Acridone alkaloids compounds

Fewer than 100 acridone alkaloids are known. Typical compounds include, for example, atalaphylline, acronycine and preacronycine. Acridone alkaloids occur in plants and animals. They are especially characteristic of the Rutaceae plant... 

Chen, J.-J. Deady, L. W. Mackay, M. F. Synthesis of some acridone alkaloids and related compounds. Tetrahedron 1997, 53, 12717-12728. 

Occurence and New Alkaloids.—Six acridone alkaloids have been isolated from the leaves of Bauerella simplicifolia subsp. neo-scotica. Four of the alkaloids, i.e. melicopine (27), melicopidine (28 R = Me), 1,3-dimethoxy-JV-methylacridone (29 R1 = Me, R2 — H), and xanthovodine (28 R = H), have been obtained from other sources, but the alkaloids (29 R1 = H, R2 = OMe) and (29 R1 — R2 = H) were known previously only as synthetic compounds. The new alkaloids were identified by spectroscopy, by chemical correlation, and by synthesis. 

A totally different approach to acridones involves formation of the bond adjacent to the hetero-atom during cyclisation. Thus, 2,4,6-trihydro3y-2 -nitrobenzophenone yields 1,3-diliydroxyacridone after prior reduction (I.H. Bowen, P. Gutpa and J.R. Lewis, Chem. Comm., 1970, 1625). In a similar approach, the cyclisation of 2 -amino-2-methoxybenzophenones and related compounds occurs on treatment with sodium hydride in dimethylsulphoxide, providing a route to acridone alkaloids (J.H. Adams et dl. j. chem. Soc. Perkin I, 1977, 2173). 

As part of a general study of the synthesis of 2,2-dimethylpyrano-derivatives, a convenient synthesis of the acridone alkaloid, acronycine (31 R = R = Me) was devised. Heating a solution of 1,3-dihydroxyacridone and 4,4-dimethoxy-2-methylbutan-2-ol in pyridine afforded a mixture of linear and angular pyrano derivatives. The angular product (31 R = R = H), which predominated, is itself a natural compound and was converted by methylation into acronycine. 

Five acridone alkaloids were obtained previously from the bark of Teclea boiviniana cf. Vol. 6, p. 108) a recent investigation showed that the constituents of the leaves are similar, and resulted in the isolation of arborinine (37 R = H), tecleanthine (38 R = H, R = OMe), evoxanthine (38 R = R = H), 6-methoxytecleanthine (38 R = R = OMe), and 1,3,4-trimethoxy-iV-methyl-acridone (39 R = Me, R = OMe). The latter compound has not been obtained previously from a natural source. The n.m.r. and mass spectra indicated that the new alkaloid was a trimethoxy-iV-methylacridone and that ring A was unsubstituted. The three possible acridones had been synthesized earlier, and from melting-point data the alkaloid appeared to be the 1,3,4-trimethoxy-derivative this was confirmed by synthesis using a modification of the published procedures. 1,2,3-Trimethoxy-iV-methylacridone (37 R = Me), previously isolated from Evodia alata, has now been obtained from Melicope leratii. The known alkaloids melicopidine (40 R = Me, R = OMe) and xanthovedine (40 R = R = H) were also shown to be constituents of M. leratii. Arborinine (37 R = H) has been obtained from Vepris pilosa and from Ruta chalapensis. Other known acridone alkaloids isolated from a new source include the l-hydroxy-3-methoxy-deriva-tive (39 R = R = H) and its methyl ether (39 R = Me, R = H), from Vepris pilosa. ... 

The report of these semisynthetic derivatives preceded the report of the isolation of glycobismine A, the first naturally occurring bis-acridone alkaloid isolated from the bark and root bark of Glycosmis citrifolia collected in Taiwan [7]. Oligomers of noracronycine and related alkaloid derivatives, dimers and trimers, tetramers, and pentamers were also reported [8], and these oligomers and the chemical reactions concerning acronycine and related compounds were reviewed [9,10]. 

Interest in the 2-substituted quinolin/ones, quinazolines and acridones alkaloids has accelerated rapidly with the finding that these compounds display marked biological activities, such as leishmanicidal, antimicrobial, anticancer activities. 

A wide spectrum of other biological properties for these types of alkaloids has been discovered. It is proposed in this chapter to present the latest developments in the 2-substituted quinolin/ones, quinazolines, and acridones alkaloids biological activities as well as a overview of all members of these classes of compounds. 

A number of derivatives of acronycine, a variety of acridone alkaloids, some synthetic acridones, acridines and related compounds, have been studied for antitumour activity [94]. Only acronycine displayed activity, thus demonstrating a strict structure-activity relationship. Clinical studies on the drug have commenced, but no results have been published on the effectiveness of acronycine in the treatment of human neoplasms. 

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. 

A further study of the root alkaloids of Ruta graveolens has resulted in the identification of a new chlorine-containing acridone (31), named iso-gravacridonchlorine.29 The same source yielded an inseparable mixture of alkaloids, shown by n.m.r. spectroscopy to consist of the new compound furacridone (32) and the known compound l-hydroxy-3-methoxy-N-methylacridone (29 R = H) in a ratio of 4 1. 

Rutacridone, previously obtained from Ruta graveolens, had been assigned structure (33) the alkaloid has now been isolated from R. chalepensis and its structure has been re-examined by n.m.r. spectroscopy.30 The resonance at — 5.2r indicates the presence of a 5-hydroxy-group intramolecularly hydrogen-bonded to the acridone carbonyl, as in compounds (34) or (35). The linear structure (35) is... 

A diprenylacridone (41) obtained from the roots of Atalantia monophylta33 has unfortunately been given the same name, i.e. atalaphyllidine, as a different acridone isolated previously from this species (see Vol. 7). The presence of two prenyl groups in the new alkaloid was indicated by the n.m.r. spectrum, by catalytic reduction to a tetrahydro-derivative, and by conversion into compound (42) when treated with formic acid. The reaction of the alkaloid with methyl iodide and potassium carbonate afforded the corresponding N-methyltrimethoxyacridone. 

The structure (26) assigned to atalaphyllinine, a new acridone of Atlanta monophylla, was based on spectral data and on the conversion of the alkaloid by heating with formic acid followed by reduction into the known compound, bi-cycloatalaphylline (27). ... 

The alkaloids melicopicine from Melicope fareana [86], acronycine from Acrony-chia baueri [87, 88], and rutacridone from R. graveolens (Rutaceae) typify some of the structural variety that may then ensue. For instance, radioactivity biosynthetic studies on R. graveolens, using [1- H]DMAPP (dimethylallyl diphosphate), demonstrated that 1,3-dihydroxy-A-methylacridone reacted with DMAPP upon mediation of a monoprenyl aryl transferase. The formed prenylated acridone glycocitrine-H in turn cyclized to give the dihydrofuran portion of rutacridone. Compounds 21 and 22 are hypothetical intermediates (Figure 6.18) [89]. 

The Rutaceae is one of the most interesting families in regard to alkaloid chemistry as well as the formation of fla-vonoids, mono-, sesqui-, and triterpenes, furocoumarins, and other secondary compounds (Waterman and Grundon, 1983). Many chemical features support the view that the Rutaceae is a distinct and homogenous group. Essential oils and coumarins are found in at least four subfamilies. Furo-quinoline alkaloids are essentially ubiquitous in the family, and acridones are common. 

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