Synthesis and evaluation of a large library of nitroxoline derivatives as pancreatic cancer antiproliferative agents

Veschi, Serena; Carradori, Simone; Lellis, Laura De; Florio, Rosalba; Brocco, Davide; Secci, Daniela; Guglielmi, Paolo; Spano, Mattia; Sobolev, Anatoly P.; Cama, Alessandro

doi:10.1080/14756366.2020.1780228

Cited by 9 publications

(8 citation statements)

References 32 publications

(63 reference statements)

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“…The presence and the position of the nitro group, –NO 2 , were shown to be crucial for nitroxoline MOA: none of the other 8-HQ derivatives demonstrate such antibacterial actions [ 15 , 35 ]. The p-position of –NO 2 reinforces hydroxide group acidity, enhancing the chelating ability for the abovementioned reasons [ 86 ]. Furthermore, it acts as a nitrogen radical source that alters intracellular signaling, leading to the inhibition of tumor cell growth [ 79 , 80 ], and provides a point of interaction with two histidines of human cathepsin B, enabling its inhibition [ 19 , 87 ].…”

Section: Nitroxolinementioning

confidence: 99%

Chelation in Antibacterial Drugs: From Nitroxoline to Cefiderocol and Beyond

et al. 2022

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In the era of escalating antimicrobial resistance, the need for antibacterial drugs with novel or improved modes of action (MOAs) is a health concern of utmost importance. Adding or improving the chelating abilities of existing drugs or finding new, nature-inspired chelating agents seems to be one of the major ways to ensure progress. This review article provides insight into the modes of action of antibacterial agents, class by class, through the perspective of chelation. We covered a wide scope of antibacterials, from a century-old quintessential chelating agent nitroxoline, currently unearthed due to its newly discovered anticancer and antibiofilm activities, over the commonly used antibacterial classes, to new cephalosporin cefiderocol and a potential future class of tetramates. We show the impressive spectrum of roles that chelation plays in antibacterial MOAs. This, by itself, demonstrates the importance of understanding the fundamental chemistry behind such complex processes.

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Section: Nitroxolinementioning

confidence: 99%

Chelation in Antibacterial Drugs: From Nitroxoline to Cefiderocol and Beyond

et al. 2022

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“…Cell viability was assessed by MTT assay (Sigma-Aldrich, St. Louis, MO, USA), as previously described [43]. Specifically, MTT assays were performed by exposing cancer cell lines to benzimidazoles at the indicated concentrations (1, 10, 20 µM) or with vehicle DMSO (0 µM).…”

Section: Cell Viability Assaymentioning

confidence: 99%

Screening of Benzimidazole-Based Anthelmintics and Their Enantiomers as Repurposed Drug Candidates in Cancer Therapy

et al. 2021

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Repurposing of approved non-antitumor drugs represents a promising and affordable strategy that may help to increase the repertoire of effective anticancer drugs. Benzimidazole-based anthelmintics are antiparasitic drugs commonly employed both in human and veterinary medicine. Benzimidazole compounds are being considered for drug repurposing due to antitumor activities displayed by some members of the family. In this study, we explored the effects of a large series of benzimidazole-based anthelmintics (and some enantiomerically pure forms of those containing a stereogenic center) on the viability of different tumor cell lines derived from paraganglioma, pancreatic and colorectal cancer. Flubendazole, parbendazole, oxibendazole, mebendazole, albendazole and fenbendazole showed the most consistent antiproliferative effects, displaying IC50 values in the low micromolar range, or even in the nanomolar range. In silico evaluation of their physicochemical, pharmacokinetics and medicinal chemistry properties also provided useful information related to the chemical structures and potential of these compounds. Furthermore, in view of the potential repurposing of these drugs in cancer therapy and considering that pharmaceutically active compounds may have different mechanisms of action, we performed an in silico target prediction to assess the polypharmacology of these benzimidazoles, which highlighted previously unknown cancer-relevant molecular targets.

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“…Nitroxoline is an old antibiotic, belonging to the class of 8-hydroxyquinolines (Figure 1), used for the treatment of urinary tract infections, that received attention for its antitumor activities displayed in preclinical cancer models, including xenograft and genetically modified mice models of several tumors [14,[194][195][196][197]. Recently, nitroxoline proved to be effective also in PC [42,63,198]. The drug was able to affect viability of different PC cell lines, by altering cell cycle and fostering apoptosis.…”

Section: Nitroxolinementioning

confidence: 99%

“…The drug was able to affect viability of different PC cell lines, by altering cell cycle and fostering apoptosis. Moreover, it markedly hampered self-renewal capacity, migration and invasion of PC cells, although with slight differences in potency among the three tested PC cell lines possibly due to their distinct genetic backgrounds [42,63,198]. Remarkably, combinations of nitroxoline with the HIV-protease inhibitor nelfinavir, with or without erlotinib, resulted in dose-dependent synergistic effects on PC cell viability, paralleled by profound cell cycle perturbation, drastic clonogenicity impairment and more consistent apoptosis promotion, as compared to single agents [42].…”

Section: Nitroxolinementioning

confidence: 99%

Drug Repurposing, an Attractive Strategy in Pancreatic Cancer Treatment: Preclinical and Clinical Updates

Lellis

Veschi

Tinari

et al. 2021

Cancers

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Pancreatic cancer (PC) is one of the deadliest malignancies worldwide, since patients rarely display symptoms until an advanced and unresectable stage of the disease. Current chemotherapy options are unsatisfactory and there is an urgent need for more effective and less toxic drugs to improve the dismal PC therapy. Repurposing of non-oncology drugs in PC treatment represents a very promising therapeutic option and different compounds are currently being considered as candidates for repurposing in the treatment of this tumor. In this review, we provide an update on some of the most promising FDA-approved, non-oncology, repurposed drug candidates that show prominent clinical and preclinical data in pancreatic cancer. We also focus on proposed mechanisms of action and known molecular targets that they modulate in PC. Furthermore, we provide an explorative bioinformatic analysis, which suggests that some of the PC repurposed drug candidates have additional, unexplored, oncology-relevant targets. Finally, we discuss recent developments regarding the immunomodulatory role displayed by some of these drugs, which may expand their potential application in synergy with approved anticancer immunomodulatory agents that are mostly ineffective as single agents in PC.

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Synthesis and evaluation of a large library of nitroxoline derivatives as pancreatic cancer antiproliferative agents

Cited by 9 publications

References 32 publications

Chelation in Antibacterial Drugs: From Nitroxoline to Cefiderocol and Beyond

Chelation in Antibacterial Drugs: From Nitroxoline to Cefiderocol and Beyond

Screening of Benzimidazole-Based Anthelmintics and Their Enantiomers as Repurposed Drug Candidates in Cancer Therapy

Drug Repurposing, an Attractive Strategy in Pancreatic Cancer Treatment: Preclinical and Clinical Updates

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