Ellipticine, 9-methoxy

A fluorodensitometric assay was developed by Montague and co-workers 140) to analyze cultures from Ochrosia elliptica for ellipticine (1), 9-methoxy-ellipticine (2), and 9-hydroxyellipticine (3) by thin-layer chromatography (TLC) without the need for prior purification. Using silica gel impregnated with dimethyl sulfoxide and a mobile phase of EtOAc-water-l-octanol (17 2 2), these workers were able to achieve good separation of these alkaloids and to assay the resulting chromatograms by fluorodensitometry (40-300 fmol detection limits of alkaloid). 

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)... 

A further modification of methods which have already been described has been discussed by French workers (316) for the formation of 9-methoxy ellipticine (743). It combines the Borsche (317) synthesis of tetrahydrocarbazoles with the Cranwell-Saxton approach (318) for the pyridine ring, to produce the carbazole aldehyde 744 (Scheme 60). 

Besselievre and Husson have published full details of their syntheses of ellipticine, olivacine, and guatambuine.86 A new approach to the synthesis of ellipticine87 involves construction of an appropriately substituted anilino-isoquinoline, e.g. (166) closure of the five-membered ring then constitutes the last stage (Scheme 24). Other synthetic work in this area includes syntheses of 16-desmethyl-16-methoxyellipticine88 and 11-hydroxy- and 11-methoxy-ellipticines.89... 

A number of species of the genus Ochrosia have been investigated, and among the alkaloids already discussed are ellipticine and methoxy-ellipticine from 0. elliptica (Section VII, D). Other alkaloids from this species include elliptinine for which structure CCCLVIII has been... 

The antitumor activity of these alkaloids has led to renewed interest in their synthesis. Saxton s synthesis of ellipticine (CCXCVI Volume VIII, pp. 477-480), the most adaptable to large-scale production, has been shortened by two steps by the direct cyclization of the intermediate (CCXCVII) in 90-100% phosphoric acid. The same route has been used to synthesize 9-methoxyellipticine (CCXCIX) from 5-methoxyindole (CCXCVIII) 88). This alkaloid, earlier thought to be 8-methoxy-ellipticine (CCC) on the basis of UV- and fluorescence-spectra 47), is identical with the methoxyellipticine referred to in Volume VIII. 

Ellipticine, 9-methoxy- O-Demethylation Cunninghamella (2), Penicillium, Botrytis. 143... 

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... 

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. 

Strychnine-Akuammicine-Condylocarpine-Uleine Group. Details39 have appeared of a synthesis1" of the ( )-dasycarpidones and ( )-epi-uleine. Ellipticine, appari-cine, and isoreserpiline have been isolated from Ochrosia silvatica 0a and the last two, together with 10-methoxy-19,20-dihydrocorynantheol, from O. vieillardii.40b... 

In the ellipticine series,Sainsbury et al. have developed an improved synthesis of 3-[1-(3-ethylpyridyl)]-indoles, which were important intermediates in an earlier route to ellipticine. Several ellipticines, including 11-hydroxy- and 10-methoxy-ellipt-icine, were prepared by the new route. 

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... 

StiU with a tetrahydopyridine derivative alcohol 354, a high-yielding orthoester rearrangement was used in a synthesis of antitumor alkaloid ellipticine 353 [82] (Scheme 6.60). The same kind of reaction was applied to a synthesis of descarbo-methoxy vobasine 356b (Scheme 6.60) [83]. This type of rearrangement was also used by Kametani [84] in an approach to ervitsine 359 (Scheme 6.60). 

Giralt EG, Coelho MS 1970 Methoxy-9-ellipticine. II. Analysis in vitro of the mechanism of action. Rev Eur Etud Clin Biol 15 539-541... 

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