In 1996, a series of 5-aminoflavone derivatives were tested for anti-tumor activity against the MCF-7 breast cancer cell line. The 5,4'-diaminoflavone was most effective (1 ), and 4'-NH2 was found to be essential to the anti-tumor activity. It was proposed that a nitrenium ion intermediate was generated as the active intermediate due to indirect evidence that precursor (2 ) is generated during metabolism. 3 , a derivative of 1  has reached phase II clinical studies in United States. To verify whether a nitrenium ion could form under such condition, 4  and 5,  as potential precursors of the corresponding nitrenium ions, were synthesized and purified. A series of kinetics studies are under way. The monomethoxy compound 4  reacts very slowly over a 3-week period, while the dimethoxy compound 5  decomposes over a convenient time scale of 10-12 h with two products, observed by HPLC, generated during the hydrolysis 5 . Preliminary N3- trapping studies on 5  did not detect a nitrenium ion intermediate. The same two products formed in the presence of N3- as in the hydrolysis reaction and no new products were detected. A large-scale product study is under way. A mechanism for decomposition of the model esters will be proposed based on experiments currently under way.

Test for nitrenium ion involvment in the action of diaminoflavone anti-tumor drugs

248th National Meeting (2014)

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