Acridone alkaloids simple

Members of the family contain alkaloids based on several major pathways such as benzylisoquinoline (tyrosine derived), quinolone, furoquinoline, quinazoline (all from anthranilic acid), imidazole (histidine), indoloquinazoline (tryptophan), and both simple aliphatic and aromatic amines. In the tribe Ruteae (Rutoideae), no fewer than five types of alkaloids are common to the three major genera. Quinolone, furoquinoline, and acridone alkaloids are especially widespread within the family, being found in four of the five... 

Acridone alkaloids (49) were first isolated from the bark and leaves of some Rutaceae species in Australian tropical rain forests. The best known acridone alkaloid, acronycine, was obtained from the bark of Acronycia bauri together with the related alkaloids (noracronycine, de-A/-methylacronycine, and de-A/-methyl-noracronycine) and simple acridone alkaloids (l,3-dimethoxy-A/-methylacrydone, melicopine, melicopicine, etc.). Acronycine displayed significant activity in several tumor test systems and it was reported to be orally active. 

In terms of organization, biosynthetic considerations take precedence. These are followed by a description of the various groiqrs of naturally occurririg acridone alkaloids the simple aoidones, C-prenylacridones, futoacridones, pyranoacridones, and finally the dimeric acridone all oids and related compounds. 

Table I surveys the structures, the properties, and the distribution of the naturally occurring simple acridone alkaloids.

Dihydroxyacridone prepared in this way has been used fiequently as a starting material for e synthesis of other acridone alkaloids including simple O-and JV-alkylated derivatives (288) and more complex C-prenylanidones (289), pyranoacridones (290,291), and acridone-coumarin mers (292). 

The second involves construction of the acridone nucleus in the course of the synthesis. The main approaches used in this latter case are very similar to those which permitted access to the simple acridone alkaloids, e.g. (i) cyclization of a diarylamine intermediate, (ii) cyclization of a benzophenone intermediate, or (iii) construction of the acridone system starting from a quinoline or a quinolinone which bring together the A and B or B and C rings of the acridone skeleton. 

Alkaloids can be divided into different t q3es according their pure chemical structures pointing first at the alkaloid base, a basic chemical nucleus. The following are basic types of alkaloids acridones, aromatics, carbo-lines, ephedras, ergots, imidazoles, indoles, bisindoles, indolizidines, manza-mines, oxindoles, quinolines, quinozolines. quinolizidines, phenylisoquinolines, phenylethylamines, piperidines, purines, pyrolidines, pyrrolizidines, pyrro-loindoles, pyrydines, sesquiterpenes, simple tetrahydroisoquinolines, stereoids, tropanes, terpenoids, diterpenes, and triterpenes. 

In addition to the relatively simple anthranilic-derived metabolites mentioned above, several distinctive types of alkaloids are derived from this amino acid. Most of these are associated with the Rutaceae and related families of the Rutales. Among these groups of alkaloids are the quinazoline, pyrroloquinazoline, quinazolinocarboline, quinoline, furoquinoline, and acridone types. 

Alkaloids considered in this section derive biogenetically from 1,3-dihydroxy-lO-methylacridone (19) and 1,3-dihydroxyacridone (22) by simple deoxygenation and/or oxidation of the acridone aromatic skeleton. Subsequent O-alkylation very often takes place, and most natural acridones bear methoxy or methylenedioxy substituents. A few, exemplified by vebilocine (27) (94), evoprenine (28) (95), and 3-graanyloxy-l-hydroxy-4-methoxy-10-methylacridone (29) (96), are also substituted by prenyloxy or geranyloxy groups. 

Most methods applicable for the synthesis of a greater vari of simple acridones, including alkaloids bearing numerous oxygenated substituents, also rely on the coupling of two aromatic substrates, which bring the preformed A and C rings of the fiiture acridone skeleton. Thus, closure of the central B lii can be obtained either by cyclization of an intermediate diphenylamine or by cyclization of an intermediate benzophenone. 

The introduction of polyphosphoric acid, instead of phosphoryl chloride, as the reagent for the cyclization of carboxylic diphenylamines permitted the direct access to 9-acridanones, avoiding the tedious steps of acid hydrolysis or alkaline methanolysis of the intermediate 9-chloroacridines (304). This modified process appears as the most popular for the synthesis of simple natural acridones and has been applied to the synthesis of 1,3-dimethoxyacridone (49) (305), 1,3-dimethoxy-lO methylacridone (53) (30S), 1,2,3-trimethoxyacridone (223) (306), 1,2,3-trimethoxy-lO-methylacridone (73) (306), l,2,4-trimethoxy-10-me(iiylacridone (72) (202), l-hydroxy-7-methoxyacridone (46) (307), 1,2,3,5,6-pentamethoxyacridone (95) (210), l-hydroxy-2,3,5,6-tetramethoxyacridone (92) (210), glyfoline (96) (308), and severd congeners of this latter alkaloid (309). 

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