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Biomedical subjects

S Tanida

Publications and source records attributed to S Tanida.

At least 37 records · Page 2Linked to original sources

New naphthacenecarboxamide antibiotics, TAN-1518 A and B, have inhibitory activity against mammalian DNA topoisomerase I.

New naphthacenecarboxamide antibiotics, TAN-1518 A and B, were isolated from a culture broth of Streptomyces sp. AL-16012. Their structures were elucidated from their reactions and from spectroscopic analyses. The relaxation of supercoiled pBR322 DNA by calf thymus DNA topoisomerase I was inhibited by these metabolites as potently as by camptothecin. However, the decatenation of kinetoplast DNA by calf thymus DNA topoisomerase II was little affected by these agents. The major metabolite, TAN-1518 A, strongly suppressed the growth of various murine and human tumor cells, inducing apoptosis. Unlike camptothecin, TAN-1518 A did not stimulate cleavable complex formation in the nuclei of CHO-K1 cells and had weak activity in intercalating into DNA strands. This metabolite arrested the growth of human tumor cell lines in G1 phase of the cell cycle. These results suggest that TAN-1518 A and B are novel antitumor agents targeting topoisomerase I.

Animals↗

Structures of dnacin A1 and B1, new naphthyridinomycin-type antitumor antibiotics.

Dnacin A1 and B1 were revealed to be new naphthyridinomycin-type antitumor antibiotics with formulae of C20H23N5O4 and C19H24N4O5, respectively. The gross structure of dnacin A1 was elucidated by the spectroscopic analyses. Conversion of dnacin B1 into A1 by treatment with potassium cyanide indicated the presence of an alpha-carbinolamine moiety in dnacin B1. The relative stereochemistry of dnacins was clarified by analysis of the NOESY spectra.

Antibiotics, Antineoplastic↗

Absolute structure-cytotoxic activity relationships of steganacin congeners and analogues.

The cytotoxic activities of optically pure and racemic steganacin congeners and analogues against KB cells in culture and the inhibitor activity of cilia regeneration in Tetrahymena were studied with regard to absolute and relative configurations. The stereochemical requirements of dibenzocyclooctadiene lignan lactones for activity were clarified.

4-Butyrolactone↗

Marked reduction of subcutaneous tumor growth by intraperitoneal administration of recombinant human interleukin 2 with a cell accumulator, proteose-peptone, in mice.

The growth of 3-methylcholanthrene-induced fibrosarcomas, Meth 1 and Meth A, was strongly suppressed by a combination of recombinant human interleukin 2 (rIL-2) with proteose-peptone (PP) administered i.p. to syngeneic mice. When 1 ml of 10% PP was injected i.p. on Day 6 followed by rIL-2 (50 micrograms) administered i.p. on Days 7 and 8 after the s.c. inoculation of tumor cells into female BALB/c mice, the tumors regressed. A similar result was also obtained when 12.5 micrograms of rIL-2 were injected on Days 7, 8, and 9 after s.c. inoculation of Meth 1 cells. The treatment with an anti-asialo-GM1 antibody had no effect on the regression of the Meth 1 tumor induced by the combination. However, the combined treatment with rIL-2 and PP did not suppress the growth of the Meth 1 tumor in adult thymectomized, irradiated, and fetal liver cell-reconstituted BALB/c mice. Therefore, this suggests that the T-cells might be the principal effectors of this antitumor system. The cytolytic activity of splenocytes and peritoneal exudate cells from Meth 1 tumor-bearing mice against Meth 1 cells was significantly augmented by the combined treatment. This peritoneal exudate cell also showed cytolytic activity against other target cells such as Meth A, antigenically distinct from Meth 1, YAC-1, a leukemic cell line sensitive to natural killer cells, and EL-4, a lymphoma cell line resistant to natural killer cells. The cytolytic activity of these effectors was reduced by the treatment with anti-thy1.2 antibody plus complement. The adherent cells in this peritoneal cavity had only a small cytolytic activity on Meth 1 and Meth A targets. The mechanism of antitumor immunity by rIL-2 in combination with PP and the therapeutic availability of this lymphokine are discussed.

Animals↗

TAN-999 and TAN-1030A, new indolocarbazole alkaloids with macrophage-activating properties.

Two new indolocarbazole alkaloids, TAN-999 and TAN-1030A, were isolated from culture broths of Nocardiopsis dassonvillei C-71425 and Streptomyces sp. C-71799, respectively. Their structures were elucidated on the basis of their reactions, spectroscopic analyses and in particular, comparison of spectral data with that of staurosporine. These metabolites induced spreading of a murine macrophage cell line, Mm 1. They also augmented the phagocytic activity, Fc gamma receptor expression and beta-glucuronidase activity of murine macrophage cell lines, Mm 1 and J774A.1. When proteose-peptone elicited peritoneal macrophages from mice were incubated with these metabolites for 2 days, the phagocytosis-dependent respiratory burst of these cells was enhanced. Similar enhancement was also observed when the peritoneal macrophages in mice were modulated by intraperitoneal administration of these metabolites. These results reveal that TAN-999 and TAN-1030A can activate macrophage functions in mice.

Alkaloids↗

A new pyrrole-amidine antibiotic TAN-868 A.

A new pyrrole-amidine antibiotic TAN-868 A was isolated from the culture broth of Streptomyces idiomorphus sp. nov. Its chemical structure was determined by spectroscopic analyses and degradation studies to be 4-[(2S,4R)-4-hydroxy-5-iminoprolyl]amino- N-(2-amidinoethenyl)-2-pyrrolecarboxamide. The antibiotic is active against bacteria, fungi and a protozoan, and has cytotoxic activity against murine tumor cells. DNA thermal denaturation studies suggest that TAN-868 A preferentially interacts with AT rich regions of double-stranded DNA.

Anti-Bacterial Agents↗

Two sulfur-containing ansamycin antibiotics from Streptomyces albolongus.

Two sulfur-containing ansamycin antibiotics were isolated from the culture broth of Streptomyces albolongus C-46366; the major one was identical with awamycin and the minor one was a new ansamycin antibiotic, ansathiazin. Their structures were elucidated from their reactions and spectroscopic analyses. These antibiotics were active against gram-positive bacteria, acid-fast bacteria and a protozoan.

Anti-Bacterial Agents↗

Mechanism of action of dnacin B1, a new benzoquinoid antibiotic with antitumor properties.

Dnacin B1 preferentially inhibited the incorporation of [3H]thymidine into acid-insoluble fractions in Escherichia coli. At a sublethal concentration, dnacin B1 caused filamentous growth in E. coli and induced prophage lambda. The antibiotic also showed potent bactericidal activity against repair-deficient E. coli strains, such as recA, recB, and polA strains, In in vitro studies, dnacin Ba raised the melting temperatures of various double-stranded DNAs. In addition, the antibiotic showed DNA-cleaving activity against PM2 DNA in the presence of reducing agents, and the activity was suppressed by scavengers for oxygen free radicals and an iron-specific chelator, desferrioxamine E. The stimulation of the generation of superoxide radical by dnacin B1 was confirmed by measuring the reduction of neotetrazolium. Therefore, it can be presumed that the primary cellular target of dnacin B1 is DNA in susceptible cells, and the autooxidation of DNA-bound dnacin B1 causes the generation of oxygen-free radicals that result in the damage of DNA and the inhibition of its synthesis.

Antibiotics, Antineoplastic↗

Ansamitocin analogs from a mutant strain of Nocardia. I. Isolation of the mutant, fermentation and antimicrobial properties.

A mutant having a high ability to produce ansamitocins was derived from a dnacin-producing strain, Nocardia sp. No. C-14482 (N-1001), by treatment with ethidium bromide. Mutant N-1231 produced ansamitocins P-3 and P-4 as major components, but was deficient in its ability to produce dnacins. Strain N-1231 also produced fifteen novel ansamitocin analogs as minor components. These analogs showed no activity against prokaryotic micro-organisms. The results of determining the activity inhibiting cilia regeneration of deciliated Tetrahymena pyriformis suggest that hydroxylation of C15, C26 and the acyl moiety at C3 of ansamitocins may cause marked reduction of their antitubulinic activities whereas demethylation of -NCH3 at C18 slightly affected their activities.

Anti-Bacterial Agents↗

Ansamitocin-induced synchrony in Tetrahymena pyriformis.

Ansamitocins inhibited cell division in Tetrahymena pyriformis W at low concentrations and caused cells to become more rounded. Exposure to ansamitocins for 5 h or more resulted in a burst of synchronous division at 100 min after removal of the antibiotics with a maximum division index of 70%. A second burst of synchronous division occurred 300 min after removal with a peak division index of 55%. The rounding of the cell shape was restored by the completion of the first division. When RNA or protein synthesis was blocked by chromomycin A3 or cycloheximide, the first division was suppressed. When DNA synthesis was blocked by methotrexate plus uridine, synchronous division still occurred; furthermore, the DNA content of T. pyriformis cells did not increase before the first division. These findings suggests that the first synchronous division requires RNA and protein synthesis but does not require DNA synthesis. Interference by ansamitocins with the fuction of microtubule systems in T. pyriformis is discussed.

Animals↗

Dnacins, new antibiotics. I. Producing organism, fermentation, and antimicrobial activities.

Dnacins are new antibiotics produced by an actinomycete, strain No. C-14482 (N-1001). The characteristic features of the organism are: the formation of coremia on solid media, production of rod-shaped motile spores with peritrichous flagella from mature aerial mycella, fragmentation of the mature organism (at later stage of growth) in liquid media in which some fragmented elements have motility, lysozyme resistance, meso-diaminopimelic acid in the cell wall, and a guanine-cytosine content of 71 +/- 1 mol%. The organism has been designated as Nocardia sp. No. C-14482 (N-1001). Dnacins show strong activity against various GRam-negative, Gram-positive, and acid-fast bacteria, but slight activity against fungi. The antibiotics hardly affect the growth of Escherichia coli K-12 under anaerobic condition even at concentrations more than five times that of the minimum inhibitory concentrations under aerobic conditions.

Anti-Bacterial Agents↗

Dnacins, new antibiotics II. Isolation and characterization.

Dnacins A1 and B1, new basic antibiotics with strong and broad antibacterial activities, were isolated as dark red or reddish brown needles from the culture broth of Nocardia sp. No. C-14482. The characteristic absorption maxima at 213 nm, 281 or 283 nm and 496 nm in the UV and visible range and other physicochemical properties indicated that dnacins A1 and B1 are novel antibiotics which belong to the group having aminobenzoquinone moieties.

Anti-Bacterial Agents↗

Macbecins I and II, new antitumor antibiotics. I. Producing organism, fermentation and antimicrobial activities.

New antibiotics, macbecins I and II, have been found in the culture fluid of an actinomycete, which has the following properties: delayed fragmentation of vegetative mycelia, formation of coremia on solid media, the occurrence of meso-diaminopimelic acid in the cell wall, lysozyme resistance, and guanine-cytosine content of 71 +/- 1 mol%. The organism has been designated Nocardia sp. No. C-14919 (N-2001). A marked enhancement of the production of macbecins I and II was observed in cultures containing L-tyrosine. The antibiotics are moderately active against several Gram-positive bacteria and fungi. The antibiotics also inhibit the growth of Tetrahymena pyriformis W at 2 microgram/ml but show no activity against the regeneration of cilia in partially deciliated Tetrahymena at 10 microgram/ml.

Amino Acids↗