Acronycine antitumor activity

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

Despite the broad antitumor activity of acronycine, the mechanism of its action at both cellular and molecular levels has not yet been clearly established. First observations suggested that the drug did not interact with DNA but acted primarly by alteration of subcellular organelle membranes and that its delayed effects were due to interference with the structure, function, and turnover of cell-surface components (30-33). More recently Dorr and Liddil reinvestigated the DNA-binding property of acronycine. 

Some acronycine derivatives substituted at 9, 10 or 11-position have been tested for cytotoxic and/or antitumor activity. 

A series of 6-alkoxy analogues of acronycine 12-16. was obtained by Fryer et al. (38) upon treatment of noracronycine (111 with an appropriate alkyl sulfate or alkyl halide under basic conditions. Among the derivatives 12-16. only 1 exhibited significant antitumor activity causing a 52% reduction in tumor size in mice bearing the solid form of sarcoma 180 and a 60% prolongation of the lives of mice injected with Ehrlich ascites (38). 

The two geminal methyl groups at C-3 appear as an important structural requirement for antitumor activity in the series. Indeed, 3-hydroxymethylacronycine (321. obtained by addition of acronycine to a metabolizing culture of Streptomyces spectabilicus, was devoid of antitumor activity when tested in mice implanted with X-5563 plasma cell myeloma or C-1498 myelogenous leukemia (36). More recently, Reisch et al. prepared... 

Table 3 - Antitumor activities of 2-nitroacronycine (371 in comparison with acronycine (1) against P 388 leukemia and C 38 colon carcinoma in mice.

Gerzon, K. and G. H. Svoboda, Acridone alkaloids Experimental antitumor activity of acronycine, in The Alkaloids, Vol. 21 (A. Brossi, ed.), 1-28, Academic Press, New York, 1983. 

In addition, oxidation reactions performed on pyranoacridones led to several alkaloids modified on the C and D rings, and to acronycine analogues with improved antitumor activity. 

Since the discovery of the broad experimental antitumor spectrum of acronycine in 1966, more than one hundred compounds derived from the 3,12-dihydro-7//-pyrano[2,3c]acridin-7-one basic skeleton have been synthesized or isolated from natural sources. Unfortunately, many of these compounds have not been studied from a biological point of view. Only a few have been tested in vitro for cytotoxic activity. Even fewer have been studied in vivo for antitumor properties. In addition, the experimental conditions and the cell lines used for the tests greatly vary from one compound to another. It nevertheless seems possible to draw some limited... 

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