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The Journal of Antibiotics Feb 1992A method of synthesis of antibiotic streptonigrin 8'-O-alkyl ethers by alkylation of streptonigrin diphenylmethyl ester and consequent deprotection of carboxylic group...
A method of synthesis of antibiotic streptonigrin 8'-O-alkyl ethers by alkylation of streptonigrin diphenylmethyl ester and consequent deprotection of carboxylic group with CF3COOH is developed. An attempt to deblock carboxylic group of 8'-O-methylstreptonigrin diphenylmethyl ester by hydrogenation over Pd produced 8'-O-methylstreptonigrone. Similarly streptonigrin was transformed into streptonigrone over Pd-black in H2 stream. Methylation of streptonigrone afforded 5',5'-N-dimethyl-2',8'-O-dimethylstreptonigrone and 1',5',5'-tri-N-trimethyl-8'-O-methylstreptonigrone. Alkyl streptonigrin ethers demonstrated lower antibacterial activity in vitro than the parent antibiotic.
Topics: Alkylation; Methylation; Microbial Sensitivity Tests; Streptonigrin; Structure-Activity Relationship
PubMed: 1556014
DOI: 10.7164/antibiotics.45.227 -
Bioscience, Biotechnology, and... May 1996The immune system is composed of various cells with distinct functions. Thus, highly selective immunomodulators are necessary for artificial regulation of immune... (Comparative Study)
Comparative Study
The immune system is composed of various cells with distinct functions. Thus, highly selective immunomodulators are necessary for artificial regulation of immune reactions. We screened microbial products for such immunomodulators and we identified streptonigrin as a selective suppressor of B-cell proliferation induced by lipopolysaccharide. Streptonigrin directly suppressed the late phase of proliferation of B-cells. The inhibition of topoisomerase II was implicated as the mechanism of the B-cell-selective suppression. In cultured cell lines, however, streptonigrin preferentially suppressed the growth of an interleukin-3-dependent myeloid cell line rather than B-cell lines. In addition, the treatment with streptonigrin in vivo suppressed T-cells more significantly than B-cells and dramatically reduced the spleen weight. These results suggest that streptonigrin preferentially suppresses myeloid T-cell precursors in vivo.
Topics: Adjuvants, Immunologic; Agglutination Tests; Animals; Antibiotics, Antineoplastic; Antibody Formation; B-Lymphocytes; Cell Line; Cells, Cultured; Female; Flow Cytometry; In Vitro Techniques; Interleukin-3; Lipopolysaccharides; Lymphocyte Activation; Mice; Mice, Inbred C57BL; Specific Pathogen-Free Organisms; Spleen; Streptonigrin; T-Lymphocytes; Topoisomerase II Inhibitors
PubMed: 8704308
DOI: 10.1271/bbb.60.789 -
Molecules (Basel, Switzerland) Nov 2019Natural 5,8-quinolinedione antibiotics exhibit a broad spectrum of activities including anticancer, antibacterial, antifungal, and antimalarial activities. The... (Review)
Review
Natural 5,8-quinolinedione antibiotics exhibit a broad spectrum of activities including anticancer, antibacterial, antifungal, and antimalarial activities. The structure-activity research showed that the 5,8-quinolinedione scaffold is responsible for its biological effect. The subject of this review report is a presentation of the pharmacological activity of synthetic 5,8-quinolinedione compounds containing different groups at C-6 and/or C-7 positions. The relationship between the activity and the mechanism of action is included if these data have been included in the original literature. The review mostly covers the period between 2000 and 2019. Previously published literature data were used to present historical points.
Topics: Molecular Structure; Quinolines; Streptonigrin; Structure-Activity Relationship
PubMed: 31739496
DOI: 10.3390/molecules24224115 -
Acta Crystallographica. Section E,... Jun 2011The title compound, C(27)H(24)N(4)O(5), is an inter-mediate in the synthesis of lavendamycin via a ruthenium-catalysed [2 + 2 + 2] cyclo-addition. An intra-molecular...
The title compound, C(27)H(24)N(4)O(5), is an inter-mediate in the synthesis of lavendamycin via a ruthenium-catalysed [2 + 2 + 2] cyclo-addition. An intra-molecular hydrogen-bond bridge from the carboline to the quinoline stabilizes a highly planar geometry [maximum deviation = 0.065 (6) Å] for the two rigid units. This hydrogen-bond-stabilized coplanarity has a very close analogy in the structure of the anti-tumor anti-biotic streptonigrin in the solid state and in solution. Inter-molecular hydrogen-bond bridges of amides groups along the a axis and π-π stacking inter-actions [centroid-centroid distance = 3.665 (9) Å] connect mol-ecules arranged in a parallel manner.
PubMed: 21754865
DOI: 10.1107/S1600536811018794 -
Journal of Bacteriology Dec 1989An S-adenosylhomocysteine deaminase has been isolated and purified from streptonigrin-producing Streptomyces flocculus ATCC 13257. Deamination represents the major...
An S-adenosylhomocysteine deaminase has been isolated and purified from streptonigrin-producing Streptomyces flocculus ATCC 13257. Deamination represents the major metabolic route of S-adenosylhomocysteine in this organism. The protein was found to be monomeric with a molecular weight of 56,100 +/- 1,600. The activity was optimal at pH 7.0 and 37 degrees C, and the deaminase was inactivated by p-chloromercuribenzoate but not by metal chelators. The Km for S-adenosylhomocysteine is 2.5 mM, and the Ki for inhibition by deoxycoformycin is 1.6 nM.
Topics: Chromatography, Gel; Chromatography, Ion Exchange; Electrophoresis, Polyacrylamide Gel; Kinetics; Molecular Weight; Nucleoside Deaminases; Streptomyces; Streptonigrin
PubMed: 2592350
DOI: 10.1128/jb.171.12.6840-6844.1989 -
Bioorganic & Medicinal Chemistry Feb 2014Protein citrullination is just one of more than 200 known PTMs. This modification, catalyzed by the protein arginine deiminases (PADs 1-4 and PAD6 in humans), converts...
Protein citrullination is just one of more than 200 known PTMs. This modification, catalyzed by the protein arginine deiminases (PADs 1-4 and PAD6 in humans), converts the positively charged guanidinium group of an arginine residue into a neutral ureido-group. Given the strong links between dysregulated PAD activity and human disease, we initiated a program to develop PAD inhibitors as potential therapeutics for these and other diseases in which the PADs are thought to play a role. Streptonigrin which possesses both anti-tumor and anti-bacterial activity was later identified as a highly potent PAD4 inhibitor. In an effort to understand why streptonigrin is such a potent and selective PAD4 inhibitor, we explored its structure-activity relationships by examining the inhibitory effects of several analogues that mimic the A, B, C, and/or D rings of streptonigrin. We report the identification of the 7-amino-quinoline-5,8-dione core of streptonigrin as a highly potent pharmacophore that acts as a pan-PAD inhibitor.
Topics: Animals; Antineoplastic Agents; Cell Line; Cell Proliferation; Cell Survival; Enzyme Inhibitors; Humans; Hydrolases; Kinetics; Mice; Protein Binding; Protein Isoforms; Protein-Arginine Deiminases; Quinolines; Streptonigrin; Structure-Activity Relationship
PubMed: 24440480
DOI: 10.1016/j.bmc.2013.12.064 -
Proceedings of the National Academy of... Sep 1965
Topics: Anti-Bacterial Agents; Bacillus megaterium; DNA, Bacterial; Electron Spin Resonance Spectroscopy; Escherichia coli; Flavins; In Vitro Techniques; Phenazines; Streptonigrin
PubMed: 4286419
DOI: 10.1073/pnas.54.3.887 -
PloS One 2014Accumulating evidence supports the concept that melanoma is highly heterogeneous and sustained by a small subpopulation of melanoma stem-like cells. Those cells are...
BACKGROUND
Accumulating evidence supports the concept that melanoma is highly heterogeneous and sustained by a small subpopulation of melanoma stem-like cells. Those cells are considered as responsible for tumor resistance to therapies. Moreover, melanoma cells are characterized by their high phenotypic plasticity. Consequently, both melanoma stem-like cells and their more differentiated progeny must be eradicated to achieve durable cure. By reevaluating compounds in heterogeneous melanoma populations, it might be possible to select compounds with activity not only against fast-cycling cells but also against cancer stem-like cells. Natural compounds were the focus of the present study.
METHODS
We analyzed 120 compounds from The Natural Products Set II to identify compounds active against melanoma populations grown in an anchorage-independent manner and enriched with cells exerting self-renewing capacity. Cell viability, cell cycle arrest, apoptosis, gene expression, clonogenic survival and label-retention were analyzed.
FINDINGS
Several compounds efficiently eradicated cells with clonogenic capacity and nanaomycin A, streptonigrin and toyocamycin were effective at 0.1 µM. Other anti-clonogenic but not highly cytotoxic compounds such as bryostatin 1, siomycin A, illudin M, michellamine B and pentoxifylline markedly reduced the frequency of ABCB5 (ATP-binding cassette, sub-family B, member 5)-positive cells. On the contrary, treatment with maytansine and colchicine selected for cells expressing this transporter. Maytansine, streptonigrin, toyocamycin and colchicine, even if highly cytotoxic, left a small subpopulation of slow-dividing cells unaffected. Compounds selected in the present study differentially altered the expression of melanocyte/melanoma specific microphthalmia-associated transcription factor (MITF) and proto-oncogene c-MYC.
CONCLUSION
Selected anti-clonogenic compounds might be further investigated as potential adjuvants targeting melanoma stem-like cells in the combined anti-melanoma therapy, whereas selected cytotoxic but not anti-clonogenic compounds, which increased the frequency of ABCB5-positive cells and remained slow-cycling cells unaffected, might be considered as a tool to enrich cultures with cells exhibiting melanoma stem cell characteristics.
Topics: Apoptosis; Biological Products; Cell Cycle Checkpoints; Cell Survival; Colony-Forming Units Assay; Drug Discovery; Gene Expression Regulation; Humans; Melanoma; Microphthalmia-Associated Transcription Factor; Naphthoquinones; Neoplastic Stem Cells; Proto-Oncogene Mas; Streptonigrin; Toyocamycin
PubMed: 24595456
DOI: 10.1371/journal.pone.0090783 -
Molecular Oral Microbiology Dec 2016SloR, a 25-kDa metalloregulatory protein in Streptococcus mutans modulates the expression of multiple genes, including the sloABC operon that encodes essential Mn...
SloR, a 25-kDa metalloregulatory protein in Streptococcus mutans modulates the expression of multiple genes, including the sloABC operon that encodes essential Mn transport and genes that promote cariogenesis. In this study, we report on SloC- and SloR-deficient strains of S. mutans (GMS284 and GMS584, respectively) that demonstrate compromised survivorship compared with their UA159 wild-type progenitor and their complemented strains (GMS285 and GMS585, respectively), when challenged with streptonigrin and/or in growth competition experiments. The results of streptonigrin assays revealed significantly larger zones of inhibition for GMS584 than for either UA159 or GMS585, indicating weakened S. mutans survivorship in the absence of SloR. Competition assays revealed a compromised ability for GMS284 and GMS584 to survive peroxide challenge compared with their SloC- and SloR-proficient counterparts. These findings are consistent with a role for SloC and SloR in S. mutans aerotolerance. We also predicted differential expression of oxidative stress tolerance genes in GMS584 versus UA159 and GMS585 when grown aerobically. The results of quantitative RT-PCR experiments revealed S. mutans sod, tpx, and sloC expression that was upregulated in GMS584 compared with UA159 and GMS585, indicating that the impact of oxidative stress on S. mutans is more severe in the absence of SloR than in its presence. The results of electrophoretic mobility shift assays indicate that SloR does not bind to the sod or tpx promoter regions directly, implicating intermediaries that may arbitrate the SloR response to oxidative stress.
Topics: Bacterial Proteins; DNA, Bacterial; Gene Expression Regulation, Bacterial; Genetic Complementation Test; Hydrogen Peroxide; Metals; Mutation; Oxidative Stress; Streptococcus mutans; Streptonigrin; Superoxide Dismutase-1; Virulence
PubMed: 26577188
DOI: 10.1111/omi.12147 -
Journal of Microbiology, Immunology,... Dec 2022Klebsiella pneumoniae is a gram-negative opportunistic pathogen that causes diseases mostly in immunocompromised individuals. Recently, hypervirulent K. pneumoniae...
BACKGROUND
Klebsiella pneumoniae is a gram-negative opportunistic pathogen that causes diseases mostly in immunocompromised individuals. Recently, hypervirulent K. pneumoniae strains also cause severe disease in healthy individuals. Capsular polysaccharide (CPS) is the major virulence determinant in hypervirulent K. pneumoniae and protects the cell against the bactericidal activity of the immune system. Gallic acid (GA), a natural phenolic compound, is known to exhibit wide spectrum antibacterial activity; however, its effect on hypervirulent K. pneumoniae remains largely unresolved. We aimed to identify the effects of GA on CPS biosynthesis in hypervirulent K. pneumoniae.
METHODS
Antibacterial activity of GA was evaluated by counting colonies. CPS amount was determined by glucuronic acid content. The transcriptions of cps gene cluster were measured by quantitative real time PCR (qRT-PCR) and the β-galactosidase activity. The effect of GA on the resistance of K. pneumoniae to streptonigrin (SNG), an iron-activated antibiotic, was evaluated. The effect of GA on the resistance of K. pneumoniae to serum killing and phagocytosis by macrophages was observed.
RESULTS
GA inhibited the growth and CPS biosynthesis in K. pneumoniae. GA may affect the iron availability in K. pneumoniae, thus possibly repressing the cps transcription. In addition, GA reduced the resistance of K. pneumoniae to serum killing and enhanced its susceptibility to phagocytosis.
CONCLUSION
GA possesses bactericidal activity and inhibits the CPS biosynthesis in hypervirulent K. pneumoniae, thereby facilitating pathogen clearance by the host immune system. Therefore, GA may represent a promising strategy for the prevention or treatment of patients with hypervirulent K. pneumoniae infections.
Topics: Humans; Klebsiella pneumoniae; Gallic Acid; Virulence Factors; Anti-Bacterial Agents; Iron; Klebsiella Infections
PubMed: 34326026
DOI: 10.1016/j.jmii.2021.07.002