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Drug Design, Development and Therapy 2023Streptonigrin is an aminoquinone alkaloid isolated from and is gaining attention as a drug molecule owing to its potential antitumor and antibiotic effects. It was... (Review)
Review
Streptonigrin is an aminoquinone alkaloid isolated from and is gaining attention as a drug molecule owing to its potential antitumor and antibiotic effects. It was previously used as an anticancer drug but has been discontinued because of its toxic effects. However, according to the most recent studies, the toxicity of streptonigrin and its structurally modified derivatives has been reduced while maintaining their potential pharmacological action at lower concentrations. To date, many investigations have been conducted on this molecule and its derivatives to determine the most effective molecule with low toxicity to enable new drug discovery. Therefore, the main objective of this study is to provide a comprehensive review and to discuss the prospects for streptonigrin and its derived compounds, which may boost the molecule as a highly interesting target molecule for new drug design, development and therapy. To complete this review, relevant literature was collected from several scientific databases, including Google Scholar, PubMed, Scopus and ScienceDirect. Following a complete screening, the obtained information is summarized in the present review to provide a good reference and accelerate the development and utilization of streptonigrin and its derivatives as pharmaceuticals.
Topics: Streptonigrin; Antineoplastic Agents; Drug Design
PubMed: 37064433
DOI: 10.2147/DDDT.S388490 -
Molecules (Basel, Switzerland) Jul 2023This review uses the National Cancer Institute (NCI) COMPARE program to establish an extensive list of heterocyclic iminoquinones and quinones with similarities in... (Review)
Review
This review uses the National Cancer Institute (NCI) COMPARE program to establish an extensive list of heterocyclic iminoquinones and quinones with similarities in differential growth inhibition patterns across the 60-cell line panel of the NCI Developmental Therapeutics Program (DTP). Many natural products and synthetic analogues are revealed as potential NAD(P)H:quinone oxidoreductase 1 (NQO1) substrates, through correlations to dipyridoimidazo[5,4-]benzimidazoleiminoquinone (DPIQ), and as potential thioredoxin reductase (TrxR) inhibitors, through correlations to benzo[1,2,4]triazin-7-ones and pleurotin. The strong correlation to NQO1 infers the enzyme has a major influence on the amount of the active compound with benzo[]perimidines, phenoxazinones, benz[]pyrido[1,2-]indole-6,11-quinones, seriniquinones, kalasinamide, indolequinones, and furano[2,3-]naphthoquinones, hypothesised as prodrugs. Compounds with very strong correlations to known TrxR inhibitors had inverse correlations to the expression of both reductase enzymes, NQO1 and TrxR, including naphtho[2,3-][1,4]oxazepane-6,11-diones, benzo[]carbazole-1,4-diones, pyranonaphthoquinones (including kalafungin, nanaomycin A, and analogues of griseusin A), and discorhabdin C. Quinoline-5,8-dione scaffolds based on streptonigrin and lavendamycin can correlate to either reductase. Inhibitors of TrxR are not necessarily (imino)quinones, e.g., parthenolides, while oxidising moieties are essential for correlations to NQO1, as with the mitosenes. Herein, an overview of synthetic methods and biological activity of each family of heterocyclic imino(quinone) is provided.
Topics: United States; National Cancer Institute (U.S.); Quinones; Indolequinones; Oxidoreductases; NAD(P)H Dehydrogenase (Quinone); Antineoplastic Agents; Neoplasms
PubMed: 37446864
DOI: 10.3390/molecules28135202 -
Scientific Reports Feb 2020Heterochromatin is essential for regulating global gene transcription and protecting genome stability, and may play a role in tumor suppression. Drugs promoting...
Heterochromatin is essential for regulating global gene transcription and protecting genome stability, and may play a role in tumor suppression. Drugs promoting heterochromatin are potential cancer therapeutics but very few are known. In order to identify drugs that can promote heterochromatin, we used a cell-based method and screened NCI drug libraries consisting of oncology drugs and natural compounds. Since heterochromatin is originally defined as intensely stained chromatin in the nucleus, we estimated heterochromatin contents of cells treated with different drugs by quantifying the fluorescence intensity of nuclei stained with Hoechst DNA dye. We used HeLa cells and screened 231 FDA-approved oncology and natural substance drugs included in two NCI drug libraries representing a variety of chemical structures. Among these drugs, streptonigrin most prominently caused an increase in Hoechst-stained nuclear fluorescence intensity. We further show that streptonigrin treated cells exhibit compacted DNA foci in the nucleus that co-localize with Heterochromatin Protein 1 alpha (HP1α), and exhibit an increase in total levels of the heterochromatin mark, H3K9me3. Interestingly, we found that streptonigrin promotes heterochromatin at a concentration as low as one nanomolar, and at this concentration there were no detectable effects on cell proliferation or viability. Finally, in line with a previous report, we found that streptonigrin inhibits STAT3 phosphorylation, raising the possibility that non-canonical STAT function may contribute to the effects of streptonigrin on heterochromatin. These results suggest that, at low concentrations, streptonigrin may primarily enhance heterochromatin formation with little toxic effects on cells, and therefore might be a good candidate for epigenetic cancer therapy.
Topics: Antibiotics, Antineoplastic; Cell Nucleus; Cell Proliferation; Chromatin Assembly and Disassembly; Chromobox Protein Homolog 5; Chromosomal Proteins, Non-Histone; HeLa Cells; Heterochromatin; Histones; Humans; Phosphorylation; STAT3 Transcription Factor; Streptonigrin
PubMed: 32103104
DOI: 10.1038/s41598-020-60469-6 -
Biochemistry Mar 2018Streptonigrin (CAS no. 3930-19-6) is a natural product shown to have antitumor activities in clinical trials conducted in the 1960s-1970s. However, its use in clinical...
Streptonigrin (CAS no. 3930-19-6) is a natural product shown to have antitumor activities in clinical trials conducted in the 1960s-1970s. However, its use in clinical studies eventually faded, and the molecular mechanisms of streptonigrin antitumor effects remain poorly defined. Despite its lack of current clinical use, efforts on its total synthesis have continued. Here, we show that streptonigrin binds and inhibits the SUMO-specific protease SENP1. NMR studies identified that streptonigrin binds to SENP1 on the surface where SUMO binds and disrupts SENP1-SUMO1 interaction. Site-directed mutations in combination with NMR chemical shift perturbation suggest key roles of aromatic π stacking interactions in binding streptonigrin. Treatment of cells with streptonigrin resulted in increased global SUMOylation levels and reduced level of hypoxia inducible factor alpha (HIF1α). These findings inform both the design of SENP1 targeting strategy and the modification of streptonigrin to improve its efficacy for possible future clinical use.
Topics: Cell Line, Tumor; Cysteine Endopeptidases; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Magnetic Resonance Spectroscopy; SUMO-1 Protein; Streptonigrin; Sumoylation
PubMed: 29481054
DOI: 10.1021/acs.biochem.7b00947 -
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 -
Accounts of Chemical Research Mar 2019Proteins are well-known to undergo a variety of post-translational modifications (PTMs). One such PTM is citrullination, an arginine modification that is catalyzed by a...
Proteins are well-known to undergo a variety of post-translational modifications (PTMs). One such PTM is citrullination, an arginine modification that is catalyzed by a group of hydrolases called protein arginine deiminases (PADs). Hundreds of proteins are known to be citrullinated and hypercitrullination is associated with autoimmune diseases including rheumatoid arthritis (RA), lupus, ulcerative colitis (UC), Alzheimer's disease, multiple sclerosis (MS), and certain cancers. In this Account, we summarize our efforts to understand the structure and mechanism of the PADs and to develop small molecule chemical probes of protein citrullination. PAD activity is highly regulated by calcium. Structural studies with PAD2 revealed that calcium-binding occurs in a stepwise fashion and induces a series of dramatic conformational changes to form a catalytically competent active site. These studies also identified the presence of a calcium-switch that controls the overall calcium-dependence and a gatekeeper residue that shields the active site in the absence of calcium. Using biochemical and site-directed mutagenesis studies, we identified the key residues (two aspartates, a cysteine, and a histidine) responsible for catalysis and proposed a general mechanism of citrullination. Although all PADs follow this mechanism, substrate binding to the thiolate or thiol form of the enzyme varies for different isozymes. Substrate-specificity studies revealed that PADs 1-4 prefer peptidyl-arginine over free arginine and certain citrullination sites on a peptide substrate. Using high-throughput screening and activity-based protein profiling (ABPP), we identified several reversible (streptomycin, minocycline, and chlorotetracycline) and irreversible (streptonigrin, NSC 95397) PAD-inhibitors. Screening of a DNA-encoded library and lead-optimization led to the development of GSK199 and GSK484 as highly potent PAD4-selective inhibitors. Furthermore, use of an electrophilic, cysteine-targeted haloacetamidine warhead to mimic the guanidinium group in arginine afforded several mechanism-based pan-PAD-inhibitors including Cl-amidine and BB-Cl-amidine. These compounds are highly efficacious in various animal models, including those mimicking RA, UC, and lupus. Structure-activity relationships identified numerous covalent PAD-inhibitors with different bioavailability, in vivo stability, and isozyme-selectivity (PAD1-selective: D-Cl-amidine; PAD2-selective: compounds 16-20; PAD3-selective: Cl4-amidine; and PAD4-selective: TDFA). Finally, this Account describes the development of PAD-targeted and citrulline-specific chemical probes. While PAD-targeted probes were utilized for identifying off-targets and developing high-throughput inhibitor screening platforms, citrulline-specific probes enabled the proteomic identification of novel diagnostic biomarkers of hypercitrullination-related autoimmune diseases.
Topics: Animals; Aspartic Acid; Catalysis; Catalytic Domain; Citrullination; Cysteine; Enzyme Inhibitors; HEK293 Cells; Histidine; Humans; Mice; Models, Chemical; Mutation; Protein Processing, Post-Translational; Protein-Arginine Deiminases; Proteins
PubMed: 30844238
DOI: 10.1021/acs.accounts.9b00024 -
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 -
PLoS Pathogens Jun 2022The Neisseria gonorrhoeae Type IV pilus is a multifunctional, dynamic fiber involved in host cell attachment, DNA transformation, and twitching motility. We previously...
The Neisseria gonorrhoeae Type IV pilus is a multifunctional, dynamic fiber involved in host cell attachment, DNA transformation, and twitching motility. We previously reported that the N. gonorrhoeae pilus is also required for resistance against hydrogen peroxide-, antimicrobial peptide LL-37-, and non-oxidative, neutrophil-mediated killing. We tested whether the hydrogen peroxide, LL-37, and neutrophil hypersensitivity phenotypes in non-piliated N. gonorrhoeae could be due to elevated iron levels. Iron chelation in the growth medium rescued a nonpiliated pilE mutant from both hydrogen peroxide- and antimicrobial peptide LL-37-mediated killing, suggesting these phenotypes are related to iron availability. We used the antibiotic streptonigrin, which depends on free cytoplasmic iron and oxidation to kill bacteria, to determine whether piliation affected intracellular iron levels. Several non-piliated, loss-of-function mutants were more sensitive to streptonigrin killing than the piliated parental strain. Consistent with the idea that higher available iron levels in the under- and non-piliated strains were responsible for the higher streptonigrin sensitivity, iron limitation by desferal chelation restored resistance to streptonigrin in these strains and the addition of iron restored the sensitivity to streptonigrin killing. The antioxidants tiron and dimethylthiourea rescued the pilE mutant from streptonigrin-mediated killing, suggesting that the elevated labile iron pool in non-piliated bacteria leads to streptonigrin-dependent reactive oxygen species production. These antioxidants did not affect LL-37-mediated killing. We confirmed that the pilE mutant is not more sensitive to other antibiotics showing that the streptonigrin phenotypes are not due to general bacterial envelope disruption. The total iron content of the cell was unaltered by piliation when measured using ICP-MS suggesting that only the labile iron pool is affected by piliation. These results support the hypothesis that piliation state affects N. gonorrhoeae iron homeostasis and influences sensitivity to various host-derived antimicrobial agents.
Topics: Bacterial Proteins; Fimbriae, Bacterial; Hydrogen Peroxide; Iron; Neisseria gonorrhoeae; Streptonigrin
PubMed: 35714158
DOI: 10.1371/journal.ppat.1010561 -
Marine Drugs Mar 2019Two new piperazine-triones lansai E and F (, ), together with four known secondary metabolites lansai D (), 1--methyl-()-albonoursin (), imidazo[4,5-]-1,2,4-triazine (),...
Two new piperazine-triones lansai E and F (, ), together with four known secondary metabolites lansai D (), 1--methyl-()-albonoursin (), imidazo[4,5-]-1,2,4-triazine (), and streptonigrin () were isolated from a deep-sea-derived sp. strain SMS636. The structures of the isolated compounds were confirmed by comprehensive spectroscopic analysis, including HRESIMS, 1D and 2D NMR. Compound exhibited moderate antibacterial activities against and methicillin resistant (MRSA) with Minimum Inhibitory Concentration (MIC) values of 12.5 and 25 μg/mL, respectively. Compound displayed significant antibacterial activities against , MRSA and Bacillus Calmette-Guérin (BCG) with MIC values of 0.78, 0.78 and 1.25 μg/mL, respectively.
Topics: Anti-Bacterial Agents; Candida albicans; Escherichia coli; Methicillin-Resistant Staphylococcus aureus; Microbial Sensitivity Tests; Piperazine; Pseudomonas aeruginosa; Staphylococcus aureus; Streptomycetaceae
PubMed: 30901830
DOI: 10.3390/md17030186