids produced by plants. A particular focus will be on the reactions leading to the biosynthesis of vindoline (Fig. 8.1) in Catharanthus roseus. 

Geraniol 10 hydroxylase catalyzes the the cytochrome P450 dependent hydroxylation of geraniol at the C-10 position to commit this substrate to the formation of iridoid monoterpenoids (Fig. 8.2). In Catharanthus roseus, this intermediate is converted to secologanin for producing the tryptamine containing monoterpenoid indole alkaloids characteristic of this plant. 

Another all-carbon Diels-Alder reaction is proposed for the biosynthesis of the indole alkaloids tabersonine 1-6 and catharanthine 1-7 of the Aspidosperma and Iboga family [28-31]. The compounds are formed via strictosidine 1-3, the first nitrogen-containing precursor of the monoterpenoid indole alkaloids, and stemmadenine 1-4, which is cleaved to give the proposed intermediate dehy-drosecodine 1-5 with an acrylate and a 1,3-butadiene moiety (Scheme 1-1). 

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