Abstract
NQO1 (DT-diaphorase) and its truncated isoenzyme, the metalloenzyme NQO2, can reduce quinone substrates by two-electron transfer. While NQO1 is a known detoxification enzyme, the function of NQO2 is less well understood. Both rat NQO1 and human NQO2 reductively bioactivate the dinitroarene CB 1954 to a cytotoxic product that behaves as a difunctional DNA-crosslinking species with potent anti-tumour activity, although human NQO1 is much less effective. A FMN-dependent nitroreductase from E. coli B also reduces quinones and reductively bioactivates CB 1954. However, this enzyme reduces CB 1954 to the 2- and 4-hydroxylamines in equivalent yield, whereas NQO1 and NQO2 generate only the 4-isomer. The reduction profile is a key factor in the development of anti-tumour prodrugs, where distinct delivery strategies are being evaluated: prodrug therapy, antibody-, macromolecule- and gene-directed enzyme prodrug therapy (ADEPT, MDEPT or GDEPT). The flavoprotein enzymes are explored in terms of structure and bioreduction mechanism, particularly for use in the design of novel prodrugs with potential application as chemotherapeutic agents.
Keywords: Aerobic Nitroreduction, Flavoproteins, Cancer Chemotherapy, anti-tumour prodrugs, flavoprotein enzymes, Quinone reductase type 1, Quinone reductase type 2 (NQO2)
Mini-Reviews in Medicinal Chemistry
Title: Aerobic Nitroreduction by Flavoproteins: Enzyme Structure, Mechanisms and Role in Cancer Chemotherapy
Volume: 1 Issue: 3
Author(s): Jane V. Skelly, Richard J. Knox and Terence C. Jenkins
Affiliation:
Keywords: Aerobic Nitroreduction, Flavoproteins, Cancer Chemotherapy, anti-tumour prodrugs, flavoprotein enzymes, Quinone reductase type 1, Quinone reductase type 2 (NQO2)
Abstract: NQO1 (DT-diaphorase) and its truncated isoenzyme, the metalloenzyme NQO2, can reduce quinone substrates by two-electron transfer. While NQO1 is a known detoxification enzyme, the function of NQO2 is less well understood. Both rat NQO1 and human NQO2 reductively bioactivate the dinitroarene CB 1954 to a cytotoxic product that behaves as a difunctional DNA-crosslinking species with potent anti-tumour activity, although human NQO1 is much less effective. A FMN-dependent nitroreductase from E. coli B also reduces quinones and reductively bioactivates CB 1954. However, this enzyme reduces CB 1954 to the 2- and 4-hydroxylamines in equivalent yield, whereas NQO1 and NQO2 generate only the 4-isomer. The reduction profile is a key factor in the development of anti-tumour prodrugs, where distinct delivery strategies are being evaluated: prodrug therapy, antibody-, macromolecule- and gene-directed enzyme prodrug therapy (ADEPT, MDEPT or GDEPT). The flavoprotein enzymes are explored in terms of structure and bioreduction mechanism, particularly for use in the design of novel prodrugs with potential application as chemotherapeutic agents.
Export Options
About this article
Cite this article as:
Skelly V. Jane, Knox J. Richard and Jenkins C. Terence, Aerobic Nitroreduction by Flavoproteins: Enzyme Structure, Mechanisms and Role in Cancer Chemotherapy, Mini-Reviews in Medicinal Chemistry 2001; 1 (3) . https://dx.doi.org/10.2174/1389557013406800
DOI https://dx.doi.org/10.2174/1389557013406800 |
Print ISSN 1389-5575 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-5607 |
Call for Papers in Thematic Issues
Bioprospecting of Natural Products as Sources of New Multitarget Therapies
According to the Convention on Biological Diversity, bioprospecting is the exploration of biodiversity and indigenous knowledge to develop commercially valuable products for pharmaceutical and other applications. Bioprospecting involves searching for useful organic compounds in plants, fungi, marine organisms, and microorganisms. Natural products traditionally constituted the primary source of more than ...read more
Computational Frontiers in Medicinal Chemistry
The thematic issue "Computational Frontiers in Medicinal Chemistry" provides a robust platform for delving into state-of-the-art computational methodologies and technologies that significantly propel advancements in medicinal chemistry. This edition seeks to amalgamate top-tier reviews spotlighting the latest trends and breakthroughs in the fusion of computational approaches, including artificial intelligence (AI) ...read more
Mitochondria as a Therapeutic Target in Metabolic Disorders
Mitochondria are the primary site of adenosine triphosphate (ATP) production in mammalian cells. Moreover, these organelles are an important source of reactive oxygen and nitrogen species in virtually any nucleated cell type. The modulation of a myriad of cellular signaling pathways depends on the mitochondrial physiology. Mitochondrial dysfunction is observed ...read more
Natural Products and Dietary Supplements in Alleviation of Metabolic, Cardiovascular, and Neurological Disorders
Metabolic disorders like diabetes, obesity, inflammation, oxidative stress, cancer etc, cardiovascular disorders like angina, myocardial infarction, congestive heart failure etc as well as neurological disorders like Alzheimer?s, Parkinson?s, Epilepsy, Depression, etc are the global burden. They covered the major segment of the diseases and disorders from which the human community ...read more
- Author Guidelines
- Graphical Abstracts
- Fabricating and Stating False Information
- Research Misconduct
- Post Publication Discussions and Corrections
- Publishing Ethics and Rectitude
- Increase Visibility of Your Article
- Archiving Policies
- Peer Review Workflow
- Order Your Article Before Print
- Promote Your Article
- Manuscript Transfer Facility
- Editorial Policies
- Allegations from Whistleblowers
Related Articles
-
Gene Therapy Approaches for the Selective Killing of Cancer Cells
Current Pharmaceutical Design Carbon Nanotubes in the Diagnosis and Treatment of Malignant Melanoma
Anti-Cancer Agents in Medicinal Chemistry Molecular Pathology of Sarcomas
Reviews on Recent Clinical Trials Molecular Targets in Malignant Pleural Mesothelioma Treatment
Current Drug Targets Genistein Potentiates the Anti-cancer Effects of Gemcitabine in Human Osteosarcoma via the Downregulation of Akt and Nuclear Factor-κB Pathway
Anti-Cancer Agents in Medicinal Chemistry P68 RNA Helicase (DDX5) Required for the Formation of Various Specific and Mature miRNA Active RISC Complexes
MicroRNA A Review of Pharmacological Treatment Options for Lung Cancer: Emphasis on Novel Nanotherapeutics and Associated Toxicity
Current Drug Targets Current Molecularly Targeting Therapies in NSCLC and Melanoma
Anti-Cancer Agents in Medicinal Chemistry Plasminogen Activator System and Vascular Disease
Current Vascular Pharmacology Manipulation of the Immune System for Cancer Defeat: A Focus on the T Cell Inhibitory Checkpoint Molecules
Current Medicinal Chemistry Peeking into the Black Box: How Cytokine Antibody Arrays Shed Light on Molecular Mechanisms of Breast Cancer Development and its Treatment
Current Proteomics Pemetrexed: Potential Role in the Adjuvant Chemotherapy of Non-Small Cell Lung Cancer
Current Drug Targets The Potential and Rationale for COX-2 Inhibitors in Lung Cancer
Anti-Cancer Agents in Medicinal Chemistry Antibody-Onconase Conjugates: Cytotoxicity and Intracellular Routing
Current Pharmaceutical Biotechnology Matching Chelators to Radiometals for Positron Emission Tomography Imaging- Guided Targeted Drug Delivery
Current Drug Targets Phase 1 Clinical Experience Using Intravenous Administration of PV701, an Oncolytic Newcastle Disease Virus
Current Cancer Drug Targets Recent Advances in the Development of Thioredoxin Reductase Inhibitors as Anticancer Agents
Current Drug Targets Pharmacological Characterization of Histone Deacetylase Inhibitor and Tumor Cell-Growth Inhibition Properties of New Benzofuranone Compounds
Current Cancer Drug Targets A Combined Approach with Rituximab Plus Anti-TRAIL-R Agonistic Antibodies for the Treatment of Haematological Malignancies
Current Pharmaceutical Design Applications of Nanocarbons in Bio-Medical Devices
Recent Innovations in Chemical Engineering