Nitroaromatic Hypoxia-Activated Prodrugs for Cancer Therapy

Denny, William A.

doi:10.3390/ph15020187

Cited by 27 publications

(23 citation statements)

References 85 publications

(119 reference statements)

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“…Specifically, A549 cells (not expressing Luc) were cultured in an atmosphere consisting of 1 or 20% oxygen for 2 days. Because aryl nitro reduction mediated by mammalian NTRs can be inhibited by molecular oxygen, we expect there to be greater probe activation under oxygen-deficient conditions . After incubating with BL660-NTR for 60 min, the cells were washed with fresh PBS, detached, pelleted, and lysed via sonication.…”

Section: Resultsmentioning

confidence: 99%

“…Because aryl nitro reduction mediated by mammalian NTRs can be inhibited by molecular oxygen, we expect there to be greater probe activation under oxygen-deficient conditions. 54 After incubating with BL660-NTR for 60 min, the cells were washed with fresh PBS, detached, pelleted, and lysed via sonication. The lysates were then transferred to 24well plates, treated with luciferase and imaged immediately using the IVIS imaging system.…”

Section: Design and Synthesis Of Substituted Benzyl Estersmentioning

confidence: 99%

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Hydrolysis-Resistant Ester-Based Linkers for Development of Activity-Based NIR Bioluminescence Probes

et al. 2023

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Activity-based sensing (ABS) probes equipped with a NIR bioluminescence readout are promising chemical tools to study cancer biomarkers owing to their high sensitivity and deep tissue compatibility. Despite the demand, there is a dearth of such probes because NIR substrates (e.g., BL660 (a NIR luciferin analog)) are not equipped with an appropriate attachment site for ABS trigger installation. For instance, our attempts to mask the carboxylic acid moiety with standard self-immolative benzyl linkers resulted in significant background signals owing to undesirable ester hydrolysis. In this study, we overcame this longstanding challenge by rationally designing a new hydrolysis-resistant ester-based linker featuring an isopropyl shielding arm. Compared to the parent, the new design is 140.5-fold and 67.8-fold more resistant toward spontaneous and esterase-mediated hydrolysis, respectively. Likewise, we observed minimal cleavage of the ester moiety when incubated with a panel of enzymes possessing ester-hydrolyzing activity. These impressive in vitro results were corroborated through a series of key experiments in live cells. Further, we showcased the utility of this technology by developing the first NIR bioluminescent probe for nitroreductase (NTR) activity and applied it to visualize elevated NTR expression in oxygen deficient lung cancer cells and in a murine model of non-small cell lung cancer. The ability to monitor the activity of this key biomarker in a deep tissue context is critical because it is associated with tumor hypoxia, which in turn is linked to drug resistance and aggressive cancer phenotypes.

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Section: Resultsmentioning

confidence: 99%

Section: Design and Synthesis Of Substituted Benzyl Estersmentioning

confidence: 99%

Hydrolysis-Resistant Ester-Based Linkers for Development of Activity-Based NIR Bioluminescence Probes

et al. 2023

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“…An important feature of nitroreduction is the change in the electron-withdrawing and -donating properties that result. The Hammett equation predicts that the NO 2 group σp = +0.78 (electron-withdrawing) when changed to the NH 2 group σp = −0.66 (electron-donating) will have a dramatic effect on the chemistry of a nitroaromatic …”

Section: General Chemistrymentioning

confidence: 99%

Nitroreduction: A Critical Metabolic Pathway for Drugs, Environmental Pollutants, and Explosives

Penning¹,

Su²,

El‐Bayoumy

2022

Chem. Res. Toxicol.

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Nitro group containing xenobiotics include drugs, cancer chemotherapeutic agents, carcinogens (e.g., nitroarenes and aristolochic acid) and explosives. The nitro group undergoes a sixelectron reduction to form sequentially the nitroso-, N-hydroxylamino-and amino-functional groups. These reactions are catalyzed by nitroreductases which, rather than being enzymes with this sole function, are enzymes hijacked for their propensity to donate electrons to the nitro group either one at a time via a radical mechanism or two at time via the equivalent of a hydride transfer. These enzymes include: NADPH-dependent flavoenzymes (NADPH: P450 oxidoreductase, NAD(P)H-quinone oxidoreductase), P450 enzymes, oxidases (aldehyde oxidase, xanthine oxidase) and aldo-keto reductases. The hydroxylamino group once formed can undergo conjugation reactions with acetate or sulfate catalyzed by N-acetyltransferases or sulfotransferases, respectively, leading to the formation of intermediates containing a good leaving group which in turn can generate a nitrenium or carbenium ion for covalent DNA adduct formation. The intermediates in the reduction sequence are also prone to oxidation and produce reactive oxygen species. As a consequence, many nitro-containing xenobiotics can be genotoxic either by forming stable covalent adducts or by oxidatively damaging DNA. This review will focus on the general chemistry of nitroreduction, the enzymes responsible, the reduction of xenobiotic substrates, the regulation of nitroreductases, the ability of nitrocompounds to form DNA adducts and act as mutagens as well as some future directions.

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“…It affects several tissues and it is correlated to many effects at cellular and molecular levels [53,54]. One characteristic that can be used for developing new drugs is the fact that cancer tissue is usually in some degree of hypoxia, so it becomes a target for some nitro aromatic hypoxia-activated prodrugs [55,56]. Heterocycle compounds often show biological activity, particularly the ones with nitrogen and oxygen as the heteroatoms.…”

Section: Antitumoral Activitymentioning

confidence: 99%

The Diverse Biological Activity of Recently Synthesized Nitro Compounds

et al. 2022

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The search for new and efficient pharmaceuticals is a constant struggle for medicinal chemists. New substances are needed in order to treat different pathologies affecting the health of humans and animals, and these new compounds should be safe, effective and have the fewest side effects possible. Some functional groups are known for having biological activity; in this matter, the nitro group (NO2) is an efficient scaffold when synthesizing new bioactive molecules. Nitro compounds display a wide spectrum of activities that include antineoplastic, antibiotic, antihypertensive, antiparasitic, tranquilizers and even herbicides, among many others. Most nitro molecules exhibit antimicrobial activity, and several of the compounds mentioned in this review may be further studied as lead compounds for the treatment of H. pylori, P. aeruginosa, M. tuberculosis and S. mutans infections, among others. The NO2 moiety triggers redox reactions within cells causing toxicity and the posterior death of microorganisms, not only bacteria but also multicellular organisms such as parasites. The same effect may be present in humans as well, so the nitro groups can be considered both a pharmacophore and a toxicophore at the same time. The role of the nitro group itself also has a deep effect on the polarity and electronic properties of the resulting molecules, and hence favors interactions with some amino acids in proteins. For these reasons, it is fundamental to analyze the recently synthesized nitro molecules that show any potential activity in order to develop new pharmacological treatments that enhance human health.

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Nitroaromatic Hypoxia-Activated Prodrugs for Cancer Therapy

Cited by 27 publications

References 85 publications

Hydrolysis-Resistant Ester-Based Linkers for Development of Activity-Based NIR Bioluminescence Probes

Hydrolysis-Resistant Ester-Based Linkers for Development of Activity-Based NIR Bioluminescence Probes

Nitroreduction: A Critical Metabolic Pathway for Drugs, Environmental Pollutants, and Explosives

The Diverse Biological Activity of Recently Synthesized Nitro Compounds

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