The reactivity of antitumor anthracycline and mitomycin C antibiotics with the oxomorpholinyl radical dimers, bi(3,5,5-trimethyl-2-oxomorpholin-3-yl) (TM3) and bi(3,5-dimethyl-5-hydroxymethyl-2-oxomorpholin-3-yl) (DHM3), was studied in vitro. The oxomorpholinyl radical reduced daunorubicin to a quinone methide intermediate that reacted with solvent to form 7-deoxydaunorubicinone. The solvolysis reaction followed first order kinetics, and the reactivity rate constants (k2) measured for seven anthracycline analogues ranged from 2 X 10-2 S-1 to 8.0 X O'4 S-l. The chemical reactivity of each anthracycline quinone methide correlated with the total skin toxicity caused by the respective parent anthracycline following injection into swine skin.Microscopic examination of experimental lesions in swine skin resemble those observed in humans after inadvertant chemotherapy extravasation. Hydrocortisone sodium succinate was not effective for the treatment of doxorubicin-induced skin necrosis, whereas DHM3 was effective for the treatment of skin necrosis caused by all seven anthracyclines and by the quinone containing antibiotic, mitomycin C.
Menogaril, 7-con-O-methylnogarol (1), is a semisynthetic antitumor drug of the anthracycline class presently in clinical trials.3 It is formed from nogalamycin, a product of the organism Streptomyces nogalater,4 Because of the oxygen substitution (1) Facilitated by PHS Grant no. CA-24665 and gifts of menogaril and 7-deoxynogarol from Dr. Paul Wiley of the Upjohn Co. We wish to thank Professors Edward King and Stanley Gill and Dr. Timothy Dietz for assistance.
Reduction of 11-deoxydaunomycin (8), adriamycin (1), 4-demethoxydaunomycin (9), and 4-methoxy-6deoxydaunomycin (10) with meso-and d,/-3,3',5,5,5,,5,-hexamethyl-2,2,-dioxo-3,3'-bimorpholinyl (3 and 4) is described. Quinone methide intermediates from glycosidic cleavage of reduced 1, 8, and 9 were characterized by UV-vis spectroscopy and the rate constants for their tautomerization to the respective 7-deoxyaglycons were determined. These rate constants together with those from earlier measurements, ranging from 0.013 to 0.000095 s™1, establish an order of nucleophilicity of the quinone methides from reductive glycosidic cleavage of five anthracyclines of biological interest. The dimerization of the quinone methide from reduction of 11-deoxydaunomycin was established and the rate constant determined for comparison with the rate constant for dimerization of the quinone methide from reduction of aclacinomycin A. Reduction of 10 did not yield glycosidic cleavage but only catalysis of the disproportionation of 4 most likely by hydride transfer from the hydroquinone of 10 to 5,6-dihydro-3,5,5-trimethyl-l,4-oxazin-2-one (5), the product of oxidation of 4. The rate constant for hydride transfer was measured as a function of pH and compared with the rate constant for hydride transfer from 7-deoxydaunomycinone hydroquinone to 5.
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