Acronycinic acid

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]. 

An interesting development in the chemistry of this alkaloid is the discovery that when acronycine is demethylated with methanolic hydrochloric acid the product noracronycine reacts further to give dimers (51) and (52), a trimer (53) and oligomers (S. Funayama and G.A. Cordell, Planta Med., 1983, 48, 253 J.org.Chem., 1985, 50, 1737). 

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... 

Loughhead (90JOC2445) coupled 5-amino-2,2-dimethyl-7-methoxy-chromene 244 with 2-bromobenzoic acid, and the resultant product 245 was cyclized with TFAA. The de-A-methylacronycine 210 was then converted to acronycine 208 by methylation under phase-transfer conditions (Scheme 40). The same approach has been used by Elomri et al. to prepare 6-demethoxyacronycine 246 which was found to be more potent than acronycine 208 in some biological assays (92H799). 

Effect of substitution on the 1,2-double bond remains unclear. Nitration of acronycine using nitric acid leads to a mononitroacronycine, whose structure was reported as 1-nitroacronycine by Drummond and Lahey (8) and as 2-nitroacronycine by Svoboda (27). This compound was described as biologically inactive by Svoboda (27). It has been more recently evaluated by Cordell et al. (35) who found that nitroacronycine demonstrated a greater... 

In order to ensure that the reactivity of cjj-1,2-dihydroxy-1,2-dihydroacronycine diesters towards nucleophilic agents was similar to that of acronycine and precocene epoxides, the diester was reacted with benzylmercaptan (2i) in acidic medium. The cis and trans adducts 7 and with the sulfur atom linked to the benzylic position of the pyranyl ring were obtained in almost quantitative yield under these conditions (58). 

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. ... 

Fewer than 200 acridone alkaloids are known. Typical compounds include atalaphylline, acronycine, and preacronycine. Acridone alkaloids occur in plants and animals. They are especially characteristic of the Rutaceae plant family. The a is anthranilic acid, the p is Af-methyl anthraniloyl-CoA, and... 

Several individual groups of alkaloids incorporate terpenoid units. For example, acronycine (Section 9.3) and reserpine (Section 2.10) incorporate C5- or Cjo-based terpenoid units, respectively. However, the origin of the nitrogen of these alkaloids is amino acids (anthranilic acid and tryptophan, respectively), so these alkaloids are not included in this chapter. 

---