Acronycine synthesis

Phase I and II clinical trials indicated that acronycine reduced pain of the spine in some patients with multiple myeloma [280,282,283]. Acronycine has been reported to cause leukopoenia and to have CNS-depressant activity [284], Biochemically, acronycine inhibits incorporation of extracellular nucleosides into the RNA and DNA of leukaemia L-5178Y cell culture. There is, however, no evidence of interaction between acronycine and DNA or inhibition of template activity of DNA. This alkaloid does not inhibit nucleic acid synthesis in the cell, but rather inhibits the accumulation of extracellular uridine or thymidine, as nucleotides, in the intracellular precursor pool [285, 286], Acronycine, acting primarily on membranous organelles [287], seems to interfere with the structure, function and/or turnover of cell membrane components, thereby changing the fluidity of the plasma membrane [288]. 

Hydroxynoracronycine (40) is a constituent of Atalantia ceylonica and a metabolite of the antitumour compound acronycine its synthesis has been reported (Scheme 6).31 The reaction of l,3-dihydroxy-5-methoxy-9-acridone (36) with 3-chloro-3-methylbut-l-yne and cyclization in situ of the products furnished the chromenes (38) and (39) the formation of the intermediate (37) involves C-alkylation with the chlorobutyne, a reaction encountered previously during the synthesis of flindersine.32 Chromene (39) was converted into 11-hydroxy-noracronycine by successive methylation and demethylation. 

A one-step synthesis of ( )-rutacridone (37) was achieved by the reaction of acridone (32 R = H) with isoprene dibromide isorutacridone (36), the isomer with linear annelation, was a minor product of the reaction (Scheme 5).19 A full account of the synthesis of acronycine from o-aminobenzophenones has now appeared (c/. Vol. 7, p. 90) and a modified route has been described (Scheme 6).20 Cyclization of the benzophenone derivative (38 R = Me) gave acronycine (39) (38%) and isoacronycine (40) (38%) a similar ring-closure of compound (38 R = H) furnished des-iV-methylacronycine. 

Acridines (Phe pyridine Phe) include arborinine from Ruta graveolens and other Rutaceae (a spasmolytic and A1 adenosine receptor antagonist) and the pyranoquinoline acronycine (with cytotoxic and antitumour activity) from Acronychia species and Melicope leptococca (Rutaceae) and which has become a useful lead compound for the synthesis of other anticancer compounds. A variety of synthetic acridines are DNA binding anticancer compounds. 

Acridone alkaloids, experimental antitumor activity of acronycine 21, I (1983) N-Acyliminium ions as intermediates in alkaloid synthesis, 32, 271 (1988) Ajmaline-Sarpagine alkaloids, 8, 789 (1%5), 11, 41 (1968)... 

Hydroxynoracronycine (16) occurs in the plant Atalantia coylonica, it is also a metabolite of acronycine in maimnals. A part synthesis from 1,3-dihydroxy-S-nethoxy-9-acridone (15) (outlined in Scheme 1) confirms this structural assignment (J.K. Adams, P.T. Bruce and J.R. Lewis, Lloydia, 1976, 39, 399). ... 

Various approaches have been used to synthesize acronycine 208 and its derivatives. Lahey and Stick s synthesis (Scheme 38) involves the condensation of 2,3-dimethylchroman-5,7-dioI 236 with anthranilic acid, followed by V-methylation of the minor product 238 to produce 1,2-dihydronoracrony-cine 239 (73AJC2311). 

Beck et al. (68JA4706) have reported three interrelated syntheses of acronycine. One synthesis (Scheme 39) used 5,7-dimethoxy-l,2,3,4-tetrahy-droquinolin-2(l//)-one 240, which was coupled with 2-iodobenzoic acid to give the acid 241. Ring closure with PPA, followed by refluxing with... 

Bandaranayaka et al. [74JCS(P1)998] devised an efficient synthesis of acronycine 208 that involves the condensation of 1,3-dihydroxyacridin-... 

Lewis and his co-workers have reported three interrelated syntheses of acronycine 208 (81T209). In one synthesis, 2,6-dimethoxy-4-hydroxy-2 -nitrobenzophenone 250, obtained as a minor product from Friedel-Crafts acylation of 3,5-dimethoxyphenol with 2-nitrobenzoylchloride, was treated with 3-chloro-3-methylbut-l-yne under basic conditions. The resultant nitro compound 251 was reduced to the amine 252 with zinc. Upon reaction with sodium hydride in DMSO, this amine provided a mixture of de-N-methylisoacronycine 253 and de-N-methylacronycine 210. T>e-N-methylacronycine 210 was converted to acronycine 208 by methylation with methyl iodide (Scheme 42). 

Watanabe et al. (84CPB1264) have reported a one-step synthesis of acronycine 208. Lithium methyl(2-methoxycarbonyl)phenyl amide 258 generated from methyl Al-methylanthranilate 257 in situ in the presence of excess lithium cyclohexylamide (LCA), was reacted with 6-bromo-2, 2-dimethyl-7-methoxychromene 259 to produce acronycine 208. A benzyne intermediate 260 is believed to be involved in this reaction (Scheme 44). 

A regiospecific synthesis of acronycine 208 from 3-acetyl-4-chloro-2-cyanomethylquinoline 261 has been described by Anand and Sinha (Scheme... 

Details of the previously outlined32 synthesis of acronycine (58), an alkaloid isolated from Acronychia baueri which showed anti-tumour activity, have now appeared.33 In this paper, it is shown that unequivocal confirmation of structure (58) for acronycine may also be obtained from n.m.r. and nuclear Overhauser effect studies. 

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. 

Acronycine was first synthesized in 1967-68 by Beck et al. who published simultaneously three interrelated syntheses of that alkaloid (13, 14). Around ten other total syntheses have been reported up till now (15-26). Most of the synthetic strategies developped are sufficiently versatile to permit access to acronycine structural analogues as far as substitution on the A ring is concerned. Syntheses of analogues modified at B, C and D rings have been comparatively less explored. Most of them rely on chemical modifications performed on a preformed pyranoacridone skeleton, at the latest steps of the synthesis. 

Methoxyacronycine (1) was first obtained by total synthesis (39) and was later isolated from various Citrus species (40, 41). It was tested for human promyelocytic leukemic cell line HL-60 growth inhibition. Under such conditions, it was shown to be significantly active (IC50 = 17.2 pM), as was 10,11-dimethoxyacronycine (8.) (IC50 = 15.5 pM), when compared with acronycine (IC50 = 26.2 pM) (42, 43). In contrast, it should be noted here that 11-azaacronycine ( = 6-methoxy-3,3,12-trimethyl-3,12-dihydrochromeno-... 

Acronycine epoxide 61 was isolated in minute amounts from Sarcomelicope agyrophylla Guill. and from Sarcomelicope simplicifolia (Endl.) Hartley ssp. neo-scotica (P.S. Green) Hartley (68). This compound should be considered as a biogenetic intermediate between acronycine itself and the cis and frans-dihydrodiols 48. and in Sarcomelicope species. It is a highly unstable compound whose reactivity most probably explains the difficulties encountered by us (72) and by others (73, 74) in attempts towards its synthesis. Reisch et al. finally succeeded in synthesizing in 14 % yield by treatment of acronycine with dimethyldioxirane in the presence of potassium carbonate (75). 

The effect of acronycine (30) on the growth of cultured cells and of nucleoside uptake and incorporation into nucleic acids by the cells has been studied. It was found that, although acronycine does not inhibit nucleic acid synthesis, it does inhibit the accumulation of extracellular uridine and thymidine nucleotides in the precursor pool. Oral administration of dubamine to mice shows no apparent toxic elTects. ... 

Winterfeldt and co-workers have described a novel regiospecific synthesis of acronycine (48 R = Me) which may be applicable to the preparation of metabol-... 

The synthesis of natural pyranoacridone alkaloids and analogues has received more attention than that of their flirano counterparts, due to the interesting antitumor properties exhibited by acronycine and some of its derivatives. Two main strategies have been developed for the synthesis of pyrano[2,3-c]acridin-7-one and pyrano[3,2-A]acridin-7-one alkaloids. 

---