[14-O-hemiesters and 13-hydrazones of anthracyline antibiotics of the daunorubicin series. Synthesis and cytostatic activity with respect to tumor cells sensitive or resistant to doxorubicin]. / 14-O-gemiéfiry i 13-gidrazony antratsiklinovykh antibiotikov riada daunorubitsina. Sintez i tsitostaticheskaia aktivnost' v otnoshenii opukholevykh kletok, chuvstvitel'nykh ili ustoichivykh k doksorubitsinu.

Doxorubicin and 14-hydroxycarminomycin 14-O-hemiadipates and 14-O-hemipimelates, synthesized from 14-bromo derivatives of daunorubicin and carminomycin and monosodium adipate and pimelate, were converted to the corresponding N-trifluoroacetylated compounds. 13-(4-Methylpiperazine-1-yl)imino derivatives of the anthracycline antibiotics were also obtained. The cytostatic activity of the compounds synthesized was studied using a panel of human and animal tumor cell lines sensitive or resistant to doxorubicin. N-Trifluoroacetylation of the antibiotics resulted in a decrease in the cytostatic activity. The activity of the water-soluble 13-(4-methylpiperazine-l-yl)imino derivatives is close to that of the corresponding parent antibiotics.

[Synthesis and antitumor action of 14-N-substituted derivatives of rubomycin and karminomycin]. / Sintez i protivoopukholevoe deistvie nekotorykh 14-N-zameshchennykh proizvodnykh rubomitsina i karminomitsina.

The reaction of nucleophilic substitution of 14-bromine derivatives of carminomycin and rubomycin with respective nitrogen-containing heterocycles yielded six novel derivatives of carminomycin and rubomycin: 14-N-imidazolyl-carminomycin, 14-carminomycyl-N-pyridinium bromide, 14-carminomycyl-N-(3-aminocarbonyl)-pyridinium chloride, 14-rubomycyl-N-(3-amino-carbonyl)-pyridinium chloride, 14-N-succinimidocarminomycin and 14-N-succinimidorubomycin. In vitro and in vivo antitumor activity of the above derivatives and three other derivatives described earlier: 14-rubomycyl-N-pyridinium bromide, 14-N-imidazolylrubomycin and 14-N-phthalimidorubomycin was studied. It was shown that in vitro all the 9 semisynthetic derivatives had a lower (by 1.5-6 times) cytostatic action on murine lymphadenosis cells NK/LI as compared to the initial antibiotics. The in vivo experiments on mice revealed that by acute toxicity the rubomycin derivatives administered intravenously were close to rubomycin, whereas the toxicity of the analogous derivatives of carminomycin was 5-17 times lower. The in vivo experiments also showed that seven out of the nine 14-N-substituted derivatives of carminomycin and rubomycin were practically deprived of antitumor activity (strain LIO-1), while 14-carminomycyl-N-pyridinium bromide and 14-N-succinimidocarminomycin inhibited the tumor growth by 40-60 per cent.

[Quantitative determination of the antibiotic doxorubicin by high-performance liquid chromatography]. / Kolichestvennoe opredelenie antibiotika doksorubitsina metodom vysokoéffektivnoi zhidkostnoi khromatografii.

A new three-component system was developed for separation of a mixture containing 6 components: doxorubicin, rubomycin, dihydrorubomycin, 14-bromrubomycin, doxorubicinone and rubomycinone. The system uses reverse phase high performance liquid chromatography. Separation was performed on a column with Spherisorb C18 (4.6 X 250 mm) with the particle size of 10 microns. Relationships between the capacity factor k1 for the above 6 components and relative arresting alpha for 3 hardly separating components: doxorubicin, rubomycinone and dihydrorubomycin, as well as between the percentage content of the organic component, acetonitrile and the percentage content of the buffer solution were studied. The external standard method was used for determination of purity of doxorubicin standard preparations. The method provides routine quantitative assay of doxorubicin hydrochloride.