Ellipticine quinones

Mai et al. reported a formal total synthesis of ellipticine (228) starting from the furoindolone 649 (583,724). In this strategy, the key step is the anionic [4+2] cycloaddition of furoindolone 649 with 3,4-pyridyne (1193). Reaction of compound 1270 with 3,4-pyridyne (1193) in the presence of LDA gave ellipticine quinone (1272)... 

Attention was centered on radical precursors in which the 3-pyridyl moiety was attached at the indole-3-position with the aim of directly producing the pyrido[4,3-b]carbazole skeleton of ellipticine by regioselective cyclization upon the 4-position of the pyridine ring. Satisfactorily, A-methyl and A-benzyl selenoesters 52a and 52b led to the ellipticine quinones 53a and 53b in acceptable yields (60 and 42% yield, respectively), after the radical cyclization and the in situ oxidation at the interannular methylene group. The cyclization was clearly less efficient from A-(methoxymethyl) selenoester 52c and no reaction was observed... 

Ellipticine quinones have an intrinsic interest as antitumor agents <04JME4958> and are also known intermediates in the synthesis of ellipticines <02CRV4303>. For instance, ellipticine quinones 53b and 53c have been transformed into the alkaloid ellipticine <80JA1457 90J(P1)1319 98H(48)1593>. Hence, these homolytic pyridine acylations by 2-indolylacyl radicals also constitute formal syntheses of the natural product. 

Scheme 5. Ketcha-Gribble synthesis of ellipticine quinone 33 and ellipticine (I) (42).

Scheme 42. Reassignment of ellipticine quinone amino acid adduct 258 and proposed mechanism of formation by Potier and co-workers (107).

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. 

To rationalize the remarkable regioselectivity and stereoselectivity of these alkylation reactions, Potier and co-workers (777,775) proposed that a stacking interaction occurs between quinone imine 256 and the nucleic acid base prior to covalent bond formation. Moreover, the appropriate intermolecular NOE is observed to support this contention. The fact that these ribonucleotide adducts form so easily may suggest that ellipticine quinone imines could alkylate at the 3 end of transfer RNA or at similar sites on other RNA molecules to inhibit protein synthesis. Thus, RNA would seem to be a reasonable target for elliptinium and related ellipticines (775). 

The cytotoxicity of several benzo-annulated iso-a-carbolines (369-372, 377, 378, 380) has been studied in vitro on human tumor KB cells (Table X) 136). The linear ellipticine analog 371 is 10 times more active than ellipticine (1) in this screen. As was mentioned earlier, this derivative also displays significant in vivo activity against P388, L1210, and B16 implanted mouse tumors TIC values 190, 175, and 224%, respectively). The resemblance of the imine grouping of these iso-a-carbolines to ellipticine quinone imine 6 is obvious. It will be of interest to see how the electrophilic behavior of these compounds compares to that of the quinone imines. 

A few radical annulation approaches to fused indoles have been reported. 2-Indolylacyl radicals generated from selenoesters provided ellipticine quinones <05JOC9077>. A radical cyclization of haloacetamide derivatives was applied to the preparation of indolo[2,l-rf][l,5]benzodiazocines <05T941> and indolo[3,2-d][l]benzazepin-6-ones <05T5489>. 3,3-... 

This process involves a straightforward directed ortho metallation (chapter 7) of the pyridine amide 206 and capture by the indole aldehyde 208. Without work-up, the product 209 is lithiated again and the ellipticine quinone 210 is formed in good yield.26... 

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

Two years later, the same group reported a formal synthesis of ellipticine (228) using 6-benzyl-6H-pyrido[4,3-f>]carbazole-5,ll-quinone (6-benzylellipticine quinone) (1241) as intermediate (716). The optimized conditions, reaction of 1.2 equivalents of 3-bromo-4-lithiopyridine (1238) with M-benzylindole-2,3-dicarboxylic anhydride (852) at —96°C, led regioselectively to the 2-acylindole-3-carboxylic acid 1233 in 42% yield. Compound 1233 was converted to the corresponding amide 1239 by treatment with oxalyl chloride, followed by diethylamine. The ketone 1239 was reduced to the corresponding alcohol 1240 by reaction with sodium borohydride. Reaction of the alcohol 1240 with f-butyllithium led to the desired 6-benzylellipticine quinone (1241), along with a debrominated alcohol 1242, in 40% and 19% yield, respectively. 6-Benzylellipticine quinone (1241) was transformed to 6-benzylellipticine (1243) in 38% yield by treatment with methyllithium, then hydroiodic acid, followed... 

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). 

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). 

Snieckus synthesis85 involves an application of his ingenious tandem directed metallation reaction, which provides a one-step construction of the ellipticine ring system. Introduction of the remaining carbon atoms by the reaction of the quinone (120) with methyl-lithium, and removal of the protecting group, then gave ellipticine (119) in an overall yield of 40% (Scheme 16). 

Bisagni and team (96) have also reported a synthesis of the related 5H-pyrido[4,3-6]benzo[/]indolo-6,l 1-quinone ring system (e.g., 200) (Scheme 34). Using a modification of the Watanabe-Snieckus synthesis (97) of ellipticine, the... 

In conclusion, although it is fair to say that the mechanism of the antitumor activity of ellipticines and related compounds remains unproved, metabolic activation of an ellipticine to a quinone imine or related species of high elec-... 

The metabolism of 6-methylelliptinium (420) in rats (bile and urine) gives rise to the O-sulfate and O-glucuronide conjugates, but no demethylation of the N-6 methyl group (260) (Scheme 68). Likewise, the HRP/H2O2 system gives rise to the ort/io-quinone 421 and the oxazolopyridocarbazole 422, when alanine is present, but not to N-6 demethylation (261). The metabolism of olivacine (4) in rats and microsomes is faster than that of ellipticine, and leads to hydroxylation at the C-7 and C-9 positions (as conjugates) (55). 

S. Bernard, M. A. Schwaller, J. Moiroux, E. A. Bazzaoui, G. Ldvi, and J. Aubard, SERS identification of quinone-imine species as oxidation products of antitumour ellipticines, I. Raman Spectrosc. 27, 539-547 (1996). 

Many of the enzyme/microorganism mediated dealkylation procedures that have been reported have come from the work of Rosazza and his coworkers as a consequence of their studies on Microbial models on Mammalian metabolism. These studies have largely concerned with demethylation of various alkaloids with bacteria and fungi. 0-deethylation reactions with Streptomyces griseus as with dealkylation of 7-ethoxy coumarin gave very poor yields and therefore was not considered a viable synthetic procedure. The quinone imine(I), has been prepared in 64%isolated yield by horseradish peroxidase/hydrogen peroxide O-demethylation of 9-methoxy-ellipticine(II). Studies with H2 0 as a reaction medium demonstrated that the reaction was not a simple demethylation but rather a replacement of the methoxy group by OH from the solvent (as shown in Fig.l)... 

Ellipticine (E) 1 is an indolic alkaloid with antitumor activity. Some of its phenolic derivatives as N-methyl-9-hydroxyellipticine (Celiptinium), obtained from 9-hydroxy ellipticine (9-OH E), exhibit high cytotoxicity. 38 Syntheses of 9-OH E are not satisfactory considering yields and cost, justifying the attempts at the direct conversion of E to 9-OH E via 9-oxoellipticine (9-0X0 E). Potassium nitrosodisulfonate (Fremy s salt), a valuable oxidant for the synthesis of quinone-imine from heterocyclic amines,139 was used. Under these conditions the conversion of E to 9-0X0 E was observed for the first time. Its reduction to 9-OH E is then easily achieved with ascorbic acid. The radical nature of Fremy s salt [ 0-N(S03K)2] led us to carry out the oxidation reaction under sonication in order to increase the yields via an easier electron transfer.1 1... 

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