Indole alkaloids group

One of the major subdivisions of plant alkaloids is termed the indole alkaloid group. All contain the basic indole heterocycle, and many have valuable pharmacological activity that can be exploited in drug materials. The indole portion is very often fused to another heterocycle we shall see some typical stractures in Section 11.9, where we shall consider them under fused heterocycles. 

Other representatives of the complex indole alkaloid group also tend to veer more towards the structurally specific type, and the more important of these will, in fact, be briefly discussed under the general heading of structurally specific agents. 

The isoquinoline alkaloids (1-4) along with the indole alkaloids are the most abundant groups of alkaloids. Their chemistry and synthesis have been extensively studied. In recent years one of the most interesting features of the chemistry of these alkaloids is the transformation among the different types. 

Researchers from Eli Lilly pharmaceuticals, (a company founded in 1876 by Colonel Eli Lilly veteran of the US Civil War), undertook further intensive phytochemical studies and characterized 60 alkaloids, of which a group of 20 binary indole alkaloids—including vincristine and vinblastine. Vinblastine sulphate (Velbe ) inhibits the polymerization of tubulin and is used to treat generalized Hodgkin s disease and chorionepithelioma, whereas vincristine sulphate (Oncovin ) is used to treat leukemia in children. 

A fourfold anionic domino process consistingofadominoMichael/aldol/Michael/ aldol process was used by Koo and coworkers for the synthesis of bicyclo[3.3.1]non-anes. They employed 2 equiv. of inexpensive ethyl acetoacetate and 1 equiv. of a simple a, 3-unsaturated aldehyde [290]. Differently substituted dihydroquinolines were assembled in a Michael/aldol/elimination/Friedel-Crafts-type alkylation protocol by the Wessel group [291]. An impressive approach in this field, namely the construction of the indole moiety 2-557, which represents the middle core of the man-zamines, has been published by Marko and coworkers [292]. Manzamine A (2-555) and B (2-556) are members of this unique family of indole alkaloids which were isolated from sponges of the genus Haliclona and Pelina (Scheme 2.126) [293]. 

Having an efficient total synthesis of the indole alkaloid vindoline in mind, the Boger group [47] developed a facile entry to its core structure using a domino [4+2]/[3+2] cycloaddition. Reaction of the 1,3,4-oxadiazoles 4-139 led to 4-140 in high yield and excellent stereoselectivity via the intermediates 4-141 and 4-142 (Scheme 4.29). 

The formation of the indole moiety has found immense attention, since it exists in many bioactive compounds such as the indole alkaloids [302]. Whilst the Fischer indole synthesis remains the most important procedure, during the past few years several transition metal-catalyzed syntheses have been developed. Recently, a Cu11-catalyzed cyclization of anilines containing an ortho-alkynyl group was published by Hiroya and coworkers [303], which allows a double cyclization in domino fashion to provide annulated indoles. Thus, reaction of 6/4-92 in the presence of... 

The relative and absolute configurations of diepoxydicarbazoles involving the 2,6-dioxa-4,8-diazaadamantane system were determined in the course of a study on indole and indole alkaloids.242 Water-soluble azo, anthraquinone, and phthalocyanine dyes which are substituted by a 4-chloro-s-triazin-2-ylamino group can be quaternized with a l-aza-3-methyl-4,6,10-trioxa-adamantane unit in aqueous medium at 40 50"C.243 Dyes mixed with... 

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... 

During the past two decades a great number of papers have been published on the isolation, structure elucidation, synthesis and transformation, biogenesis, chemotaxonomy, and pharmacology of indole alkaloids. In this chapter we summarize the new results that appeared from 1968 to mid 1984 for the cory-nantheine-yohimbine group of monoterpene indole alkaloids with greater emphasis on their chemistry, excluding the related oxindoles and heteroyohimbines. 

Cryptopine-type indole alkaloid bumamicine (572) has been synthesized from geissoschizine methyl ether (31) (287). In the first step, geissoschizol (34) was prepared, and then cleavage of the C/D ring fusion was carried out by means of ethyl chloroformate. Finally, C-3 carbonyl and 7V-methyl groups were developed by simple oxidation, reduction, and repeated oxidation steps. 

Bosch s group cross-coupled both 2- and 3-indolylzinc derivatives with diversely substituted 2-halopyridines to assemble 2- and 3-(2-pyridyl)indoles, which have become important intermediates in indole alkaloid synthesis [23-28]. Thus, l-(phenylsulfonyl)indole (30) was converted to 2-indolylzinc reagent 32, which was then coupled with 2-halopyridine 33 to secure 2-(2-pyridyl)indole 34. 

The Nagata group also developed a new approach to the construction of bridged aziridines via nitrene intermediates that led to the total synthesis of the indole alkaloids, ibogamine, velbanamine, and coronaridine (1968-1971). 

The psychoactive constituents of rauwolfia are alkaloids classified in three groups (1) weakly basic indole alkaloids, (2) intermediate basic indoline alkaloids, and (3) strong anhydronium bases. Approximately 50 alkaloids have been identified, but the principal indole alkaloids... 

The list of tryptophan-derived molecules could be extended almost without end tryptophan is the parent molecule of the indole alkaloids, a large group of plant compounds. 

The conversion of anhydrovinblastine (8) to vinblastine (1) has been examined by several different groups, using intact plants, cell suspension systems, and cell-free preparations. From the studies discussed above it was clear that 3, 4 -anhydrovinblastine (8) was probably the initially formed intermediate in the condensation of vindoline (3) and catharanthine (4) prior to vinblastine (1). Kutney and co-workers have reported (225,226) on the biotransformation of 3, 4 -anhydrovinblastine (8) using cell suspension cultures of the 916 cell line from C. roseus a line which did not produce the normal spectrum of indole alkaloids. After 24 hr the major alkaloid products were leurosine (11) and Catharine (10) in 31 and 9% yields, respectively, with about 40% of the starting alkaloid consumed. 

The indole alkaloid vinpocetine (93), has a vasodilatory effect and a clinical study on patients with CNS degenerative function due to vascular deficiency, demonstrated that those who were given vinpocetine, scored significantly better for cognitive function than a placebo group. However, these results are not translated into clinical use yet. 

An oxime derivative of indirubin (a natural bis-indole alkaloid used in traditional Chinese medicine to treat chronic myelocytic leukemia), indirubin-3 -monoxime (37), was found to be a potent inhibitor of cyclin-dependent kinases (CDKs), and of the proliferation of myeloid leukemia cells via inhibition of a tyrosine kinase . The 3D structure of the complex of 37 with CDK revealed that the oxime function is intact, and that it occupies the ATP-ribose site of the CDK-ATP structure. While the specific role of the oxime group in the biological activity of 37 is not clear, it was proposed that its reactivity may be utilized for further drug design... 

This is the latest volume in the series "The Alkaloids Chemistry and Biology and covers a group of alkaloids comprising the carbazole nucleus. Single-topic volumes in this series have been rare, and the last one discussed antitumor alkaloids and was published as Volume 25 in 1985. This is the first volume dedicated to a single alkaloid structure type since Volume 8, which dealt with the monoterpene indole alkaloids over 40 years ago. 

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