Synthesis and cytostatic properties of daunorubicin derivatives, containing N-phenylthiourea or N-ethylthiourea moieties in the 3'-position.

A series of phenylthiourea and ethylthiourea derivatives of daunorubicin and its congeners was prepared by reaction of the 3'-amino group of the antibiotic with phenylisothiocyanate or ethylisothiocyanate. S-Methylation yielded S-methylisothiouromium salts which when reacted with amines resulted in an intramolecular cyclization with the participation of the neighboring 4'-OH group. The structures and predominant conformations of the thiourea derivatives and daunorubicino(3'-N,4'-O-d)oxazolines were determined by 1H and 13C NMR. Cytostatic activities of the thiourea and oxazoline derivatives were compared with the cytostatic activities of N-methylurea and N-methyl-N-nitrosourea containing daunorubicin and its congeners. Carminomycin derivatives were endowed with the highest cytostatic activity.

[Establishing the structure of anthracyclinones produced by Streptomyces griseoruber]. / Ustanovlenie stroeniia antratsiklinonov, produtsiruemykh Streptomyces griseoruber.

Streptomyces grisoruber strain 1618-306 produces three types of anthracycline antibiotics, derivatives of epsilon-pyrromycinone (methyl (7S, 9R, 10R)-9-ethyl-5,7,8,9,10,12-hexahydro-1,4,6,7,9-pentahydroxy-5,12-di oxo-10- naphthacenecarboxylate), epsilon-1-hydroxyauramycinone and epsilon-1-hydroxysulfurmycinone, differing in C-9 substituent in D ring of anthracyclines (Et, Met or CH2COCH3, respectively). Besides 7-O-glycosides of these aglycones, complex of antibiotics contains corresponding 7-deoxy- and 7,8,9,10-bisanhydroanthracyclinones.

[Derivatives of antineoplastic antibiotics of the daunorubicin series containing methylurea or nitrosomethylurea residues]. / Proizvodnye protivoopukholevykh antibiotikov riada daunorubitsina, soderzhashchie ostatok metilmocheviny ili nitrozometilmocheviny.

Derivatives of antitumour anthracycline antibiotics containing N-methylurea moiety in the carbohydrate ring were obtained by the interaction of methyl isocyanate with daunorubicin, doxorubicin, carminomycin and daunorubicin 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 oxazoline-2-ones the predominant conformations of sugar ring has changed from 1C4 to 4C1, 2,5B, or B0,3 (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.