Ellipticine derived alkaloids

A few alkaloids are derived from carbazole, e.g. murrayanine 1 (l-methoxycarbazole-3-carbaldehyde) and ellipticine 2, which is a carbazole system with a fused pyridine ring. Ellipticine is one of the substances which can intercalate into human DNA. The molecule is inserted between two paired bases. Ellipticine derivatives are approved in some countries for use as cytostatic agents [59]. 

Diels-Alder reactions using 2-vinylindoles as the diene were used as the key step in syntheses of olivacine derivatives (155), ellipticine derivatives (157), and ( )-3-epi-dasycarpidone (162) [65] (Scheme 39). In the synthesis of ( )-3-epi-dasycarpidone, the appropriate 2-vinylindole 159 was prepared via a one-pot procedure, and then subjected to deprotection of the aUyl carbamate, and subsequent enamine formation, followed by an intramolecular Diels-Alder reaction to produce 161, thereby producing the indole alkaloid framework in three steps from a rather simple starting material, 158. The attempted cycloaddition reaction... 

L-Tryptophan is an indole ring containing aromatic amino acid derived via the shikimate pathway. The tryptophan-derived alkaloids are found in eight families, of which, Apocynaceae, Loganiaceae, Rubiaceae, and Nyssaceae are the best sources. The alkaloids under discussion are the Catharanthus alkaloids, namely, ajmalicine, tabersonine, catharanthine, vindoline, vinblastine, vincristine and vincamine as well as terpenoid alkaloids derived from other families, namely, yohimbine, reserpine, strychnine, brucine, and ellipticine. The above-mentioned alkaloids are pharmacologically very important and hence extremely valuable. This chapter describes various aspects of the tryptophan-derived alkaloids like occurrence, biological activity, phytochemistry, and commercial and biotechnological aspects. 

Several of the naturally occurring indoles also have clinical importance. The dimeric vinca alkaloid vincristine and closely related compounds were among the first of the anti-mitotic class of chemotherapeutic agents for cancer[14]. The mitomycins[15] and derivatives of ellipticine[16] are other examples of compounds having anti-tumour activity. Reserpine, while not now a major drug, was one of the first compounds to show beneficial effects in treatment of mental disorders[17]... 

The antitumor alkaloid ellipticine (5,1 l-dimethyl-6//-pyrido[4,3-b]carbazole) has been isolated from many species of Ochrosia and Aspidosperma. Ellipticine and its derivatives are highly active versus several experimental neoplasms, and the compound has been widely subjected to studies devoted to its total synthesis, the preparation of derivatives, and metabolism. Metabolic transformation studies with ellipticines have been conducted, using microorganisms, in vivo and in vitro... 

In 1981, Potier et al. reported the isolation of N-oxyellipticine (240) from O. moorei (181). In the following year, Michel et al. reported the isolation of another N-oxyellipticine derivative, N-oxy-13-oxoellipticine (241), from the stem bark of S. dinklagei (184). Five years later, the same authors isolated from the bark of the same natural source, a novel, natural, bis-ellipticine alkaloid, strellidimine (242), in racemic form (221). Strellidimine represented the first example of a natural bis-ellipticine alkaloid, containing a 9-hydroxyellipticine (230) unit (see Scheme 2.56) linked to a 3,4-dihydroellipticine (236) unit (see Scheme 2.57) (221) (Scheme 2.59). 

In a sequence that proceeds by tandem directed ortho metalation steps (Scheme 133) the N,N-diethyl isonicotinamide (447a) has been converted into the chemotherapeutic alkaloid ellipticine (589) (Scheme 182) (80JA1457). Thus, in a rapid, one-pot procedure, metalation of 447a followed by condensation with N-protected indole-3-carboxaldehyde derivatives leads to the intermediates 615 which, upon second metalation and aerial oxidation affords the quinones 616 in modest to good yields. Established steps were used to convert 616, R = CH2OMe into ellipticine (589), concluding a route which complements that based on the oxazolino DMG (Scheme 175). 

Ellipticine inhibits DNA, RNA and protein synthesis. The inhibition is not reversible by removal of the alkaloid. It has no appreciable effects on thymidine and uridine kinases or on RNA polymerase, but it markedly inhibits DNA polymerase activity [240, 241]. The actual mechanism of action of ellipticine and related compounds has not yet been elucidated. Ellipticine and derivatives have been found to interact with bacterial membranes [242]. Many investigators have categorized these compounds as DNA-interacting or intercalating agents [230, 235, 237,243-246]. It has recently been postulated that mammalian DNA topoisomerase II may be a common target of these antitumour compounds [247],... 

A further extension of this strategy has been employed as a route to carbazoles, as illustrated by the synthesis of the system 116 from the 2-nitrobiphenyl derivative 117 (Equation 30) <20040L533>. A substituted 2-nitrobiphenyl derivative has been cyclized to a carbazole using P(OEt)3 en route to the pyridocarbazole alkaloid ellipticine <2006HCA111>. It should also be mentioned that annulation of o-(alkynyl)nitrobenzene precursors with TBAF or pyridine gave access to indol-3-one-l-oxides (isatogens) <2003T2497>. 

Ellipticine (1) and 9-methoxyellipticine (2) have been isolated from Ochrosia acuminata stems (22) and from in vitro callus cultures derived from the stems of Ochrosia elliptica (23,24). It is found that the in vitro production of these alkaloids can be increased by cloning small cell aggregates. 

Sainsbury and co-workers (121) have synthesized several ellipticine dimers tethered through the C-5 methyl group (333) (Scheme 53) or the C-9 position (334). The 9-methoxy derivative of 333 was also prepared. The nitrile 329 was available from the Sainsbury ellipticine synthesis (122) and was transformed into the alkaloid 17-oxoellipticine (148). A clever maneuver was to add nitric acid to protonate the pyridine nitrogen of 330. This precluded A-oxide formation during dithiane hydrolysis. Reductive amination in two steps afforded the amine 332. Coupling with adipic acid gave the target bisellipticine 333. 

The metabolism of any drug is invariably of theoretical and practical importance, and the metabolic behavior of the ellipticine family of antitumor alkaloids and synthetic derivatives is no exception. A number of new developments have been described since the Suffness and Cordell review 10). The pharmacokinetics of elliptinium (5) have been studied in a human brain tumor clonogenic cell assay (250) and in metastatic breast cancer patients (257). In the latter study, the drug was mainly excreted in the feces ( C-labeled 5)... 

Phenethylamine-type N-oxides also undergo carbon-carbon bond fragmentation under modified Polo-novski conditions, as illustrated by the reaction of N,A -dimethyltryptamine N-oxide (66), wherein cleavage of the side chain is facilitated through participation of the electrons on the indole nitrogen (equation 18). The ease with which N-oxide (66) undergoes fragmentation implies that the in vivo equivalent of this reaction is important in the biosynthesis of certain indole alkaloids, such as ellipticine (38) and val-lesamine (67 Scheme 13), whose derivation from tryptophan is not immediately obvious. 

Ellipticine and derivatives can be detected at their UV-maximum of about 300 nm with a detection limit of about 1 ng. For some alkaloids, fluorescence detection is even more sensitive - allowing detection in pg amounts (excitation 305 nm, emission 470 nm). A poorly fluorescent compound such as 9-hydroxy-2-methylellipticinium acetate could be transformed to its fluorescent acetoxy derivative36. Bykadi et al. 8 also detected ellipticine fluorimetrically (excitation 360 nm, emission 455 nm). 

Early examples of the total synthesis of naturally occurring indole alkaloids employing the Suzuki reaction include ellipticine (10) as repotted by Miller et al. [34], The aryl bromide, 6-amino-7-bromo-5,8-dimethylisoquinoline (45) was derived from 2,5-dimethylanilinc in nine steps. The Suzuki coupling of 45 with phenylboronic acid was carried out using catalytic tetrakis(triphenylphosphine)palladium in benzene and with Na,CO, serving as the base to furnish... 

Ellipticine (41) and its 9-methoxy derivative (42) have great interest as antitumor dmgs. These alkaloids are isolated from the leaves of Ochrosia elliptica, a shmb found on scattered islands in the Indian and Pacific Oceans. Plant cell cultures would thus be of interest as an alternative means of production of the antitumor alkaloids. For a review on the genus, its alkaloids, and cell culture, the reader is also refered to Chenieux et al. (716). 

Kouadio and co-workers (717) reported the initiation of callus cultures of this plant. Best results were obtained with calli derived from leaves. Both ellipticine and its methoxy derivative were present in the calli at levels similar to those found in the leaves of the plant (60 and 150 fig/g DW). About 5-10% of the total alkaloids could be isolated from the medium. Production of the alkaloids remained stable for a prolonged period. Weber et al. (718) could not detect alkaloids in calli derived from... 

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