Biological properties of streptonigrin derivatives. I. Antimicrobial and cytocidal activities.

Inouye, Yoshio; Okada, Hiromasa; Roy, Swapan Kumar; Miyasaka, T.; Hibino, Satoshi; Tanaka, Nobuo; Nakamura, Shoshiro

doi:10.7164/antibiotics.38.1429

Cited by 17 publications

(4 citation statements)

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“…We have previously observed a pronounced increase in the expression of the P. aeruginosa class II RNR gene and impaired dNTP synthesis caused by hydroxyurea treatment (33). The increased RNR gene expression in conjunction with depletion of dNTP levels indicates that RNR is targeted by toluidine blue and streptonigrin, thus suggesting a novel activity for these compounds that may be as relevant as their previously reported effects (26)(27)(28)(29)(30)(31)(32). Our results suggest that inhibition of growth is attributable to impaired DNA synthesis as a result of low dNTP pools.…”

Section: Discussionmentioning

confidence: 79%

“…Among the 10 compounds in this group, the streptonigrin exhibited antibacterial activity against P. aeruginosa that was in line with common antibiotics. Streptonigrin is produced by Streptomyces flocculus, and it has activity against several microbial pathogens (28,29). Its cytotoxic effects are enhanced by metal ions, and its mechanism of action is proposed to involve redox cycling, formation of radicals, genotoxic effects, or interference with cell respiration (30,31).…”

Section: Discussionmentioning

confidence: 99%

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Discovery of antimicrobial ribonucleotide reductase inhibitors by screening in microwell format

Tholander

Sjöberg²

2012

Proc. Natl. Acad. Sci. U.S.A.

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Ribonucleotide reductase (RNR) catalyzes reduction of the four different ribonucleotides to their corresponding deoxyribonucleotides and is the rate-limiting enzyme in DNA synthesis. RNR is a wellestablished target for the antiproliferative drugs Gemzar and Hydrea, for antisense therapy, and in combination chemotherapies. Surprisingly, few novel drugs that target RNR have emerged, partly because RNR activity assays are laboratory-intense and exclude high-throughput methodologies. Here, we present a previously undescribed PCRbased assay for RNR activity measurements in microplate format. We validated the approach by screening a diverse library of 1,364 compounds for inhibitors of class I RNR from the opportunistic pathogen Pseudomonas aeruginosa, and we identified 27 inhibitors with IC 50 values from ∼200 nM to 30 μM. Interestingly, a majority of the identified inhibitors have been found inactive in human cell lines as well as in anticancer and in vivo tumor tests as reported by the PubChem BioAssay database. Four of the RNR inhibitors inhibited growth of P. aeruginosa, and two were also found to affect the transcription of RNR genes and to decrease the cellular deoxyribonucleotide pools. This unique PCR-based assay works with any RNR enzyme and any substrate nucleotide, and thus opens the door to high-throughput screening for RNR inhibitors in drug discovery.National Cancer Institute diversity set II | nucleotide metabolism | ribonucleotide reductase assay | high-throughput assay R ibonucleotide reductase (RNR) is an essential enzyme for de novo synthesis of DNA building blocks via reduction of the 2′-hydroxyl of ribonucleotides (1, 2). With its key role in the DNA synthesis pathway, RNR is an absolute requirement for cellular proliferation and a prerequisite for life. RNR is found in all freeliving organisms as well as in some dsDNA viruses. The only known exceptions to this ubiquitous presence are a few parasites and obligate intracellular endosymbionts (3) that rely on the host cell for production of DNA precursors. Thus, RNR is a potential antimicrobial drug target in a wide variety of organisms. RNR enzymes exist in three different classes, each with different cofactor requirements. Eukaryotes generally possess only one class, whereas bacteria possess any combination of RNR classes (3). Different oligomeric states of RNRs are known, and a common active form of the major variants of RNR is a dimer of dimers (α 2 β 2 ) (4). RNR exhibits a radical-based catalytical mechanism that involves redox cycling of cysteine residues, specific metal ion dependencies, essential subunit interactions, and sophisticated allosteric regulation (1). Thus, in addition to conventional competitive inhibition, pharmaceuticals may interfere with subunit interactions, binding to allosteric effector sites, metal chelation, radical formation and transfer, or inhibition of cysteine disulfide exchange. These sites of potential intervention offer a plethora of possibilities for the design of pathogen-specific antibiotics. Because sequence...

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Section: Discussionmentioning

confidence: 79%

Section: Discussionmentioning

confidence: 99%

Discovery of antimicrobial ribonucleotide reductase inhibitors by screening in microwell format

Tholander

Sjöberg²

2012

Proc. Natl. Acad. Sci. U.S.A.

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Section: Challenges and Future Prospects For Streptonigrin In New Dru...mentioning

confidence: 99%

“…Streptonigrin amide and streptonigrin hydrazide showed cytocidal activity against marine lymphosarcoma L5178Y cells to various extents, although the antibacterial activity against Gram-positive and Gram-negative bacteria was almost lost. 62 With the advent of multiple nanoparticulate drug delivery systems and various drug targeting strategies, it is anticipated that streptonigrin could be delivered to targeted sites in the body with minimal toxicity. Moreover, with the use of streptonigrin derivatives, the clinical efficacy of the drug could still be maintained with reduced toxicity.…”

Section: Development and Therapymentioning

confidence: 99%

Chemistry, Biosynthesis and Pharmacology of Streptonigrin: An Old Molecule with Future Prospects for New Drug Design, Development and Therapy

Nasir¹,

Sekar²,

Ravi³

et al. 2023

DDDT

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Streptonigrin is an aminoquinone alkaloid isolated from Streptomyces flocculus 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.

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Streptonigrin and lavendamycin partial structures. Preparation of 7‐amino‐2‐(2′‐pyridyl)quinoline‐5,8‐quinone‐6′‐carboxylic acid: A probe for the minimum, potent pharmacophore of the naturally occurring antitumor‐antibiotics

Yasuda

Boger

1987

Journal of Heterocyclic Chem

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The preparation of 7‐amino‐2‐(2′‐pyridyl)quinoline‐5,8‐quinone‐6′‐carboxylic acid (4) constituting a potential minimum, potent pharmacophore of streptonigrin (1) and lavendamycin (2), two structurally‐related naturally‐occurring antitumor‐antibiotic, is detailed. In contrast to observations associated with streptonigrin and lavendamycin in which the C‐6′ acid potentiates the antitumor, antimicrobial, and cytotoxic activity of the naturally‐occurring, substituted 7‐aminoquinoline‐5,8‐quinone AB ring systems, the C‐6′ carboxylic acid of 4 diminishes the observed antimicrobial and cytotoxic properties of 7‐amino‐2‐(2′‐pyridyl)quinoline‐5,8‐quinone.

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Biological properties of streptonigrin derivatives. I. Antimicrobial and cytocidal activities.

Cited by 17 publications

References 1 publication

Discovery of antimicrobial ribonucleotide reductase inhibitors by screening in microwell format

Discovery of antimicrobial ribonucleotide reductase inhibitors by screening in microwell format

Chemistry, Biosynthesis and Pharmacology of Streptonigrin: An Old Molecule with Future Prospects for New Drug Design, Development and Therapy

Streptonigrin and lavendamycin partial structures. Preparation of 7‐amino‐2‐(2′‐pyridyl)quinoline‐5,8‐quinone‐6′‐carboxylic acid: A probe for the minimum, potent pharmacophore of the naturally occurring antitumor‐antibiotics

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