Ellipticine derivatives

Biochemical oxidation of the ellipticine derivative 241 to the o-quinone 242 has been achieved using hydrogen peroxide and horseradish peroxidase (HRP) as a catalyst (83JMC574). Compound 242 was easily protonated to form a tautomeric equilibrium between 243 and 244 it gave an addition product with methanol and was reduced by cysteine (Scheme 41). 

Most of the new synthetic work on ellipticine in the late 1980s has dealt with modified ellipticine derivatives. Several French groups have made enormous strides in the design and synthesis of ellipticine analogs. The material in this section is divided into nine areas A. Synthesis of Substituted Ellipticines B. Synthesis of Isoellipticines C. Synthesis of Azaellipticines D. Synthesis of Nonlinear Pyridocarbazoles E. Synthesis of Oxazolopyridocarbazoles F. Syn-... 

In the late 1980s, several new ellipticine derivatives and modified ellipticines... 

The interaction of ellipticine derivatives with topoisomerase II enzymes in Plasmodium berghei (163), a parasite of mouse red blood cells, mouse lymphoma L5178Y cells (164), simian virus 40 CV-1 cells (165), Trypanosoma cruzi (166,167), and the human small-cell lung cancer cell line NCI N417 (168,169) has been studied. In the latter study, the highest in vitro activity in the topoisomerase II-DNA cleavage reaction and decatenation was observed for elliptinium (5) and datelliptium (384) (769). 

The effect of ellipticine derivatives on membranes and model membranes continues to be of interest to Sautereau and co-workers (184-186), who included 3ip-NMR techniques in their study (185). The ellipticine derivatives, such as 5, are deeply embedded in the acyl chain region of cardiolipin-containing model membranes. Sautereau et al. (186) studied the effects of elliptinium (5) on Streptococcus pneumoniae and concluded that the toxicity of 5 is related to its intracellular concentration. 

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. 

The binding characteristics of oxazolopyridocarbazoles toward bacterial DNA have been studied (275). It was found that these ellipticine derivatives invariably exhibit DNA intercalation but with no sequence specificity. The new clinical candidate datelliptium (384) shows increased lipophilicity but no difference in binding or intercalation to DNA compared to elliptinium (5) (750). This new... 

The effects of amine-substituted ellipticine derivatives 88 and 105-111 on L1210 and the human colon tumor (HCT8) in vitro (Table III) indicate that these compounds are not more cytotoxic than ellipticine (1) (71). Furthermore, only a low order of activity was revealed in vivo against P388 for 110 and 111. The N-6 derivatives were inactive as antitumor agents. However, the DNA binding properties of all of these amine-substituted ellipticines were superior to 1, as determined by the ethidium displacement assay. 

The major problem in some patients [20% in one study (267)] treated with elliptinium is the development of antielliptinium antibodies (267-270). When these antibodies reach a certain concentration, the red blood cells rupture, causing anemia. This hemolysis is more frequent in patients treated weekly with 5 than in those who are treated every 2-4 weeks (277). Provided the antibody titer in patients is monitored, the onset of hemolysis can be prevented (268). In addition to elliptinium, several other ellipticine derivatives and analogs react with this specific antibody (420, 463-465), whereas the oxazolopyridocarbazole 466 (incorrect structure given in Ref. 268), 9-methoxyellipticine (2), and 9-bromoellipticine do not (268). 

Rivalle, C., and Bisagni, E., Synthesis of 9-methoxyellipticine A-oxide and its transformation into 1-functionalized ellipticine derivatives, Heterocycles. 38. 391, 1994. 

The Roche group (265) has also been interested in the synthesis of ellipticine derivatives. In particular, 8,9-dimethoxy- and 8,9-methyl-enedioxyellipticines (659) and 660 were their synthetic targets. 

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... 

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... 

P. Bellon, P. Canal, J. Bernadou and G. Soula, Use of electrochemical detection in the high-performance liquid chromatographic determination of hydroxylated ellipticine derivatives, J. Chromatogr., 1984, 309, 170-176. 

Figure 4 A triple helix formed by a pyrimidine oligonucleotide (black ribbon) covalently linked to an intercalating agent (star). The intercalating agent binds at the triplex-duplex junction and can i) stabilize the triple-helical structure (acridine derivative, 7), ii) induce double strand cleavage (phenanthroline, 12), iii) photo-induce cleavage (ellipticine derivative, 13), iv) photo-induce cross-linking of the two DNA strands (psoralen, 10).

An ellipticine derivative attached to the 5 -end of a triple helixforming oligonucleotide was shown to induce cleavage of the targeted... 

Bernard J, Riou G 1976 Biochemical action of ellipticine derivatives in Trypanosoma cruzi. In H. van den Bossche (ed) Biochem Parasites Host-parasites Relate. Proc Int Symp. Orth-Holland, Amsterdam p. 477... 

Other compounds of interest in medicinal chemistry to have been prepared are the /8-D-ribofuranoside the )5-D-glucopyranoside and the )8-D-galactopyranoside of the ellipticine derivative (30) which have improved water-solubility for action as anticancer agents. ... 

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