Acronycine alkaloids

Baeyer-Villiger oxidation of the anti-tumour alkaloid acronycine and its 2-nitro derivative, led to the chromeno[5,6-b][4,l]benzoxazepin-8-one 144 (R = H) and 144 (R = NO2) respectively <00NPL183>. 

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. 

The alkaloid, acronycine, a pyrano[2,3-c]acridine (Table 12.1, ref.58), and the carbazole alkaloids (ref.81) contain cyclic systems derived from 2-hydroxy... 

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 regard to the antineoplastic properties of Rutaceae, this family has attracted a great deal of interest for its ability to elaborate series of cytotoxic benzo[c]phenanthri-dine and acridin alkaloids. Examples of acridin alkaloid are pyrano-acridone and acronycine characterized from Acronychia baueri Scott. 

Acronycine (126) Alkaloid S23906-1 (127) Oncology (solid tumors) DNA binding Phase I Laboratoires Servier (CNRS) 734-737... 

Acridone alkaloids, experimental antitumor activity of acronycine, 21, 1 (1983) Actinomycetes, isoquinolinequinones, 21, 55 (1983)... 

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... 

One particular example of the early extraction of a chemical from a plant, a small tree found in the rainforests of eastern Queensland, would be that of acronycine 1 [1,2], an alkaloid currently undergoing clinical trials as an anticancer agent. More recently, a group in Perth at Murdoch University succeeded in extracting the alkaloid, swainsonine 2 from a desert shrub which causes poisoning in cattle [3]. Swainsonine has been found to exhibit an interesting spectrum of biological activity [4], especially as a potent, reversible inhibitor of various a-D-mannosidases [5]. 

The alkaloid, 9-methoxyellipticine (42b) [201,221], possesses activity against several of the solid mouse neoplasms. It is less active than acronycine... 

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]. 

Michael JP (2000) Quinoline, quinazoline and acridone alkaloids. Nat Prod Rep 17, 603-620. Earlier reviews 1999, 16, 697-709 1998, 15, 595-606. Tillequin F, Michel S and Skaltsounis A-L (1998) Acronycine-type alkaloids chemistry and biology. Alkaloids, Chemical and Biological Perspectives (ed Pelletier SW) Vol 12. Elsevier, Amsterdam,... 

The acridone alkaloids constitute a small group of natural products found exclusively in the Rutaceae family of higher plants. A sustained interest in this field has been due to the reported activity of acronycine a constituent of Acronnychia baueri and Vepris amphody as an anti-tumor agent. 

In a major study of the microbial metabolism of acronycine (177), Rosazza and co-workers examined 47 cultures for their capacity to transform this alkaloid, 10 of which were active in producing metabolites more polar than the starting material. The major metabolite was identified as the 9-hydroxy derivative 177 following isolation from the incubation of 176 with Cunninghamella echinulata NRRL 3655. This product was characterized as the acetate 182 by MS and PMR analysis, the latter technique... 

Cells carefully control the homeostasis of their ion concentrations by the action of ion channels (Na, K , Ca " channels) and throu Na, K -ATPase and Ca -ATPase. These channels and pumps are involved in signal transduction, active transport processes, and neuronal and neuromuscular signaling. Inhibition of transport processes (ion channels, carriers) is achieved by (Table IV) acronycine, ervatamine, harmaline, quinine, reserpine, colchicine, nitidine, salsolinol, sanguinarine, stepholidine, caffeine, sparteine, monocrotaline, steroidal alkaloids, aconitine, capsaicine, cassaine, maitoxin, ochratoxin, palytoxin, pumiliotoxin, saxitoxin, sole-nopsine, and tetrodotoxin. 

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). 

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