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DERIVATIVES OF ANTITUMOUR ANTIBIOTICS OF THE DAUNORUBICINE SERIES CONTAINING N-METHYL-N-NITROSOUREA MOIETIES
L. S. POVAROV, E. V. BAK1NA *, E. I. LAZHKO, G. I. ORLOVA, O. S. ZHUKOVA**, N. A. OBIDNJAK **, N. Y. YURCHENKO **, T. Y. GLAZKOVA**,. M. N. PREOBHAZHENSKAYA
Institute of New Antibiotics, Academy of Medical Sciences of the USSR, Moscow; * Institute of Microbiology and Virusology , Academy of Sciences of the Kasakh SSH, Alma-Ata; ** All-Union Cancer Research Centre, Academy of Medical Sciences of the USSR, Moscow
Abstract: Derivatives of antitumour anthracycline antibiotics containing N-methylurea moietjr in the carbohydrate ring were obtained by the interaction of methyl isocyanate with dauno-rubicine, doxorubicine, carminomycin and daunorubicine derivatives, substituted at C-13 or C-14 positions. N-Nitrosation of these compounds yielded modified anthracycline antibiotics containing the N-methyl-N-nitrosourea substituent at C-3' position. Alkaline degradation of these derivatives produced, through corresponding isocyanates cyclic 3'-N,4'-carbonylderivatives. In these anthracycline derivatives with sugar cycles conjugated with oxazolin-2-ones the predominant conformations of sugar ring has changed from 1 C 4 to 4C1, 2,5B, or B 0 3 (shown by 1H NMR spectroscopy). It was demonstrated, both in vitro and in vivo, that introduction of methylurea or cytotoxic methylnitrosourea moieties does not potentiate antimicrobial, cytotoxic or antitumour properties of these-compounds.
Russian Journal of Bioorganic Chemistry 1990, 16 (4):559-568