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Cancer is a disease receiving an outstanding input of funds for basic and clinical research but is, nevertheless, still the second leading cause of death in the developed world and a great burden for health systems. New drugs are therefore needed to improve therapy, prolong survival of cancer patients and improve their quality of life. The high cost of development and clinical evaluation of new drugs limits the number that actually enter clinical use. To overcome this problem, repurposing of established drugs for new indications has gained a lot of interest, especially in the field of oncology. The well-established antimicrobial agent nitroxoline has been identified as a promising candidate to be repurposed for cancer treatment in several independent studies. Here we have reviewed a wide range of molecular mechanisms and tumor models involving nitroxoline in impairment of tumor progression. Furthermore, nitroxoline was used as a lead compound for structure-based chemical synthesis of new derivatives in order to improve its potency as well as selectivity for various targets. The potent antitumor activity of nitroxoline points strongly in the direction of its repurposing for cancer treatment and to the benefits of this strategy for patients and healthcare system.

BackgroundMycoplasmas primarily cause respiratory or urogenital tract infections impacting avian, bovine, canine, caprine, murine, and reptilian hosts. In animal husbandry, mycoplasmas cause reduced feed-conversion, decreased egg production, arthritis, hypogalactia or agalactia, increased condemnations, culling, and mortality in some cases. Antibiotics reduce transmission and mitigate clinical signs; however, concerning levels of antibiotic resistance inMycoplasma gallisepticumandM. capricolumisolates exist. To address these issues, we evaluated the minimum inhibitory concentrations (MICs) of halogenated phenazine and quinoline compounds, anN-arylated NH125 analogue, and triclosan against six representative veterinary mycoplasmas via microbroth or agar dilution methods. Thereafter, we evaluated the minimum bactericidal concentration (MBC) of efficacious drugs.ResultsWe identified several compounds with MICs ≤25 μM againstM. pulmonis(n = 5),M. capricolum(n = 4),M. gallisepticum(n = 3),M. alligatoris(n = 3),M. agassizii(n = 2), andM. canis(n = 1). AnN-arylated NH125 analogue, compound 21, served as the most efficacious, having a MIC ≤25 μM against all mycoplasmas tested, followed by two quinolines, nitroxoline (compound 12) and compound 20, which were effective against four and three mycoplasma type strains, respectively. Nitroxoline exhibited bactericidal activity among all susceptible mycoplasmas, and compound 21 exhibited bactericidal activity when the MBC was able to be determined.ConclusionsThese findings highlight a number of promising agents from novel drug classes with potential applications to treat veterinary mycoplasma infections and present the opportunity to evaluate preliminary pharmacokinetic indices usingM. pulmonisin rodents as an animal model of human infection.

Antimicrobial resistance has become a prime global concern. An ability of the microbes to produce enzymes to destroy antimicrobial drugs is one of the well-known mechanisms underlying the resistance. 8-Hydroxyquinoline (8HQ) and derivatives were reported to exert diverse biological effects such as antimicrobial, antioxidant and an- tineurodegenerative activities. Herein, 8HQ (1), nitroxoline (NQ, 2) and 7-Br-8HQ (3) were investigated for antimicrobial activity against Enterobacteriaceae including extended spectrum β-lactamase (ESBL)-producing and carbapenemase-producing strains as well as the effect of metal ions .These compounds (1-3) displayed the great antimicrobial activity against fifty-eight bacterial isolates of Escherichia coli, Providencia rettgeri and Klebsiella pneumoniae, in which NQ (2) exerted the highest antimicrobial activity with a MIC50 of 42.04 ❍M (8 µg/mL) and MBC50 of 168.28 ❍M (32 µg/mL). The MIC values of NQ (2) and 7-Br-8HQ (3) were significantly increased in the presence of Cu2+ and Fe3+. This finding reveals that NQ could be an effective compound to be further developed as an antimicrobial agent for combating Enterobacteriaceae infections.

Background: Accumulating evidence suggests that multi-target directed ligands have great potential for the treatment of complex diseases such as Alzheimer’s Disease (AD). Objective: To evaluate novel chimeric 8-hydroxyquinoline ligands with merged pharmacophores as potential multifunctional ligands for AD. Methods: Nitroxoline, PBT2 and compounds 2-4 were evaluated in-vitro for their inhibitory potencies on cathepsin B, cholinesterases, and monoamine oxidases. Furthermore, chelation, antioxidative properties and the permeability of Blood-Brain Barrier (BBB) were evaluated by spectroscopy-based assays and the inhibition of Amyloid β (Aβ) aggregation was determined in immunoassay. Cell-based assays were performed to determine cytotoxicity, neuroprotection against toxic Aβ species, and the effects of compound 2 on apoptotic cascade. Results: Compounds 2-4 competitively inhibited cathepsin B β-secretase activity, chelated metal ions and were weak antioxidants. All of the compounds inhibited Aβ aggregation, whereas only compound 2 had a good BBB permeability according to the parallel artificial membrane permeability assay. Tested ligands 2 and 3 were not cytotoxic to SH-SY5Y and HepG2 cells at 10 μM. Compound 2 exerted neuroprotective effects towards Aβ toxicity, reduced the activation of caspase-3/7 and diminished the apoptosis of cells treated with Aβ1-42. Conclusion: Taken together, our data suggest that compound 2 holds a promise to be used as a multifunctional ligand for AD.

Antimicrobial resistance has become a prime global concern. An ability of the microbes to produce enzymes to destroy antimicrobial drugs is one of the well-known mechanisms underlying the resistance. 8-Hydroxyquinoline (8HQ) and derivatives were reported to exert diverse biological effects such as antimicrobial, antioxidant and antineurodegenerative activities. Herein, 8HQ (1), nitroxoline (NQ, 2) and 7-Br-8HQ (3) were investigated for antimicrobial activity against Enterobacteriaceae including extended spectrum β-lactamase (ESBL)-producing and carbapenemase-producing strains as well as the effect of metal ions. These compounds (1-3) displayed the great antimicrobial activity against fifty-eight bacterial isolates of Escherichia coli, Providencia rettgeri and Klebsiella pneumoniae, in which NQ (2) exerted the highest antimicrobial activity with a MIC50 of 42.04 µM (8 µg/mL) and MBC50 of 168.28 µM (32 µg/mL). The MIC values of NQ (2) and 7-Br-8HQ (3) were significantly increased in the presence of Cu2+ and Fe3+. This finding reveals that NQ could be an effective compound to be further developed as an antimicrobial agent for combating Enterobacteriaceae infections., EXCLI Journal; 18:Doc445; ISSN 1611-2156

BackgroundInfections caused by carbapenemase-producing Enterobacterales (CPE) constitute a major global health concern and are associated with increased morbidity and mortality. Nitroxoline is an old antibiotic, which has recently been re-launched for the treatment of uncomplicated urinary tract infection. Because of low resistance rates it could be an interesting option for treatment of MDR isolates, yet data on CPE susceptibility are scarce.ObjectivesTo analyse the in vitro activity of nitroxoline against CPE.MethodsMICs of nitroxoline were determined by agar dilution for a collection of well-characterized carbapenemase producers (n = 105), producing OXA-48-like (n = 36), VIM (n = 21), IMI (n = 9), IMP (n = 6), NDM (n = 22), KPC (n = 11), OXA-58 (n = 2) and GES (n = 2). For comparison, MICs of ertapenem, imipenem and meropenem were determined by agar gradient diffusion.ResultsFor all 105 isolates, the MIC50/90 of nitroxoline was 8/16 mg/L. All Escherichia coli isolates (30/30, 100%) showed low MICs of 2–8 mg/L and were susceptible to nitroxoline. MICs of 32 mg/L were recorded for five isolates of VIM- and IMI-producing Enterobacter cloacae (n = 3) and OXA- and VIM-producing Klebsiella pneumoniae (n = 2).ConclusionsNitroxoline exhibited excellent in vitro activity against most isolates producing common and rare carbapenemases. If the current EUCAST susceptibility breakpoint of ≤16 mg/L for E. coli in uncomplicated urinary tract infections was applied, 95.2% (100/105) of isolates would be classified as susceptible. Nitroxoline could therefore be an alternative oral option for treatment of uncomplicated urinary tract infections caused by CPE.

Amide proton transfer (APT) imaging is a novel molecular MRI technique to detect endogenous mobile proteins and peptides through chemical exchange saturation transfer. In this preliminary study, the purpose was to evaluate the feasibility of APT imaging in monitoring the early therapeutic response to nitroxoline (NTX) in a temozolomide (TMZ)-resistant glioblastoma multiforme (GBM) mouse model, which was compared with diffusion-weighted imaging (DWI). Here, we prepared TMZ-resistant GBM mouse model (n = 12), which were treated with 100 mg/kg/day of NTX (n = 4) or TMZ (n = 4), or saline (n = 4) for 7 days for the evaluation of short-term treatment by using APT imaging and DWI sequentially. The APT signal intensities and apparent diffusion coefficient (ADC) values were calculated and compared before and after treatment. Moreover, immunohistological analysis was also employed for the correlation between APT imaging and histopathology. The association between the APT value and Ki-67 labeling index was evaluated by using simple linear regression analysis. The short-term NTX treatment resulted in significant decrease in APT value as compared to untreated and TMZ group, in which APT signals were increased. However, we did not observe significantly increased mean ADC value following short-term NTX treatment. The Ki-67 labeling index shows a correlation with APT value. APT imaging could show the earlier response to NTX treatment as compared to ADC values in a TMZ-resistant mouse model. We believe that APT imaging can be a useful imaging biomarker for the early therapeutic evaluation in GBM patients.

Escalating levels of antibiotic resistance in mycoplasmas, particularly macrolide resistance in Mycoplasma pneumoniae and M. genitalium, have narrowed our antibiotic arsenal. Further, mycoplasmas lack a cell wall and do not synthesize folic acid, rendering common antibiotics, such as beta-lactams, vancomycin, sulfonamides, and trimethoprim, of no value. To address this shortage, we screened nitroxoline, triclosan, and a library of 20 novel, halogenated phenazine, quinoline, and NH125 analogues against Ureaplasma species and M. hominis clinical isolates from urine. We tested a subset of these compounds (n = 9) against four mycoplasma type strains (M. pneumoniae, M. genitalium, M. hominis, and Ureaplasma urealyticum) using a validated broth microdilution or agar dilution method. Among 72 Ureaplasma species clinical isolates, nitroxoline proved most effective (MIC90, 6.25 µM), followed by an N-arylated NH125 analogue (MIC90, 12.5 µM). NH125 and its analogue had significantly higher MICs against U. urealyticum isolates than against U. parvum isolates, whereas nitroxoline did not. Nitroxoline exhibited bactericidal activity against U. parvum isolates but bacteriostatic activity against the majority of U. urealyticum isolates. Among the type strains, the compounds had the greatest activity against M. pneumoniae and M. genitalium, with 8 (80%) and 5 (71.4%) isolates demonstrating MICs of ≤12.5 µM, respectively. Triclosan also exhibited lower MICs against M. pneumoniae and M. genitalium Overall, we identified a promising range of quinoline, halogenated phenazine, and NH125 compounds that showed effectiveness against M. pneumoniae and M. genitalium and found that nitroxoline, approved for use outside the United States for the treatment of urinary tract infections, and an N-arylated NH125 analogue demonstrated low MICs against Ureaplasma species isolates.

Eight new 7-substituted quinolin-8-ol derivatives were synthesized in moderate to good yields through quinolin-8-ol, and secondary amines as the starting reagents. The struc- tures of the prepared compounds have been characterized by elemental analysis and 1 H/ 13 C NMR. The antimicrobial activity of this new series of heterocyclic compounds has been achieved "in vitro" against some bacterial strains by means of the disk method, and most of the tested compounds have shown comparable or greater antibacterial ac- tivity than nitroxoline (standard antibiotic). It was very motivating to observe that POM (Petra/Osiris/Molinspiration) bioinformatic analyses of compound 5 exhibited better an- tibacterial activity (MIC = 10 μg/mL against B. subtilis bacteria), and higher drug score (DS = 0.57) compared with Nitroxoline (DS = 0.47 ; MIC = 20 μg/mL). Molecular docking investigations were also conducted to investigate the binding affinities as well as interac- tions of some compounds with the target proteins.

The emergence of antibacterial resistance and the development of new drugs lead to a continuous change of guidelines for medical treatments. Hence, new analytical tools are required for the detection of drugs in biological fluids. In this study, the first surface enhanced Raman scattering (SERS) detection of nitroxoline (NTX) in purified water and in spiked human urine samples is reported. Insights concerning the nature of the molecule-metal interaction and its influence on the overall SERS signal are provided. Furthermore, three randomly collected urine samples originating from a healthy volunteer were spiked to assess the limit of detection (LOD), the limit of quantification (LOQ), and the linear dynamic range of the lab-on-a-chip SERS (LoC-SERS) method for NTX detection in human urine. The LOD is ∼3 μM (0.57 mg/L), LOQ ∼ 6.5 μM (1.23 mg/L) while the linear range is between 4.28 and 42.8 μM (0.81-8.13 mg/L). This covers the minimum inhibitory concentration (MIC) values of the most commonly encountered uropathogens. Finally, seven clinical samples having an "unknown" NTX concentration were simulated. The LoC-SERS technique combined with the standard addition method and statistical data analysis provided a good prediction of the unknown concentrations. Additionally, it is also demonstrated that the predictions carried out by multicurve resolution alternating least-squares (MCR-ALS) algorithm provides reliable results, and it is preferred to a univariate statistical approach.

Hintergrund Die Resistenz von uropathogenen Bakterien gegenuber den ublichen Antibiotika ist erheblich – v. a. im Alter.

BACKGROUND Yeasts are found in urine specimens relatively often, especially in the elderly and patients under treatment with broad spectrum antibiotics, i. e. especially in intensive care unit (ICU) patients. In some cases, the number of pathogens is very high, i. e. >105/ml. The clinical relevance of detecting Candida in urine is difficult to assess. In the German S3 guidelines it is apodictically stated that an ascending infection of the urinary tract by yeasts does not occur but this may undoubtedly happen in certain instances in patients at risk, for example in the elderly, in diabetic persons and in the case of foreign bodies in the urinary tract. A hematogenous spread of yeasts can lead to pyelonephritis, which accompanies candiduria. In rare cases this can be induced by prostatitis and epididymitis. Therapy is indicated in all cases when a urological manipulation is planned, particularly those with injury to the mucosal barrier, in order to prevent an intraoperative spread of pathogens. AIM The antimicrobial agents suitable for therapy of candiduria are limited, namely flucytosine, amphotericin B, which is also used for irrigation and fluconazole. MATERIAL AND METHODS The in vitro effect of nitroxoline on 100 isolates of yeasts from urine was tested by an agar diffusion test. RESULTS Nitroxoline exerted a good activity against all yeast isolates. DISCUSSION The antibiotic nitroxoline has a good antifungal activity. It achieves high concentrations in urine and in addition, it is effective at low pH as well as against pathogens in biofilms, which most antimycotics cannot achieve. Hence, nitroxoline is suitable for termination of candiduria. Foreign bodies in the urinary tract, on which biofilms are formed, should be removed whenever possible.

8-Hydroxyquinoline (8HQ) compounds have been reported to possess diverse bioactivities. In recent years, drug repositioning has gained considerable attention in drug discovery and development. Herein, 8HQ (1) and its derivatives (2–9) bearing various substituents (amino, nitro, cyano and halogen) were investigated for their antimicrobial against 27 microorganisms (agar dilution method) and antioxidant (DPPH method) activities. The parent 8HQ (1) exerted a highly potent antimicrobial activity against Gram-positive bacteria including diploid fungi and yeast with MIC values in the range of 3.44–13.78 μM. Moreover, the halogenated 8HQ, especially 7-bromo-8HQ (4) and clioquinol (6), displayed a high antigrowth activity against Gram-negative bacteria compared with the parent compound (1). Apparently, the derivatives with a relatively high safely index, e.g., nitroxoline (2), exhibited strong antibacterial activity against Aeromonas hydrophila (MIC=5.26 μM) and selectively inhibited the growth of P. aeruginosa with the MIC value of 84.14 μM; cloxyquin (3) showed a strong activity against Listseria monocytogenes and Plesiomonas shigelloides with MIC values of 5.57 and 11.14 μM, respectively. Most compounds displayed an antioxidant activity. Specifically, 5-amino-8HQ (8) was shown to be the most potent antioxidant (IC50=8.70 μM) compared with the positive control (α-tocopherol) with IC50 of 13.47 μM. The findings reveal that 8HQ derivatives are potential candidates to be further developed as antimicrobial and antioxidant agents., Highlights • 8-Hydroxyquinoline exerted highly potent antibacterial activity (Gram positive). • Nitroxoline exhibited strong antibacterial activity against Pseudomonas aeruginosa. • Cloxyquin displayed a high growth inhibition against Listeria monocytogenes and Plesiomonas shigelloides. • 5-Amino-8-hydroxyquinoline exerted the most potent antioxidant activity (IC50=8.70 μM). • Nitroxoline and cloxyquin had a relatively high selectivity index.

The established urinary antibiotic nitroxoline has recently regained considerable attention, due to its potent activities in inhibiting angiogenesis, inducing apoptosis and blocking cancer cell invasion. These features make nitroxoline an excellent candidate for anticancer drug repurposing. To rapidly advance nitroxoline repurposing into clinical trials, the present study performed systemic preclinical pharmacodynamic evaluation of its anticancer activity, including a methyl thiazolyl tetrazolium assay in vitro and an orthotopic urological tumor assay in vivo. The current study determined that nitroxoline exhibits dose-dependent anti-cancer activity in vitro and in urological tumor orthotopic mouse models. In addition, it was demonstrated that the routine nitroxoline administration regimen used for urinary tract infections was effective and sufficient for urological cancer treatment, and 2 to 4-fold higher doses resulted in obvious enhancement of anticancer efficacy without corresponding increases in toxicity. Furthermore, nitroxoline sulfate, one of the most common metabolites of nitroxoline in the urine, effectively inhibited cancer cell proliferation. This finding increases the feasibility of nitroxoline repurposing for urological cancer treatment. Due to the excellent anticancer activity demonstrated in the present study, and its well-known safety profile and pharmacokinetic properties, nitroxoline has been approved to enter into a phase II clinical trial in China for non-muscle invasive bladder cancer treatment (registration no. CTR20131716).

A series of 8-heteroaryl substituted quinolines were prepared, either by direct C-H arylation of five-membered heteroarenes, or Pd-catalyzed coupling of organoboron reagents with bromoquinolines. The use of (benzo)thiophenyl or (benzo)furanyl boron coupling partners allowed further C-H functionalization on the five-membered heteroaryl ring with aryl bromides in one flask to access a variety of polyconjugated molecular architectures. The developed methodology represents a simple approach towards 8-arylated analogues of the biologically interesting nitroxoline core.

Background: Multiple myeloma (MM) is the second most common hematological neoplasm. Wide administration of bortezomib significantly improves the survival of MM patients compared with conventional chemotherapy. Bromodomain-containing protein 4 (BRD4) inhibitors also have been demonstrated to retard cell proliferation and induce cellular apoptosis in various cancers. However, it is unclear whether the BRD4 inhibitor nitroxoline plus bortezomib has a synergistic anti-tumor effect on MM. Methods: Cell viability was determined via 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Cell cycle and cell apoptosis were assessed via flow cytometry. Protein expression levels were determined via western blotting. The expression of apoptosis-related proteins in xenograft tissue were detected by means of immunohistochemistry. Results: Treatment with nitroxoline or bortezomib suppressed cell proliferation, and caused G0/G1 phase arrest and apoptosis in H929 and RPMI8226 cells. Furthermore, nitroxoline intensified the retardation of cell proliferation, as well as further enhanced the G0/G1 phase arrest and apoptosis induced by bortezomib in H929 and RPMI8226 cells. The western blot analysis revealed that nitroxoline or bortezomib treatment markedly diminished the levels of Bcl-2 and cyclin D1, and increased the levels of p21, Bax, cleaved PARP and cleaved caspase-3. Combination of these two agents was observed to result in further marked changes on these levels compared with nitroxoline or bortezomib treatment alone. What is more, in the xenograft tumor model, combinative treatment markedly inhibited tumor growth compared with the single drug treatment. Conclusion: Combination of bortezomib with nitroxoline has a synergistic anti-tumor activity in MM cells and may be a novel treatment method for MM.

Programmed cell death protein 1 (PD-1) blockade is a promising therapeutic strategy against prostate cancer. Nitroxoline has been found to have effective anticancer properties in several cancer types. We investigated the efficacy of a combination therapy involving nitroxoline and PD-1 blockade in a prostate cancer mouse model. In our in vitro analysis, we found that nitroxoline inhibited the viability and proliferation of the mouse prostate cancer cell line RM9-Luc-PSA. Additionally, nitroxoline downregulated the expressions of phospho-PI3 kinase, phospho-Akt (Thr308), phospho-Akt (Ser473), phospho-GSK-3β, Bcl-2, and Bcl-xL. Nitroxoline also downregulated programmed death-ligand 1 (PD-L1) expression levels in prostate cancer cell line and tumor tissue. In our murine prostate cancer orthotopic model, nitroxoline plus PD-1 blockade synergistically suppressed tumor growth when compared with nitroxoline or PD-1 blockade alone, leading to reductions in tumor weight, bioluminescence tumor signals, and serum prostate-specific antigen levels. Furthermore, fluorescence-activated cell sorting analysis showed that the combination strategy significantly enhanced antitumor immunity by increasing CD44+CD62L+CD8+ memory T cell numbers and reducing myeloid-derived suppressor cell numbers in peripheral blood. In conclusion, our findings suggest that nitroxoline plus PD-1 blockade may be a promising treatment strategy in patients with prostate cancer.

Balamuthia mandrillaris is responsible for hundreds of reported cases of amoebic encephalitis, the majority of which have been fatal. Despite being an exceptionally deadly pathogen, B. mandrillaris is understudied, leaving many open questions regarding epidemiology, diagnosis, and treatment. Due to the lack of effective drugs to fight B. mandrillaris infections, mortality rates remain high even for patients receiving intensive care. This report addresses the need for new treatment options through a drug repurposing screen to identify novel B. mandrillaris inhibitors. The most promising candidate identified was the quinoline antibiotic nitroxoline, which has a long history of safe use in humans. We show that nitroxoline kills B. mandrillaris at pharmacologically relevant concentrations and exhibits greater potency and selectivity than drugs commonly used in the current standard of care. The findings that we present demonstrate the potential of nitroxoline to be an important new tool in the treatment of life-threatening B. mandrillaris infections., Balamuthia mandrillaris is a pathogenic free-living amoeba that causes a rare but almost always fatal infection of the central nervous system called granulomatous amoebic encephalitis (GAE). Two distinct forms of B. mandrillaris—a proliferative trophozoite form and a nonproliferative cyst form, which is highly resistant to harsh physical and chemical conditions—have been isolated from environmental samples worldwide and are both observed in infected tissue. Patients suffering from GAE are typically treated with aggressive and prolonged multidrug regimens that often include the antimicrobial agents miltefosine and pentamidine isethionate. However, survival rates remain low, and studies evaluating the susceptibility of B. mandrillaris to these compounds and other potential therapeutics are limited. To address the need for more-effective treatments, we screened 2,177 clinically approved compounds for in vitro activity against B. mandrillaris. The quinoline antibiotic nitroxoline (8-hydroxy-5-nitroquinoline), which has safely been used in humans to treat urinary tract infections, was identified as a lead compound. We show that nitroxoline inhibits both trophozoites and cysts at low micromolar concentrations, which are within a pharmacologically relevant range. We compared the in vitro efficacy of nitroxoline to that of drugs currently used in the standard of care for GAE and found that nitroxoline is the most potent and selective inhibitor of B. mandrillaris tested. Furthermore, we demonstrate that nitroxoline prevents B. mandrillaris-mediated destruction of host cells in cultured fibroblast and primary brain explant models also at pharmacologically relevant concentrations. Taken together, our findings indicate that nitroxoline is a promising candidate for repurposing as a novel treatment of B. mandrillaris infections.

Small molecular inhibitors targeting BRD4 family proteins are emerging as promising therapies in many types of human malignancies. However, whether BRD4, as well as other BET family members, may serve as therapeutic targets in renal cell carcinoma (RCC) remains unknown. In this study, we found that both BRD2 and BRD4 were over-expressed in RCC tissues, knock-down both of which achieved potent anti-proliferative effects in RCC cells. A novel category of BET inhibitors, originated from an approved drug Nitroxoline, were synthesized and evaluated with biochemical and cellular assays, as well as the method of crystallography. The complex crystal structures of several compounds in this category with the first bromodomain of BRD4 (BRD4-BD1) were solved, revealing the binding mechanism and facilitating further structural optimizations. Among them, compound BDF-1253 showed an approximately four-fold improvement in BRD4 inhibition compared with the prototype Nitroxoline and had good selectivity for BET proteins against other bromodomain proteins or epi-enzymes in biochemical assays. Compound BDF-1253 efficiently suppressed the expression of BET downstream genes, impaired RCC cells viability via inducing cell cycle arrest and apoptosis, and decreased tumor growth in RCC xenografts. In summary, these results suggest that inhibition of BET family members has great therapeutic potentials in the treatment of RCC, and the novel series of BET inhibitors reported here are promising to become RCC drug candidates.

Escalating levels of antibiotic resistance in mycoplasmas, particularly macrolide resistance in Mycoplasma pneumoniae and M. genitalium, have narrowed our antibiotic arsenal. Further, mycoplasmas lack a cell wall and do not synthesize folic acid, rendering common antibiotics, such as beta-lactams, vancomycin, sulfonamides, and trimethoprim, of no value., Escalating levels of antibiotic resistance in mycoplasmas, particularly macrolide resistance in Mycoplasma pneumoniae and M. genitalium, have narrowed our antibiotic arsenal. Further, mycoplasmas lack a cell wall and do not synthesize folic acid, rendering common antibiotics, such as beta-lactams, vancomycin, sulfonamides, and trimethoprim, of no value. To address this shortage, we screened nitroxoline, triclosan, and a library of 20 novel, halogenated phenazine, quinoline, and NH125 analogues against Ureaplasma species and M. hominis clinical isolates from urine. We tested a subset of these compounds (n = 9) against four mycoplasma type strains (M. pneumoniae, M. genitalium, M. hominis, and Ureaplasma urealyticum) using a validated broth microdilution or agar dilution method. Among 72 Ureaplasma species clinical isolates, nitroxoline proved most effective (MIC90, 6.25 µM), followed by an N-arylated NH125 analogue (MIC90, 12.5 µM). NH125 and its analogue had significantly higher MICs against U. urealyticum isolates than against U. parvum isolates, whereas nitroxoline did not. Nitroxoline exhibited bactericidal activity against U. parvum isolates but bacteriostatic activity against the majority of U. urealyticum isolates. Among the type strains, the compounds had the greatest activity against M. pneumoniae and M. genitalium, with 8 (80%) and 5 (71.4%) isolates demonstrating MICs of ≤12.5 µM, respectively. Triclosan also exhibited lower MICs against M. pneumoniae and M. genitalium. Overall, we identified a promising range of quinoline, halogenated phenazine, and NH125 compounds that showed effectiveness against M. pneumoniae and M. genitalium and found that nitroxoline, approved for use outside the United States for the treatment of urinary tract infections, and an N-arylated NH125 analogue demonstrated low MICs against Ureaplasma species isolates.

The number of multi-resistant uropathogens is increasing. A multi-morbid patient developed a symptomatic urinary tract infection with two multi-resistant bacteria, namely Klebsiella pneumoniae and Proteus mirabilis. Nitroxoline was the only drug active against both uropathogens. Obviously, nitroxoline can be an option for the therapy of a urinary tract infection with multi-resistant uropathogens.

Many metal–organic complexes showed potent anticancer efficacy, but their clinical applications were limited by the lack of administration route because of their poor solubility. To make metal–organic nanoparticles (MONPs) comprising metal complex drugs is a new formulation strategy for their administration. Herein, we developed a facile synthesis of an MONP composed of bovine serum albumin (BSA), Cu2+, and an anticancer agent, 5-nitro-8-hydroxyquinoline (NQ) with albumin as a nanoreactor. The resultant BSA/Cu/NQ nanoparticle (BSA/Cu/NQ NP) showed good stability in different physiological buffers and could target tumors through the enhanced permeability and retention effect and receptor-mediated cellular uptake. As the BSA/Cu/NQ NP could be readily and efficiently internalized by cancer cells, it showed much higher cytotoxic cancer cells than the NQ + Cu(II) complex and NQ. Therefore, the treatment with BSA/Cu/NQ NP noticeably enhanced the anticancer efficacy without causing systemic toxicity, indicating ...

Balamuthia mandrillarisis a pathogenic free-living amoeba that causes a rare but almost always fatal infection of the central nervous system called granulomatous amoebic encephalitis (GAE). Two distinct forms ofB. mandrillaris– a proliferative trophozoite form and a non-proliferative cyst form, which is highly resistant to harsh physical and chemical conditions – have been isolated from environmental samples worldwide and are both observed in infected tissue. Patients suffering from GAE are typically treated with aggressive and prolonged multi-drug regimens often including the antimicrobial agents miltefosine and pentamidine isethionate. However, survival rates remain low and studies evaluating the susceptibility ofB. mandrillaristo these compounds and other potential therapeutics are limited. To address the need for more effective treatments, we screened 2,177 clinically-approved compounds forin vitroactivity againstB. mandrillaris. The quinoline antibiotic nitroxoline, which has safely been used in humans to treat urinary tract infections, was identified as a lead compound. We show that nitroxoline inhibits both trophozoites and cysts at low micromolar concentrations, which are within a physiologically relevant range. We compare thein vitroefficacy of nitroxoline to drugs currently used in the standard of care for GAE and find that nitroxoline is the most potent and selective inhibitor ofB. mandrillaristested. Furthermore, we demonstrate that nitroxoline preventsB. mandrillaris-mediateddestruction of host cells in cultured fibroblast and primary brain explant models also at physiologically relevant concentrations. Together, our findings indicate that nitroxoline is a promising candidate for repurposing as a novel treatment ofB. mandrillarisinfections.ImportanceBalamuthia mandrillarisis responsible for hundreds of reported cases of amoebic encephalitis, the majority of which have been fatal. Despite being an exceptionally deadly pathogen,B. mandrillarisis understudied, leaving many open questions regarding epidemiology, diagnosis, and treatment. Due to the lack of effective drugs to fightB. mandrillarisinfections, mortality rates remain high even for patients receiving intensive care. This study addresses the need for new anti-amoebic drugs using a high-throughput screening approach to identify novelB. mandrillarisinhibitors. The most promising candidate identified was the quinoline antibiotic nitroxoline, which has a long history of safe use in humans. We show that nitroxoline killsB. mandrillarisat physiologically relevant concentrations and exhibits greater potency and selectivity than drugs commonly used in the current standard of care. The findings we present demonstrate the potential of nitroxoline to be an important new tool in the treatment of life threateningB. mandrillarisinfections.

Nitroxoline (NTX), 5-nitro-8-hydroxyquinoline is an oral antibiotic with mechanism of bacteriostatic activity that is based on chelation of divalent cations required for bacterial RNA polymerase. Susceptibility to NTX of 100 Escherichia coli urine isolates was determined at the Department of Clinical and Molecular Microbiology, University Hospital Centre Zagreb during September and October 2017. Antimicrobial susceptibility was tested by disc diffusion and the results were interpreted according to the European Committee for Antimicrobial Susceptibility Testing (EUCAST) standards. All E. coli isolates, including ESBL-positive ones, were fully susceptible to imipenem, meropenem, amikacin, fosfomycin and NTX. This is the first report from Croatia about sensitivity of E. coli isolates to NTX. Besides fosfomycin, NTX was the only antimicrobial drug available for peroral administration demonstrating the sensitivity for all tested isolates. The results of the study demonstrated the potential of NTX as an additional therapeutically applicable option for the treatment of uncomplicated UTI.

Background Pancreatic cancer (PC) is the fourth most common cause of cancer death. Combination therapies with classical chemotherapeutic agents improved treatment of advanced PC at the cost of a relevant toxicity, but the 5-year survival rate remains below 5%. Consequently, new therapeutic options for this disease are urgently needed. In this study, we explored the effect of two repurposed drug candidates nelfinavir and nitroxoline, approved for non-anticancer human use, in PC cell lines. Nelfinavir and nitroxoline were tested as single agents, or in combinations with or without erlotinib, a targeted drug approved for PC treatment. Methods The effects of the drugs on the viability of AsPC-1, Capan-2 and BxPC-3 PC cell lines were assessed by MTT. The impact of the treatments on cell cycle distribution and apoptosis was analyzed by flow cytometry. The effects of treatments on proteins relevant in cell cycle regulation and apoptosis were evaluated by western blot. Self-renewal capacity of PC cell lines after drug treatments was assessed using a clonogenic assay. Results When used as single agents, nelfinavir and nitroxoline decreased viability, affected cell cycle and reduced the expression of relevant cell cycle proteins. The effects on apoptosis were variable among PC cell lines. Moreover, these agents drastically impaired clonogenic activity of the three PC cell lines. Combinations of nelfinavir and nitroxoline, with or without erlotinib, resulted in dose- and cell-dependent synergistic effects on cell viability. These effects were paralleled by cell cycle alterations and more consistent apoptosis induction as compared to single agents. Treatments with drug combinations induced drastic impairment of clonogenic activity in the three cell lines. Conclusions This study shows that two non-antitumor drugs, nelfinavir and nitroxoline, as single agents or in combination have antitumor effects that appear comparable, or in some case more pronounced than those of erlotinib in three PC cell lines. Our results support repurposing of these approved drugs as single agents or in combination for PC treatment.

Waraporn Chan-on,1 Nguyen Thi Bich Huyen,2 Napat Songtawee,3 Wilasinee Suwanjang,1 Supaluk Prachayasittikul,3 Virapong Prachayasittikul2 1Center for Research and Innovation, 2Department of Clinical Microbiology and Applied Technology, 3Center of Data Mining and Biomedical Informatics, Faculty of Medical Technology, Mahidol University, Bangkok, Thailand Purpose: Fork head box M1 (FoxM1) is an oncogenic transcription factor frequently elevated in numerous cancers, including cholangiocarcinoma (CCA). A growing body of evidence documents its diverse functions contributing to tumorigenesis and cancer progression. As such, discovery of agents that can target FoxM1 would be valuable for the treatment of CCA. The quinoline-based compounds, namely clioquinol (CQ) and nitroxoline (NQ), represent a new class of anticancer drug. However, their efficacy and underlying mechanisms have not been elucidated in CCA. In this study, anticancer activities and inhibitory effects of CQ and NQ on FoxM1 signaling were explored using CCA cells.Methods: The effects of CQ and NQ on cell viability and proliferation were evaluated using the colorimetric 3-(4,5-dimethylthiazol-2yl)-5-(3-carboxymethoxyphenyl)-(4-sulfophenyl)-2H-tetrazolium (MTS assay). Colony formation and cell migration affected by CQ and NQ were investigated using a clonogenic and a wound healing assay, respectively. To demonstrate the agents’ effects on FoxM1 signaling, expression levels of the target genes were quantitatively determined using real-time polymerase chain reaction.Results: CQ and NQ significantly inhibited cell survival of HuCCT1 and Huh28 in a dose- and a time-dependent fashion. Further investigations using the rapidly proliferating HuCCT1 cells revealed significant suppression of cell proliferation and colony formation induced by low doses of the compounds. Treatment of CQ and NQ repressed expression of cyclin D1 but enhanced expression of p21. Most importantly, upon CQ and NQ treatment, expression of oncogenic FoxM1 was markedly decreased concomitant with downregulation of various FoxM1’s downstream targets including cdc25b, CENP-B, and survivin. In addition, the compounds distinctly impaired HuCCT1 migration as well as inhibited expression of matrix metalloproteinase (MMP)-2 and MMP-9.Conclusion: Collectively, this study reports for the first time the anticancer effects of CQ and NQ against CCA cells, and highlights new insights into the mechanism of actions of the quinoline-based compounds to disrupt FoxM1 signaling. Keywords: FoxM1, cholangiocarcinoma, 8-hydroxyquinoline derivatives, clioquinol, nitroxoline, migration

// Bojana Mirkovic 1,* , Bostjan Markelc 2,* , Miha Butinar 3,* , Ana Mitrovic 1 , Izidor Sosic 1 , Stanislav Gobec 1 , Olga Vasiljeva 3 , Boris Turk 3,4,5 , Maja Cemažar 2 , Gregor Sersa 2 and Janko Kos 1,6 1 Faculty of Pharmacy, University of Ljubljana, Ljubljana, Slovenia 2 Department of Experimental Oncology, Institute of Oncology Ljubljana, Ljubljana, Slovenia 3 Department of Biochemistry and Molecular and Structural Biology, Jožef Stefan Institute, Ljubljana, Slovenia 4 Centre of Excellence for Integrated Approaches in Chemistry and Biology of Proteins, Ljubljana, Slovenia 5 Faculty of Chemistry and Chemical Technology, University of Ljubljana, Ljubljana, Slovenia 6 Department of Biotechnology, Jožef Stefan Institute, Ljubljana, Slovenia * These authors have equally contributed to this work Correspondence to: Bojana Mirkovic, email: // Janko Kos, email: // Keywords : nitroxoline, cathepsin B, tumor invasion, angiogenesis, metastasis Received : November 01, 2014 Accepted : March 05, 2015 Published : March 30, 2015 Abstract Cathepsin B is a ubiquitously expressed lysosomal cysteine protease that participates in protein turnover within lysosomes. However, its protein and activity levels have been shown to be increased in cancer. Cathepsin B endopeptidase activity is involved in the degradation of extracellular matrix, a process that promotes tumor invasion, metastasis and angiogenesis. Previously, we reported an established antibiotic nitroxoline as a potent and selective inhibitor of cathepsin B. In the present study, we elucidated its anti-tumor properties in in vitro and in vivo tumor models. Tumor and endothelial cell lines with high levels of active cathepsin B were selected for functional analysis of nitroxoline in vitro . Nitroxoline significantly reduced extracellular DQ-collagen IV degradation by all evaluated cancer cell lines using spectrofluorimetry. Nitroxoline also markedly decreased tumor cell invasion monitored in real time and reduced the invasive growth of multicellular tumor spheroids, used as a 3D in vitro model of tumor invasion. Additionally, endothelial tube formation was significantly reduced by nitroxoline in an in vitro angiogenesis assay. Finally, nitroxoline significantly abrogated tumor growth, angiogenesis and metastasis in vivo in LPB fibrosarcoma and MMTV-PyMT breast cancer mouse models. Overall, our results designate nitroxoline as a promising drug candidate for anti-cancer treatment.

Human cathepsin B is a cysteine protease with many house-keeping functions, such as intracellular proteolysis within lysosomes. Its increased activity and expression have been strongly associated with many pathological processes, including cancers. We present here the design and synthesis of novel derivatives of nitroxoline as inhibitors of cathepsin B. These were prepared either by omitting the pyridine part, or by modifying positions 2, 7, and 8 of nitroxoline. All compounds were evaluated for their ability to inhibit endopeptidase and exopeptidase activities of cathepsin B. For the most promising inhibitors, the ability to reduce extracellular and intracellular collagen IV degradation was determined, followed by their evaluation in cell-based in vitro models of tumor invasion. The presented data show that we have further defined the structural requirements for cathepsin B inhibition by nitroxoline derivatives and provided additional knowledge that could lead to non-peptidic compounds with usefulness against tumor progression.

The BET family of bromodomain-containing proteins (BRDs) is believed to be a promising drug target for therapeutic intervention in a number of diseases including cancer, inflammation and cardiovascular diseases. Hence, there is a great demand for novel chemotypes of BET inhibitors. The drug repurposing strategy offers great benefits to find inhibitors with known safety and pharmacokinetic profiles, thus increasing medicinal chemists’ interest in recent years. Using the drug repurposing strategy, a BRD4-specific score based virtual screening campaign on an in-house drug library was conducted followed by the ALPHA screen assay test. Nitroxoline, an FDA-approved antibiotic, was identified to effectively disrupt the interaction between the first bromodomain of BRD4 (bromodomain-containing protein 4) and acetylated H4 peptide with IC50 of 0.98 μM. Nitroxoline inhibited all BET family members with good selectivity against non-BET bromodomain-containing proteins, thus it is defined as a selective BET inhibitor. Based on the crystal structure of the nitroxoline-BRD4_BD1 complex, the mechanism of action as well as BET specificity of nitroxoline were determined. Since the anticancer activity of nitroxoline against MLL leukemia, one of the BET related diseases, has not been studied before, we tested whether nitroxoline might serve as a potential repurposing drug candidate for MLL leukemia. Nitroxoline effectively inhibited the proliferation of MLL leukemia cells by inducing cell cycle arrest and apoptosis. The profound efficacy is, at least in part, due to the inhibition of BET and downregulation of target gene transcription. Our discovery of nitroxoline as a BET inhibitor suggests potential application of nitroxoline and its derivatives for clinical translation in BET family related diseases.

Glioblastoma multiforme (GBM) is the most common malignant primary brain tumor with often recurrence. The currently available imaging parameters often are not adequate to make the final decision for treatment. As alterations in metabolism in GBM occur earlier than other variation during chemotherapy so, it would be advantageous to identify early biomarkers for response prediction to chemotherapy. Here, we evaluate the capability of chemical exchange saturation transfer (CEST) magnetic resonance imaging (MRI) to predict the early therapeutic effects of nitroxoline in a temozolomide (TMZ) resistant GBM model. In our study, we prepared TMZ-resistant GBM mouse model treated with 100 mg/kg of nitroxoline for 7 days that resulted in dramatical decreased in amide proton transfer (APT) value, while increased in non-treated group as assessed by CEST. In addition, nitroxoline slow down the tumor progression as compared to non-treated group, in which tumor volume was significantly increased further confirmed by histological examination. Furthermore, to compare the CEST, we investigated DWI for the same step of nitroxoline treatment in which, apparent diffusion coefficient (ADC) value was not increased significantly. Our study suggests that CEST can successfully predict the early response of nitroxoline treatment as compared to DWI and may serve as a biomarker. This would have a major impact on the clinical management of patients with TMZ-resistant GBM.

Glioblastoma multiforme (GBM) is one of the most aggressive human tumors with poor survival. Current standard treatment includes chemotherapy with DNA-alkylating agent temozolomide (TMZ), but the acquisition of resistance is a persistent clinical problem limiting the successful treatment of GBM. In our study, we assessed whether nitroxoline has antiproliferative properties against TMZ-resistant cancer cell lines in vitro and in vivo using TMZ-resistant glioblastoma mouse model. Here, we prepared TMZ-resistant cancer cell lines and showed antiproliferative effect of nitroxoline by cytotoxic, migration and clonogenic assay. Anti-proliferative effect of nitroxoline was associated with G0-G1 arrest determined by fluorescence-activated cell sorting (FACS) which ultimately leads to decreased in protein levels of cyclin D1, phosphorylated Rb and cyclin A. In addition, nitroxoline treated cells showed apoptosis confirmed by increased expression of cleaved caspase-3 and cleaved poly ADP-ribose polymerase (PARP). Furthermore, nitroxoline slow down the tumor progression in TMZ-resistant GBM mouse model confirmed by T2WI-MRI, in contrast tumor was significantly increased in non-treated mice. In terms of DWI, we also observed the increased apparent diffusion coefficient (ADC) value, suggestive of decreased cellularity, in nitroxoline treated GBM in mice model, while significantly decreased in non-treated. These results suggest the potential role of nitroxoline for therapeutic development against TMZ-resistant GBM.

The adsorption performance and anticorrosion activity of nitroxoline (NHQ) on copper were evaluated by gravimetric method in 1.0, 2.0 and 3.0 M nitric acid solutions and by electrochemical techniques namely electrochemical impedance spectroscopy (EIS), Tafel polarization (TP) and linear polarization (LP) in 1.0 M nitric acid solution. In all four methods, it was observed that the percentage of inhibition efficiency increases with increasing inhibitor concentration from 50 to 300 ppm. TP curves indicate that the antibiotic drug NHQ acts as mixed-type inhibitor. EIS studies showed that the charge transfer resistance increases with inhibitor concentration. The thermodynamic parameter $$\Delta G_{\text{ads}}^{0}$$ confirmed a physisorption mechanism. The inhibitor adsorption was spontaneous and it obeyed Langmuir adsorption isotherm. The formation of adsorbed layer on the copper metal surface was confirmed by SEM, EDX, FT-IR and AFM techniques.

The aim of this study was to identify the most potent quinoline-based anti-infectives for the treatment of multiple myeloma (MM) and to understand the molecular mechanisms. A small-scale screen against a panel of marketed quinoline-based drugs was performed in MM cell lines. Cell apoptosis was examined by flow cytometry. Anti-MM activity was also evaluated in nude mice. Western blotting was performed to investigate mechanisms. Nitroxoline (NXQ) was the most effective in suppressing MM cell proliferation. NXQ induced more than 40% MM cell apoptosis within 24 h and potentiated anti-MM activities of current major drugs including doxorubicin and lenalidomide. This finding was shown by activation of caspase-3, a major executive apoptotic enzyme, and by inactivation of PARP, a major enzyme in DNA damage repair. NXQ also suppressed prosurvival proteins Bcl-xL and Mcl-1. Moreover, NXQ suppressed the growth of myeloma xenografts in nude mice models. In the mechanistic study, NXQ was found to downregulate TRIM25, a highly expressed ubiquitin ligase in MM. Notably, NXQ upregulated tumor suppressor p53, but not PTEN. Furthermore, overexpression of TRIM25 decreased p53 protein. This study indicated that the long-term use of anti-infective NXQ has potential for MM treatment by targeting the TRIM25/p53 axle.

The determination of the concentration of xenobiotics in biological matrix followed by the change of the prescribing procedure plays a major role in the transition from general to personalized medicine. For this contribution, human urine samples collected from healthy volunteers and from patients having urinary tract infection were used as biological matrix to assess the potential and limitation of LoC-SERS to detected levofloxacin and nitroxoline. The determination of both antibiotics at clinically relevant concentrations, 1.38 mM ± 0.68 mM for levofloxacin and 10-40 µM for nitroxoline, will be presented. For quantification purposes the standard addition method is combined with LoC-SERS.

Nitroxoline is an effective antibacterial agent that is industrially produced by chemical and pharmaceutical enterprises in Ukraine. Parameters of its toxicity are determined under conditions of acute and subchronic toxicological experiments on 3 kinds of laboratory animals, by administering the drug orally and by application onto the skin and mucous membranes. The duration of acute experiment was 14 days, subchronical - 24 days. It was found that median lethal dose (DL50) for white female rats is 980 (852:1127) mg/kg, of white male rats – 835 mg/kg, white male mice– 660 mg/kg, by this parameter the drug can be attributed to 3 class of hazard – moderately hazardous substance. Average effective time of death (ET50) for albino rats is 28 hours. Species sensitivity of laboratory animals to nitroxoline is slightly expressed. The death of the animals starts on the first day after the injection and is recorded during three days of the experiment. In application on intact skin, locally-irritant and skin-resorptive effects are absent. After contact with the mucous membrane of the eye the drug causes weak irritant effect. Nitroxoline has a moderate cumulative activity., Нитроксолин – эффективный антибактериальный препарат, который промышленно выпускается химико-фармацевтическими предприятиями Украины. Устанавливали параметры токсичности нитроксолина в усло­виях острых и субхронического токсикологических экспериментов на 3-х видах лабораторных животных, путем введения препарата внутрь, нанесения на кожу и слизистие оболочки. Продолжительность острого опыта составляла 14 суток, субхронического - 24 суток. Установлено, что cредне смертельная доза (DL50) для белых крыс-самок составляет 980 (852:1127) мг/кг, белых крыс-самцов – 835 мг/кг, белых мышей-самцов – 660 мг/кг и позволяет отнести препарат за этим параметром к 3 классу опасности – вещества умеренно опасные. Средне эффективное время гибели животных (ЕТ50) для белых крыс равно 28 часам. Видовая чувствительность лабораторных животных к нитроксолину слабо виражена. Смерть животных наступает начиная с первых суток после введения и регистрируется в течение трьох дней. При нанесении на не­поврежденную кожу местно-раздражающий и кожно-резорбтивный эффекты отсутствуют. При попадании на слизистые оболочки глаз препарат вызывает слабый раздражаючий эффект. Нитроксолин обладает умеренной кумулятивной активностью.

A number of new 1,3-diazaadamantane derivatives containing quinoline fragments on C2 have been synthesized by condensation of 1,5-dialkyl-3,7-diazabicyclo[3.3.1]nonan-9-one, 1,5-dimethyl-3,7-diazabicyclo-[3.3.1]nonan-9-ol, and 1,5-dimethyl-3,7-diazabicyclo[3.3.1]nonane with 2-oxo-1,2-dihydroquinoline-3-carbaldehyde, 2-chloro- and 2-iodoquinoline-3-carbaldehyde, and quinoline-2-carbaldehyde.

The development of more effective therapeutic agents for high-grade gliomas remains a major challenge in neuro-oncology. Even with state-of-the-art surgical techniques, radiation, and temozolomide treatment, the median survival for the most aggressive gliomas (grade IV, glioblastoma) is 12–16 months from diagnosis and has improved little over the past 10 years.1,2 The ultimate failure of available treatments is attributed to drug resistance, infiltrative properties of high-grade gliomas, and the inability to completely resect invading tumor cells. Molecular mechanisms that enable glioma cells to resist apoptosis, ultimately leading to treatment failure, are only partially elucidated. Glioma cells have unique properties that enable them to break down the extracellular matrix and invade adjacent brain parenchyma. The expression of plasminogen activators, matrix metalloproteinases, and cysteine proteases all correlate with glioma progression, grade, and more invasive phenotype. For these reasons, more effective therapeutic agents could be sought among the compounds that can efficiently induce apoptosis while inhibiting tumor cell invasion. Recently, the FDA-approved antibiotic 8-hydroxy-5-nitroquinoline (nitroxoline) has regained attention due to its more potent anticancer properties than similar compounds that are also structurally related to clioquinol and 8-hydroxyquinoline.3 Nitroxoline was found to be one of the most effective inhibitors of angiogenesis and type 2 methionine aminopeptidase (MetAP2) among 175 000 compounds from a library of FDA-approved drugs.4 The same study demonstrated nitroxoline's ability to significantly inhibit growth of breast and bladder cancer xenografts in vivo.4 Apart from its role in the inhibition of angiogenesis, nitroxoline was recently shown to inhibit expression of cysteine proteinase cathepsin B (catB).5,6 CatB is elevated in many neoplasms including melanoma and breast, lung, ovarian, colorectal, and brain cancers.7,8 High levels of catB are found at the invasive edge of anaplastic astrocytomas and glioblastoma and in their cell culture media.9 Therefore, as a compound with the potential to suppress glioma invasion, nitroxoline has several advantages including a long history of human use (having been prescribed for urinary tract infections for more than 50 years in Europe10), tolerable side effects, and a favorable pharmacokinetic profile. As an already FDA-approved drug, nitroxoline has the potential to quickly enter clinical trials as an anticancer agent if it is shown to be effective for specific tumor types. Animal models that faithfully mimic the glioma microenvironment are necessary to evaluate drug therapies. Orthotopic xenograft models that use glioma/glioblastoma-derived cell lines have been commonly used for interventional studies, but their clinical relevance is questionable because of the inability to recapitulate many of the features that characterize high-grade gliomas. Several novel tumor models that more closely mimic human gliomas have been recently introduced.11–13 In the current work, we employ a genetically engineered mouse model based on adult neural stem cell-specific phosphatase and tensin homolog (PTEN) deletion and overexpression of human Kirsten rat sarcoma viral oncogene homolog KRASG12D capable of recapitulating many of the characteristics of human glioma. This glioma model was combined with magnetic resonance imaging (MRI) to evaluate treatment efficacy and help develop MRI biomarkers that can be used to monitor and predict treatment response to nitroxoline.

BACKGROUND: Nitroxoline is an antibiotic agent. It is used for the treatment of the second bacterial infection by the colibacillosis, salmonellosis and viral disease of the poultry. When the nitroxoline is indiscreetly used, the problem about the abuse of the antibiotics can occur. Therefore, this study presented the residue analytical method of nitroxoline in food for the safety management of animal farming products. METHODS AND RESULTS: A simple, sensitive and specific method for nitroxoline in chicken muscle by high performance liquid chromatograph with PDA was developed. Sample extraction with acetonitrile, purification with SPE cartridge (MCX) were applied, then quantitation by HPLC with C18 column under the gradient condition with 0.1 % tetrabutylammonium hydroxide-phosphoric acid and methanol was performed. Standard calibration curve presented linearity with the correlation coefficient () > 0.999, analysed from 0.02 to 0.5 mg/L concentration. Limit of quantitation in chicken muscle showed 0.02 mg/kg, and average recoveries ranged from 72.9 to 88.1 % in chicken muscle. The repeatability of measurements expressed as coefficient of variation (CV %) was less than 12 % in 0.02 and 0.04 mg/kg. CONCLUSION(S): Newly developed method for nitroxoline in chicken muscle was applicable to food inspection with the acceptable level of sensitivity, repeatability and reproducibility.

Human cathepsin B has many house-keeping functions, such as protein turnover in lysosomes. However, dysregulation of its activity is associated with numerous diseases, including cancers. We present here the structure-based design and synthesis of new cathepsin B inhibitors using the cocrystal structure of 5-nitro-8-hydroxyquinoline in the cathepsin B active site. A focused library of over 50 compounds was prepared by modifying positions 5, 7, and 8 of the parent compound nitroxoline. The kinetic parameters and modes of inhibition were characterized, and the selectivities of the most promising inhibitors were determined. The best performing inhibitor 17 was effective in cell-based in vitro models of tumor invasion, where it significantly abrogated invasion of MCF-10A neoT cells. These data show that we have successfully explored the structure-activity relationships of nitroxoline derivatives to provide new inhibitors that could eventually lead to compounds with clinical usefulness against the deleterious effects of cathepsin B in cancer progression.

A series of title compounds (III) are prepared by Suzuki—Miyaura-coupling of organoboron reagents (II) with bromoquinolines (I).

The effect of Nitroxoline, antibiotic drug, was tested as a corrosion inhibitor for mild steel (MS) in an acidic environment by chemical method (mass loss measurement) and electrochemical methods such as electrochemical impedance spectroscopy and potentiodynamic polarization. The surface morphology of mild steel was investigated by scanning electron microscopy, energy dispersive X-ray spectroscopy, and atomic force microscopy techniques. From the chemical and electrochemical methods, the resistance of corrosion was increased with the addition of Nitroxoline concentration. Tafel curves indicate that the pharmaceutically active compound is a cathodic type inhibitor. An adsorption of Nitroxoline on the surface of mild steel was obeyed by Langmuir isotherm. SEM, EDX, and AFM techniques prove the adsorption process. All the obtained results confirmed that the investigated compound Nitroxoline acts as a good inhibitor for the corrosion of mild steel in an acidic environment.

A reliable protocol for the synthesis of a series of 8-amino analogues of pharmacologically interesting nitroxoline (5-nitro-8-hydroxyquinoline) is described. The unprecedented displacement of the cyanomethoxy group of an O-cyanomethylated quinoline derivative by various primary and secondary amines selectively affords 5-nitroquinolin-8-ylamines in moderate-to-high yields. The reactions were accelerated significantly under microwave conditions in comparison with conventional heating.