Rutacridone alkaloids

Rutacridone alkaloids Ruta graveoiens herbivory Fungal elicitors CC 474.475... 

Paulini, H., and O. Schimmer. 1989. Mutagenicity testing of mtac-ridone epoxide and rutacridone, alkaloids in Ruta graveolens L., using the Salmonella/mictosome assay. Mutagenesis 4(l) 45-50. 

Other responses, such as formation of phytoalexins, are more specific (Chappell and Hahlbrock, 1984 Luckner, 1980). It has been shown that production of secondary compounds in cell cultures also can be enhanced by environmental stress. Treatment of cell cultures with fimgal, bacterial, or plant cell wall materials often results in the formation of a number of flavonoids, stilbenes, terpenoids, anthraquinones, rutacridone alkaloids, sanguinarine, and gossypol (Eilert, 1987 Heinstein 1985). In some cases, production of these metabolites is transient. Clearly, we need more information on the basic principles of the defensive response, such as structures and perception of defensive signals, transduction, and translation of these signals into a response (Luckner, 1980 Wink, 1987). 

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... 

An antimicrobial alkaloid that was isolated from roots of Ruta graveolens and from callus tissue cultures proved to be rutacridone epoxide (31).17 The structure was determined by 2H and 13C n.m.r. and by mass spectroscopy, although the configurations at C-2 and C-18 are not known. The epoxide, rather than rutacridone (37), is a major root alkaloid clearly, the plant is chemically different from that studied previously, but the reason for the variation is unknown. 

Synthesis.—Reisch, Mester, and co-workers have made important contributions this year by synthesizing the alkaloids furacridone (34) and ( )-rutacridone (37) for the first time. Regioselective etherification of 1,3-dihydroxy-jV-methylacridone (32 R = H) gave the acetal (33), which furnished furacridone (34) as the major product of acid-catalysed cyclization (Scheme 4). Claisen rearrangements of the 3-allyloxy-acridone (32 R = CH2CH=CH2) and the propargyl derivative (32 R = CH2C=CH) were also studied.18... 

The monomeric acridone alkaloids are derived from anthranilic acid and acetate via a polyketide. First studies, in which [ C]-acetate was utilized by cell cultures of Ruta graveolens, indicated that the C-ring of the acridone nucleus was acetate derived. Further research revealed that anthranilic acid is specifically incorporated into the A-ring of rutacridone (Baumert et al, 1982). 

Synthesized 1,3-dihydroxy-N-methylacridone is readily incorporated into rutacridone by cell-free extracts of Ruta graveolens (Maier et al, 1993). It has been hypothesized that the final step in the biosynthesis of these alkaloids... 

The linear structure (53) was preferred for the Ruta alkaloid rutacridone on the basis of n.m.r. shifts induced by trifluoroacetic acid (c/. Vol. 8, p. 84), but further spectroscopic studies have now established the angular structure (54) for rutacridone. In the H n.m.r. spectrum of the alkaloid, chemical shifts for the N-methyl group and for the methylene group at C-1 were too close for direct N.O.E. studies to be carried out. In model compounds (55), however, irradiation of the N-methyl signal produced 20-30% enhancement of the signal due to the proton attached to C-4 similar treatment of rutacridone produced no effect, thus excluding structure (53). The correspondence in chemical shifts in the n.m.r. spectrum of rutacridone to those of similar angular dihydrofuroacridones, especially for C-1, C-4, and C-16, provides further support for structure (54). ... 

A preliminary study of the acridone alkaloids of the roots of Boenninghausenia albiflora resulted in the identification of 1-hydroxy-N-methylacridone (41 R = Me) now the Ruta alkaloid rutacridone (42) (c/. Vol. 8, p. 84) and noracrony-cine (43) have been isolated from this species. Of two new alkaloids obtained from B. albiflora, one was shown to be 1-hydroxyacridone (41 R = H) by methylation to (41 R = Me). The n.m.r. spectrum of the other new alkaloid suggested that it was a dihydroxy-N-methyl-acridone in which ring B contained a 1-hydroxy-group and three adjacent aromatic hydrogen atoms structure (44) was proposed. 

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 biosynthetic pathway to rutacridone, which was isolated from Ruta graveolens (Rutaceae), was studied in detail using the cell culture method [4,5]. According to these results, the biosynthetic precursors of rutacridone are anthranilic acid, acetic acid, and an isopentenyl unit, as in the case of the quinoline alkaloids described in the previous section. However, in the biosynthesis of rutacridone, two additional C2 units participate in the biosynthesis of the acridone nucleus compared with the biosynthesis of quinoline alkaloids. 

In the biosynthesis of rutacridone, it is proposed that 1,3-dihydroxyacri-done is first formed from anthranilic acid and three C2 units, then the N-10 nitrogen is methylated to form 1,3-dihydroxy-N-methylacridone. Next, a C5 unit, IPP or DMAPP, is attached to 1,3-dihydroxy-N-methylacridone to fc>rm glycocitrine II, which is probably oxidized to produce an as-yet-uniden-tified epoxide. The epoxide is cyclized and dehydrated to give rutacridone [4]. Though rutacridone is a small molecule, as in the case of the quinoline alkaloids, three main biosynthetic precursors are involved in the biosynthesis of this alkaloid. Namely, the shikimic acid, the polyketide, and probably the iso-prenoid pathways all provide precursors for the biosynthesis of rutacridone. 

A number of alkaloids have been demonstrated to act as phytoalexins (Brooks and Watson, 1985). Among these are lupanine in Lupinus species and rutacridone epoxide in Ruta graveolens. 

Rohde B, Hans J, Martens S, Baumert A, Hunziker P, Matem U (2008) Anthranilate N-methyltransferase, a branch-point enzyme of acridone biosynthesis. Plant J 53 541-553 Maier W, Schumann B, Groger D (1990) Biosynthesis of acridone alkaloids formation of rutacridone by cell-free extracts of Ruta graveolens cell suspension cultures. FEBS Lett 263 289-291... 

Nahrstedt A, Eilert U, Wolters B, Wray V 1981 Rutacridone-epoxide, a new acridone alkaloid from Ruta graveolens. Z Naturforsch Ser C 36 200-203... 

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