Semisynthetic derivatives of daunorubicin and carminomycin: inhibition of DNA synthesis after intravenous administration to mice

Inhibition of DNA synthesis in the liver, kidneys, spleen and heart of mice after intravenous administration of 0.1 and 0.3 LD50 of semisynthetic derivatives of rubomycin (daunorubicin) and carminomycin was studied. The level of DNA synthesis inhibition was estimated by a decrease in incorporation of (methyl-3H) thymidine. Under the action of 13-trebutoxycarbonyl hydrazone and 14-salicyloiloxy derivatives of rubomycin and carminomycin maximum inhibition of DNA synthesis was reached later while its recovery started earlier as compared to the initial antibiotics.     

A-Factor as a selective agent for isolation of the soil Gram-negative bacterium strain--the producent of an antibacterial antibiotic]

It was shown the stimulating role of A-factor on soil prokaryotes growth. Soil sample culturing on agar medium, containing A-factor, resulted in the colony forming units (CFU) increasing in comparison with culturing on the medium without this regulator. Gram-negative bacteria were the reason of CFU increasing; previously the effect of A-factor on bacteria of this group was not shown. Gram-negative rod bacterial strain No. 35 was isolated and shown that CFU number was approximately twice increased at A-factor concentration in agar medium 2 and 7 mcg/ml; high A-factor concentration up to 28 mcg/ml was not effective. Isolated strain No. 35 is the producer of antibiotic, effective against gram-positive bacteria.     

Distribution of 3H-carminomycin in the body of mice

Distribution of 3H-carminomycin with the specific activity of 390 mCu/g prepared by the method of isotope exchange in 3H2O was investigated on mice treated with the antibiotic administered intravenously in a dose of 2 mg/kg. It was shown that the antibiotic rapidly accumulated in the mouse tissues, mainly in the liver, kidneys, lungs and spleen. The carminomycin blood levels markedly decreased within the first 5 minutes after the drug administration and remained rather stable during the following 6 hours. The concentrations of carminomycin in the heart muscle were comparatively low. Still, at early periods they were much higher than those in the skeletal muscles. The difference disappeared by 24 hours. Carminomycin penetrated into the tissues of the brain.     

Unusual amidation reaction of asparagine-containing glycopeptide antibiotics in the presence of (benzotriazole-1-yl)oxy-tris(pyrrolidino)phosphonium hexafluorophosphate (PyBOP)

The coupling reagent (benzotriazole-1-yl)oxy-tris(pyrrolidino)phosphonium hexafluorophosphate (PyBOP) is widely used for the synthesis of different peptides and their amides, particularly carboxamides of glycopeptide antibiotics of the vancomycin or teicoplanin groups. The amidation reaction of the carboxyl group of the seventh amino acid residue (AA7) in antibiotics in the presence of PyBOP is not usually accompanied by the formation of significant amounts of byproducts. However, the amidation of eremomycin (I) with bulky amines (e.g., decyl amine and adamantyl amine) in the presence of PyBOP at pH ～8.5 (Et₃N or (i-Pr)₂EtN) yielded N-unsubstituted carboxamide of eremomycin (Ia) as an admixture. The interaction of asparagine-containing antibiotics (eremomycin or vancomycin) with the excess of PyBOP and Et₃N (pH ～8.5) in the absence of amine or ammonia led to the formation of still larger amounts of corresponding unsubstituted AA7-amides (～20%). Their structure was determined by ¹H NMR and ESI MS methods and confirmed by comparing with authentic samples. It is assumed that the amide group of the asparagine residue (AA3) is the source of ammonia in the unususal amidation reaction of Asn-containing antibiotics.     

Study of 1-deoxy-1-(indol-3-yl)-L-sorbose, 1-deoxy-1-(indol-3-yl)-L-tagatose,and their analogs

Alkaline degradation of the ascorbigen 2-C-[(indol-3-yl)methyl]-alpha-L-xylo-hex-3-ulofuranosono-1,4-lactone (1a) led to a mixture of 1-deoxy-1-(indol-3-yl)-L-sorbose (2a) and 1-deoxy-1-(indol-3-yl)-L-tagatose (3a). The mixture of diastereomeric ketoses underwent acetylation and pyranose ring opening under the action of acetic anhydride in pyridine in the presence of 4-dimethylaminopyridine (DMAP) with the formation of a mixture of (E)-2,3,4,5,6-penta-O-acetyl-1-deoxy-1-(indol-3-yl)-L-xylo-hex-1-enitol (4a) and (E)-2,3,4,5,6-penta-O-acetyl-1-deoxy-1-(indol-3-yl)-L-lyxo-hex-1-enitol (5a), which were separated chromatographically. Deacetylation of 4a or 5a afforded cyclised tetrols, tosylation of which in admixture resulted in 1-deoxy-1-(indol-3-yl)-3,5-di-O-tosyl-alpha-L-sorbopyranose (12a) and 1-deoxy-1-(indol-3-yl)-4,5-di-O-tosyl-alpha-L-tagatopyranose (13a). Under alkaline conditions 13a readily formed 2-hydroxy-4-hydroxymethyl-3-(indol-3-yl)cyclopenten-2-one (15a) in 90% yield. Similar transformations were performed for N-methyl- and N-methoxyindole derivatives.     

Balinese Y-chromosome perspective on the peopling of Indonesia: genetic contributions from pre-neolithic hunter-gatherers, Austronesian farmers, and Indian traders

The island of Bali lies near the center of the southern chain of islands in the Indonesian archipelago, which served as a stepping-stone for early migrations of hunter-gatherers to Melanesia and Australia and for more recent migrations of Austronesian farmers from mainland Southeast Asia to the Pacific. Bali is the only Indonesian island with a population that currently practices the Hindu religion and preserves various other Indian cultural, linguistic, and artistic traditions (Lansing 1983). Here, we examine genetic variation on the Y chromosomes of 551 Balinese men to investigate the relative contributions of Austronesian farmers and pre-Neolithic hunter-gatherers to the contemporary Balinese paternal gene pool and to test the hypothesis of recent paternal gene flow from the Indian subcontinent. Seventy-one Y-chromosome binary polymorphisms (single nucleotide polymorphisms, SNPs) and 10 Y-chromosome-linked short tandem repeats (STRs) were genotyped on a sample of 1,989 Y chromosomes from 20 populations representing Indonesia (including Bali), southern China, Southeast Asia, South Asia, the Near East, and Oceania. SNP genotyping revealed 22 Balinese lineages, 3 of which (O-M95, O-M119, and O-M122) account for nearly 83.7% of Balinese Y chromosomes. Phylogeographic analyses suggest that all three major Y-chromosome haplogroups migrated to Bali with the arrival of Austronesian speakers; however, STR diversity patterns associated with these haplogroups are complex and may be explained by multiple waves of Austronesian expansion to Indonesia by different routes. Approximately 2.2% of contemporary Balinese Y chromosomes (i.e., K-M9*, K-M230, and M lineages) may represent the pre-Neolithic component of the Indonesian paternal gene pool. In contrast, eight other haplogroups (e.g., within H, J, L, and R), making up approximately 12% of the Balinese paternal gene pool, appear to have migrated to Bali from India. These results indicate that the Austronesian expansion had a profound effect on the composition of the Balinese paternal gene pool and that cultural transmission from India to Bali was accompanied by substantial levels of gene flow.     

Studying hunting behaviour in the striped field mouse using data compression

We compare predatory behaviour towards a mobile insect in three species of small mammals: the granivorous striped field mouse, the insectivorous common shrew and the Norway rat (a generalist). The striped field mouse displays a surprisingly efficient hunting stereotype. We apply the data compression method (Ryabko et al. Theory Comput Syst 52:133–147, 2013) to compare the complexity of hunting behavioural patterns and to evaluate the flexibility of stereotypes and their succinctness. Norway rats demonstrated the highest level of complexity of hunting behaviour, with the highest proportion of ‘auxiliary’ and ‘noise’ elements and relatively low proportion of ‘key’ elements in their behaviours. The predominance of ‘key’ elements resulted in similarly low levels of complexity of hunting stereotypes in striped field mice and shrews. The similarity between hunting stereotypes of the insectivorous shrew and the granivorous striped field mouse enables us to argue about evolutionary roots of hunting behaviour in small mammals. We show that this method is a useful tool for comparing ethograms as ‘biological texts’.     

Localization of disulfide bonds in α1-acid glycoprotein and their effect on the ability of the protein to interact with ethidium bromide

α1-Acid glycoprotein (orosomucoid) was purified from the human and murine blood sera using phenol deproteinization. As opposed to the murine protein, the human orosomucoid bound the fluorescent dye ethidium bromide but lost this ability after treatment with β-mercaptoethanol, which breaks disulfide bonds. Disulfide bonds between the Cys²³ and Cys¹⁶⁵ residues of the human orosomucoid and between the Cys⁹¹ and Cys¹⁸⁴ residues of the murine orosomucoid were identified.     

Transformation of anthracycline antibiotics and their semisynthetic derivatives as affected by the liver aldo-keto reductase of rats

Formation of 13-dihydro derivatives of rubomycin (daunorubicin), carminomycin, doxorubicin and some of their semisynthetic derivatives under the effect of pure aldo-keto reductase from the rat liver was studied. Attachment of an oxy group to C-14 markedly retarded formation of the 13-dihydro derivatives while attachment of the bulky radicals to the same position prevented their formation. Binding of the anthracycline antibiotics to human serum albumin had no impact on the fermentative reaction rate. Rubomycin, carminomycin and doxorubicin significantly differed in their lipophilic properties and capacity for binding to serum albumin.