Abstract
Vacuolar-ATPase (V-ATPase) has been proposed as a drug target in osteoporosis due to its involvement in bone resorption, and as a target in cancer due to potential involvement in tumor invasion and metastasis. The classical selective inhibitors of V-ATPase are microbial macrolides of the bafilomycin and concanamycin class. These inhibitors have proven to be too toxic for therapeutic use, however recent structure-activity studies on bafilomycins, and the isolation of novel macrolide structures from marine sources, have provided new avenues for development of potentially less toxic V-ATPase inhibitors. The novel salicylihalamide and lobatamide series of compounds were predicted to share a common mechanism of action based on the patterns of cytotoxicity produced in the NCI 60-cell cancer screen. They have subsequently been shown to selectively interact with mammalian V-ATPases, but not with fungal V-ATPases. With the recent achievement of total syntheses of salicylihalamide, lobatamide, and related compounds, the elaboration of congeners with specificity for particular enzyme isoforms may provide drug candidates which are less toxic. This review summarizes recent advances in V-ATPase inhibition and the prospects for further progress.
Keywords: v-atpase, salicylihalamides, lobatamides, inhibitors, cancer, osteoporosis, isolation, synthesis
Current Medicinal Chemistry
Title: Novel Marine and Microbial Natural Product Inhibitors of Vacuolar ATPase
Volume: 10 Issue: 9
Author(s): John A. Beutler and Tawnya C. McKee
Affiliation:
Keywords: v-atpase, salicylihalamides, lobatamides, inhibitors, cancer, osteoporosis, isolation, synthesis
Abstract: Vacuolar-ATPase (V-ATPase) has been proposed as a drug target in osteoporosis due to its involvement in bone resorption, and as a target in cancer due to potential involvement in tumor invasion and metastasis. The classical selective inhibitors of V-ATPase are microbial macrolides of the bafilomycin and concanamycin class. These inhibitors have proven to be too toxic for therapeutic use, however recent structure-activity studies on bafilomycins, and the isolation of novel macrolide structures from marine sources, have provided new avenues for development of potentially less toxic V-ATPase inhibitors. The novel salicylihalamide and lobatamide series of compounds were predicted to share a common mechanism of action based on the patterns of cytotoxicity produced in the NCI 60-cell cancer screen. They have subsequently been shown to selectively interact with mammalian V-ATPases, but not with fungal V-ATPases. With the recent achievement of total syntheses of salicylihalamide, lobatamide, and related compounds, the elaboration of congeners with specificity for particular enzyme isoforms may provide drug candidates which are less toxic. This review summarizes recent advances in V-ATPase inhibition and the prospects for further progress.
Export Options
About this article
Cite this article as:
Beutler A. John and McKee C. Tawnya, Novel Marine and Microbial Natural Product Inhibitors of Vacuolar ATPase, Current Medicinal Chemistry 2003; 10 (9) . https://dx.doi.org/10.2174/0929867033457827
DOI https://dx.doi.org/10.2174/0929867033457827 |
Print ISSN 0929-8673 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-533X |
Call for Papers in Thematic Issues
Advances in Medicinal Chemistry: From Cancer to Chronic Diseases.
The broad spectrum of the issue will provide a comprehensive overview of emerging trends, novel therapeutic interventions, and translational insights that impact modern medicine. The primary focus will be diseases of global concern, including cancer, chronic pain, metabolic disorders, and autoimmune conditions, providing a broad overview of the advancements in ...read more
Approaches to the treatment of chronic inflammation
Chronic inflammation is a hallmark of numerous diseases, significantly impacting global health. Although chronic inflammation is a hot topic, not much has been written about approaches to its treatment. This thematic issue aims to showcase the latest advancements in chronic inflammation treatment and foster discussion on future directions in this ...read more
Cellular and Molecular Mechanisms of Non-Infectious Inflammatory Diseases: Focus on Clinical Implications
The Special Issue covers the results of the studies on cellular and molecular mechanisms of non-infectious inflammatory diseases, in particular, autoimmune rheumatic diseases, atherosclerotic cardiovascular disease and other age-related disorders such as type II diabetes, cancer, neurodegenerative disorders, etc. Review and research articles as well as methodology papers that summarize ...read more
Chalcogen-modified nucleic acid analogues
Chalcogen-modified nucleosides, nucleotides and oligonucleotides have been of great interest to scientific research for many years. The replacement of oxygen in the nucleobase, sugar or phosphate backbone by chalcogen atoms (sulfur, selenium, tellurium) gives these biomolecules unique properties resulting from their altered physical and chemical properties. The continuing interest in ...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
- Announcements
Related Articles
-
Near Infrared Spectroscopic Combined with Partial Least Squares and Radial Basis Function Neural Network to Analyze Paclitaxel Concentration in Rat Plasma
Combinatorial Chemistry & High Throughput Screening <i>In silico</i> and <i>In vitro</i> Investigation of a Likely Pathway for Anti-Cancerous Effect of Thrombocidin-1 as a Novel Anticancer Peptide
Protein & Peptide Letters Composite Lymphomas: A Challenging Entity
Current Cancer Therapy Reviews Polymorphism in Endothelin-1 Gene: An Overview
Current Clinical Pharmacology Preface
Current Cancer Drug Targets Regulation of Autophagy Through Multiple Independent Hypoxic Signaling Pathways
Current Molecular Medicine Preparation and Preliminary Evaluation of <sup>68</sup>Ga-Acridine: An Attempt to Study the Potential of Radiolabeled DNA Intercalator as a PET Radiotracer for Tumor Imaging
Anti-Cancer Agents in Medicinal Chemistry The Functional Role of Oncogenic LncRNA BCAR4 for Cancer Outcome
Current Pharmaceutical Design Clinical Evidence of Herb-Drug Interactions: A Systematic Review by the Natural Standard Research Collaboration
Current Drug Metabolism Regulation of the Endoplasmic Reticulum Ca2+-Store in Cancer
Anti-Cancer Agents in Medicinal Chemistry Estrone (E1) Based Esters as Potential Inhibitors of Type 3 17β- hydroxysteroid Dehydrogenase (17β-HSD3) in the Treatment of Hormone-Dependent Prostate Cancer
Letters in Drug Design & Discovery Dequalinium-Derived Nanoconstructs: A Promising Vehicle for Mitochondrial Targeting
Current Drug Delivery Preclinical Evaluation of New Taxoids
Current Pharmaceutical Design Pentoxifylline Use in Dermatology
Inflammation & Allergy - Drug Targets (Discontinued) Targeting Cancer Stem Cells: Promises and Challenges
Anti-Cancer Agents in Medicinal Chemistry In Vitro and In Vivo Evaluation of DMSO and Azone as Penetration Enhancers for Cutaneous Application of Celecoxib
Current Drug Delivery Metabolic Remodeling Induced by Adipocytes: A New Achilles' Heel in Invasive Breast Cancer?
Current Medicinal Chemistry Anticancer Triazenes: from Bioprecursors to Hybrid Molecules
Current Pharmaceutical Design The Natural Flavonoid Naringenin Inhibits the Cell Growth of Wilms Tumor in Children by Suppressing TLR4/NF-κB Signaling
Anti-Cancer Agents in Medicinal Chemistry Editorial: [Hot Topic: Inflammation and Cancer: New Targets and Novel Therapeutic Approach]
Current Pharmaceutical Design