[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 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.

[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.

[Production and antineoplastic activity of new asymmetric azines on the rubomycin base]. / Poluchenie i protivoopukholevaia aktivnost' novykh nesimmetrichnykh azinov na osnove rubomitsina.

New alkulidene hydrazones of rubomycin (daunorubicin) with the linear or branched chain of the carbon atoms were studied: rubomycin 13-(hexylidene-2")-hydrazone, rubomycin 13-(heptylidene-3")-hydrazone and rubomycin 13-(4"-methylpentylidene-2")-hydrazone. Alkylidene hydrazones of the formamidine derivatives were also studied: 13:cyclohexylidene hydrazone of 3'-desamino-3'-dimethylformamidine rubomycin and 13-(5"-oxypentyliden-2") hudrazone of 3'-desamino-3'-dimethylformamidine rubomycin. The latter two alkylidene hydrazones were modified twice. It was found that after a single intravenous administration to tumor-free mice the new substance had the same or lower toxicity as compared to that of rubomycin. Antitumor activity of the substances against lymphosarcoma LIO-I was studied comparatively with that of the initial rubomycin. It was shown that the molecule modification at C-13, as well as simultaneous modification at C-13 and the sugar amino group resulted in lowering of the antitumor activity in comparison to that of the starting rubomycin.

[Study of toxicity and antineoplastic activity of 14-substituted derivatives of rubomycin and carminomycin]. / Izuchenie toksichnosti i protivoopukholevoi aktivnosti 14-zameshchennykh proizvodnykh rubomitsina i karminomitsina.

Toxicity and antitumor activity of five derivatives of rubomycin and carminomycin were studied in animals. The derivatives were prepared by modification of the methyl C-14 group. These were the following: 14-chlorrubomycin, 14-chlorcarminomycin, 14-salicyloyloxyrubomycin, 14-salicyloyloxycarminomycin and 14-quinaldinoyloxyrubomycin. The chemotherapeutic study revealed that, in their activity, all the compounds were inferior to the starting antibiotics. Unlike the other derivatives, 14-chlorcarminomycin induced a significant inhibition of leukemia P-388 development (the average lifespan of the mice amounted to 165 per cent as compared to the control). However, in the magnitude of its effect, the derivative was inferior to carminomycin.

[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.

[Synthesis and antitumor properties of 3'-desamino- dimethylformamidine doxorubicin]. / Sintez i protivoopukholevye svoistva 3'-dezamino- 3'-dimethylformamidinodoksorubitsina.

Interaction of doxorubicin hydrochloride with dimethylformamide diethylacetal yielded hydrochloride of 3'-desamino-3'-dimethylformamidine doxorubicin (DFD). It was shown that with single intravenous administration to tumor-free mice DFD was 2.5 times less toxic than the initial doxorubicin. Antitumor activity of DFD was studied with respect to 6 transplantable murine tumors: lymphosarcoma LIO-1, sarcoma 180, lymphadenosis NK-Ly, Ehrlich carcinoma, hemocytoblastosis La and leukemia P-388. Selectivity of the DFD activity against all the above tumors was shown to be high and practically equal to that of doxorubicin. DFD had the highest inhibitory effect on development of Ehrlich carcinoma and lymphosarcoma LIO-1.

[Synthesis and antitumor properties of 3'-desamino-3'-dimethylformamidinorubomycin]. / Sintez i protivoopukholevye svoistva 3'-dezamino-3'-dimetilformamidinorubomitsina.

Interaction of rubomycin (daunorubicin) chlorhydrate with dimethylformamidine diethyl acetal yielded 3'-desamino-3'dimethylformamidinorubomycin chlorhydrate (DFR). Comparative antitumor activity of DFR and rubomycin was studied on mice with respect to ascitic lymphadenosis NK/Ly and Ehrlich carcinoma, hemocytoblastosis La, leukemia P-388 and two solid tumors i. e. lymphosarcoma LIO-I and sarcoma 180. The highest antitumor effect of DFR was observed in the mice with Ehrlich carcinoma and lymphadenosis NK/Ly after the drug intravenous administration for 4 times. By selectivity of the antitumor effect DFR was inferior to rubomycin with respect to lymphosarcoma LIO-I and sarcoma 180. It was shown that the antileukemic activity of DFR and rubomycin with respect to hemocytoblastosis La was practically the same. In the experiments with leukemia P-388 DFR was inferior to rubomycin.

[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.

[Synthesis and antitumor properties of rubomycin 13-cyclohexylidene hydrazone]. / Sintez i protivoopukholevye svoistva 13-tsiklogeksildengidrazona rubomitsina.

Rubomycin 13-cyclohexylidene hydrazone (RCH) was synthesized by interaction of rubomycin 13-hydrazone with cyclohexane. Antitumor activity of RCH was studied in comparison to that of the initial rubomycin on mice with ascitic lymphadenosis NK/Ly, Ehrlich carcinoma, hemocytoblastosis La, leukemia P-388, solid lymphosarcoma LIO-1 and sarcoma 180. It was shown that RCH was actually equal to rubomycin by its selective activity against lymphadenosis NK/Ly and sarcoma 180 on its 4- and 2-fold intravenous administration, respectively. RCH was superior to rubomycin by its selective activity against lymphosarcoma LIO-1 and Ehrlich carcinoma and was more efficient in treatment of hemocytoblastosis La. RCH was inferior to rubomycin by its efficacy in treatment of lymphadenosis NK/Ly on its 2-fold oral administration and against leukemia P-388 on its 2-fold intravenous administration. Comparison of RCH with an analogous derivative of carminomycin showed that analogous changes in the chemical structure of rubomycin and carminomycin induced different changes in the chemotherapeutic properties of the initial substances.

[Synthesis and antitumor properties of carminomycin 13-cyclohexylidenhydrazone]. / Sintez i protivoopukholevye svoistva 13-tsiklogeksilidengidrazona karminomitsina.

Carminomycin 13-cyclohexylidenhydrazone (CCH) was prepared by interaction of carminomycin 13-hydrazone with cyclohexane. The antiblastomic properties of CCH were studied on mice with transplantable tumors. The preparation was administered intravenously or orally. The studies showed a high antitumor activity of CCH. When CCH was administered intravenously to mice with lymphosarcoma LIO-1, the antitumor effect selectivity of it was practically equal to that of carminomycin. When used in doses equivalent by their toxicity to those of carminomycin, CCH had practically the same inhibitory effect on sarcoma 180 as carminomycin. When used orally in doses equivalent by their toxicity to those of carminomycin, CCH was more effective than carminomycin in treatment of mice with lymphosarcoma LIO-1, sarcoma 180 and lymphadenosis NK/Ly.

[Production of 14-substituted derivatives of carminomycin and rubomycin]. / Poluchenie 14-zameshchennykh proizvodnykh karminomitsina i rubomitsina.

14-Bromocarminomycin and 14-bromorubomycin were treated with alkali metal salts and nitrogen heterocycles to obtain 14-acetoxycarminomycin, 14-octamoylhydroxycarminomycin, 14-salicyloylhydroxycarminomycin, 14-salicyloylhydroxyrubomycin, 14-chinaldinoylhydroxyrubomycin and rubomycin 14-N-phthalimide, rubomycin 14-N-pyridinium bromide and 14-N-imidazolylrubomycin. It was shown that the reaction rate of the nucleophilic substitution in the acetone medium could be increased with the use of crown ethers of sodium iodide. Under such conditions 14-iodinecarminomycin and 14-iodinerubomycin, two intermediate products, partially reduced to the initial antibiotics, i.e. carminomycin and rubomycin. 14-Acetoxycarminomycin had the highest activity against Bac. mycoides, used as a test microbe. It amounted to 50 per cent, while the activity of the other derivatives did not exceed 25 per cent of the activity of the initial antibiotics.

[Synthesis and study of the antitumor properties of 13-hydrazone-substituted carminomycin]. / Sintez i izuchenie protivoopukholevykh svoistv zameshchennykh 13-gidrazonov karminomitsina.

13-Tret-butoxycarbonyl hydrazone (BOC hydrazone) of carminomycin was prepared by interaction of carminomycin with tret-butoxycarbonyl hydrazine. Interaction of carminomycin with N-amino-N'-methyl piperazine resulted in 13-(4-methyl piperazinyl) imine (MP imine) of carminomycin. BOC hydrazone and MP imine of carminomycin had a significant antiblastomic activity against lymphosarcoma LIO-1. Still, they had no advantages over carminomycin.

[Acute toxicity of the N-acyl derivatives of carminomycin and rubomycin]. / Izuchenie ostroi toksichnosti nekotorykh N-atsil'nykh proizvodnykh karminomitsina i rubomitsina.

Synthesis of 2 new N-acyl derivatives of carminomycin and rubomycin (N-L-leucylcarminomycin and N-sarcolysylrubomycin) is described. Acute toxicity of the new and 4 known N-acyl derivatives: N-acetylcarminomycin, N,L-alanylcarminomycin, N-D-phenylalanylcarminomycin and N-D-phenylalanylrubomycin was studied on albino mice. It was shown that the N-acyl derivatives of carminomycin and rubomycin had lower acute toxicity than the initial drugs. When added to blood serum in vitro N-D-phenylalanylcarminomycin and N-D-phenylalanylrubomycin induced precipitation. The carminomycin derivatives containing the residues of L-leucine and L-alanine were less toxic than the initial antibiotic, still they had a markedly pronounced retarded toxicity.

[Synthesis and properties of the N-ethyl derivatives of carminomycin and rubomycin]. / Sintez i svoistva N-étilproizvodnykh karminomitsina i rubomitsina.

N-Monoethyl derivatives of carminomycin, rubomycin, 13-dihydrocarminomycin and 13-dihydrorubomycin were synthesized by condensation of their amino groups with acetic aldehyde in the presence of sodium boron hydride. The respective N,N-diethyl derivatives of the antibiotics were formed as by-products of the reaction. New compounds such as N-ethylcarminomycin, N,N-diethylcarminomycin, N-ethyl-13-dihydrocarminomycin, N,N-diethyl-13-dihydrocarminomycin, N-ethylrubomycin and N-ethyl-13-dihydrorubomycin were synthesized. Antibacterial activity of N-ethyl- and N,N-diethyl derivatives of carminomycin and rubomycin determined with the use of Bac. mycoides as the test microbe was 40-50 per cent and that of N-ethyl- and N,N-diethyl-13-dihydro-derivatives was 15-30 per cent of the activity of the respective antibiotics, carminomycin and rubomycin.

[Synthesis of rubomycin 13-tert-butoxycarbonylhydrazone and the study of its antitumor action]. / Sintez 13-tert-butoksikrabonilgidrazona rubomitsina i izuchenie ego protivoopukholevogo deistviia.

13-Tert-butoxycarbonylhydrazone of rubomycin was prepared on interaction of rubomycin with tert-butoxycarbonylhydrazine. The new compound showed a high antitumor activity with respect to lymphosarcoma LIO-1 and Garding-Passey melanoma. The compound had no advantages over the initial rubomycin in the treatment of these tumors, was inferior to rubomycin with respect to its activity against leukemia P-388 and unlike rubomycin had practically no effect on leukemia L-1210.

[Synthesis, toxicity and antitumor action of carminomycin azine (carminazine)]. / Sintez, toksichnost' i protivoopukholevoe deistvie azina karminomitsina (karminazina).

Carminomycin azine designated as carminazine was prepared by condensation of carminomycin with hydrazine hydrate. It was shown in the experiments on mice that the toxicity of carminazine was 2 and 7 times lower than that of carminomycin on its intravenous and oral administration respectively. The effect of both drugs on hemopoiesis of the mice was similar. As regards the selectivity of the antitumor effect on lymphosarcoma, strain L10-1, carminazine was inferior to carminomycin.

[Synthesis and properties of the N-acyl derivatives of carminomycin and rubomycin]. / Sintez i svoistva nekotorykh N-atsil'nykh proizvodnykh karminomitsina i rubomitsina.

Synthesis of N-acetylcarminomycin (III) is performed for the first time and the method of selective aminoacylation of 3'-NH2 group of carminomycin (I) and rubomycin (II) is elaborated. The method is based on interaction of N alpha-protected amino acid activated with respect to the carboxyl group with one of the antibiotics followed by removal of the protective group under mild conditions. O-Nitrophenylsulphenyl group (NPS) is used as the protective agent. In case of rubomycin (II), N alpha-NPS-amino acid is attached with the carbodiimide method. In case of carminomycin (I) the similar reaction proceeds inconsistently and carminomycin is acylated with the method of activated ethers and the use of N-hydroxysuccinimide ether of N alpha-NPS-protected amino acid. The following substances were prepared: N-(N alpha-NPS-D-phenylalanyl)-carminomycin (IVa), n-(n alpha-NPIa) and N-(N alpha-NPS-L-alanyl)-rubomycin (VIIa). Removal of NPS-group is performed under mild conditions (2 equiv. HCl in acetone, 20 degrees C, 2 min) without significant destruction of the antibiotic glucoside bond and results in formation of respective water-soluble hydrochlorides of N-aminoacyl derivatives of carminomycin and rubomycin (IV-VII). Teh structures of the new compounds are confirmed by the analytical and spectral data (Rf, [alpha] D, IR-, UV- and VO-, PMR-spectra, elementary analysis) and their chemical transformations. Antimicrobial activity of N-acetylcarminomycin (III) and water-soluble hydrochlorides of carminomycin and rubomycin derivatives (IV-VII) against Bas. mycoides is 5-10% of that of the respective initial antibiotics (I) and (II).

[Synthesis of spin-labeled rubomycin and a study of its interaction with DNA]. / Sintez spin-mechenogo rubomitsina i izuchenie vzaimodeistviia ego s DNK.

Hydrochloride of 14-(I-oxyl-2,2,6,6-tetramethylpiperidyl-4)-acetoxyrubomycin (spin-labeled rubomycin or SL-rubomycin) was prepared by interaction of hydrochloride of 14-bromrubomycin with potassium salt of I-oxyl-2,2,6,6-tetramethylpiperidyl-4-acetic acid. Its interaction with DNA and synthetic poly A and poly U polyribonucleotides was studied. The character of the EPR spectra was indicative of DNA binding with SL-rubomycin and forming a system with a high level of regularity similar to that of liquid crystals. The results of the study of the EPR spectra correlated with the model of rubomycin intercalation between the pairs of DNA bases and were indicative of water surrounding of the nitroxyl group of SL-rubomycin bound with DNA.

[Immunodepressive action of carminomycin and rubomycin derivatives]. / Immunodepressivnoe deistvie proizvodnykh karminomitsina i rubomitsina.

The immunodepressive effects of carminomycin and its 3 semi-synthetic derivatives, as well as rubomycin and its derivative R-103 were compared. It was found that 14-hydroxycarminomycin was much superior to the other substances in the experiments with synthesis induction suppression of antibodies against sheep red cells in mice. Suppression of the rejection of the skin allogenic grafts in the mice by carminomycin was higher as compared to that by the other substances. Probably different populations of the immune competent cells have selective sensitivity to separate anthracyclines.