Ellipticine and derivatives

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],... 

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). 

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... 

The UV spectrum (7max 235, 270 (sh), 279,301,312, and 378 nm) of 236 indicated a dihydropyrido[4,3-l7]carbazole framework. This assignment was supported by the IR spectrum (v ax 843, 1028, 1167, 1410, 1595, and 1615 cm ). The structure for 3,4-dihydroellipticine was confirmed by synthesis from ellipticine and comparison of the IR and UV spectra, melting points and Rf values. Additional support for this assignment derived from the transformation into derivatives of 3,4-dihydroellipticine (216). 

The complete in vivo anti-tumor mechanism of action of ellipticine and its derivatives is still not well understood. However, a tremendous amount of work has... 

Of the x-ray crystal structure determinations made of 6-4-5, 6-5-5, 6-6-5, and 6-7-5 fused heterocycles, many are of furocoumarin/furochromone, ellipticine, and PQQ derivatives because of their importance to biomedical investigations. Mention is made of these in their respective sections (7.22.12.2-7.22.12.4). A bibliography which lists the remaining structures, arranged according to central ring size and ring system formula, is presented in Table 1. 

An X-ray crystal structure of 9-methoxy-ll-demethylellipticine (9) (25) reveals little difference in geometry from that previously observed in ellipticine and its derivatives (29,30). Thus, the absence of a methyl group at C-11 and the presence of the 9-methoxyl substituent does not alter the pyrido[4,3-5]carbazole structure. An X-ray crystal structure study of the charge-transfer complex formed between 9-methoxyellipticine (2) and 7,7,8,8-tetracyano-p-quinodimethane... 

Scheme 54, Synthesis of ellipticine-estrone derivative 337 by Roques and co-workers U23).

Several significant developments have occurred during the late 1980s in the study of the antitumor activity of ellipticine and its derivatives, which are highlighted in this section. Further discussion on the antitumor activity of these compounds is expounded upon in Section XI. 

Another aspect of the mode of action of ellipticine and its derivatives that has been intensely scrutinized in recent years is the chemistry of ellipticine quinone imines 6 and 256. The oxidation product of 9-hydroxyellipticine (3), formed by horseradish peroxidase-hydrogen peroxide or chemical (e.g., manganese dioxide) oxidation of 3, undergoes a rich array of chemical reactions. Meunier et al. 

Ellipticine and several derivatives were able to displace 7,12-dimethyl-benz[a]anthracene from binding to bovine and human serum albumin using the fluorescence-quenching technique (192,193). The site of binding of ellipticines appears to be on the hydrophobic regions of the enzyme. A fast kinetic experimental technique, namely, temperature-jump spectroscopy, has been developed in order to study the interaction of elliptinium, and other molecules, with biological macromolecules (194). 

Several ellipticine derivatives were evaluated for their effects on Escherichia coli strains (795). There does not appear to be a correlation between the physiological effects of the ellipticines and their physiochemical behavior in vitro. 

Several reports have appeared recently that describe the mutagenicity of ellip-ticine and derivatives. Moore and co-workers 245) have shown that ellipticine... 

Ellipticine and its derivatives as well as related quaternary ammonium compounds have been separated on an octadecyl column with methanol - water mixtures, to which 1-heptanesulfonate... 

An efficient synthesis of ellipticine quinone affords a useful improvement in syntheses of ellipticine and its derivatives via... 

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... 

Jackson et al. have reported yet another refinement of the Cranwell-Saxton synthesis of ellipticine, and have also investigated a new route, which has so far resulted in the preparation of the intermediates, (176a) and (176b). In principle, these diphenylamine derivatives should be convertible into AT-acetyl-ellipticines by thermal cyclisation and dehydrogenation, or into ellipticine by photo-cyclisation of the free amines. Although a considerable amount of (176a) was prepared, its conversion into 9-methoxyellipticine has not yet been reported. 

Olivacine (52) and ellipticine (53) are antileukemic agents in mice, and derivatives of ellipticine are used clinically in Europe (Fig. 34.14) (CordeU, 1978 Gribble, 1990). The principal mechanism of action is related to the planar structures of this group of alkaloids. Ellipticine and its derivatives appear to inhibit topoisomerase II they also are mutagenic and clastogenic at the tk locus of mouse lymphoma cells. The major mechanism of action appears to be chromosomal cleavage (Bonis and Schaeffer, 1992 Gribble, 1990). These alkaloids inhibit DNA synthesis by intercalation into DNA. 9-Methoxyellipticine and ellipticine inhibit mitochondrial respiration and cytochrome c oxidase (Wink, 1993). 

Carbazoles have a long history of examination for biological activity. Notably, in 1992 Mauffret and co-workers completed the synthesis of isomeric ellipticine and several other derivatives to test their antitumor properties. Starting with (2,5-dimethyl-3-nitrophenyl)hydrazine 23 was heated in a solution of sodium acetate and hydrochloric acid with cyclohexanone or 4-methoxycyclohexanone to provide the tetrahydro-carbazoles 24a and 24b in moderate yields. Refluxing the intermediate in xylene and 2 equiv of DDQ for 3 h provided the advanced intermediates 25a and 25b, which were carried on to the targeted derivatives in short order. 

Janot and co-workers used the cyclization to achieve the total synthesis of ellipticine and some important derivatives. The synthesis of the ellipticine derivatives began with phenyl hydrazine 26 and 2,5-dimethylcyclohexanone 27 that were heated with hydrochloric acid in ethanol to achieve both the tetrahydrocarbazole 28 and a minor component of indole 29, which differ only in the regioselectivity of the cyclization. The tetrahydrocarbazole was isolated and then oxidized by treatment with... 

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