Abstract
Charge is an important characteristic of drug molecules, since ionization sites determine the pKa at a particular pH. The pKa in turn can affect many parameters, including solubility, dissolution rate, reaction kinetics, formulation, cell permeability, tissue distribution, renal elimination, metabolism, protein binding and receptor interactions. The impact of charge dynamics is amplified in human solid tumors that exhibit the glycolytic phenotype and associated acidic extracellular microenvironment. This phenotype is driven by hypoxia and creates a pH gradient in tumors that favors uptake of weak acids and exclusion of weak bases. Established anticancer drugs exhibit a range of pKa's and thus variable ability to exploit the tumor pH gradient. The camptothecins are a prime example as they represent a diverse class of approved anticancer drugs and drug candidates whose charge distribution varies with pH. An in silico method was used to predict charge distribution of camptothecins at physiological versus acidic pH in both the lactone and carboxylate forms. A significant amount of uncharged carboxylate was predicted at acidic pH that could enter tumor cells and accumulate in mitochondria to inhibit mitochondrial topoisomerase I. A model is presented to describe the charge dynamics of a new camptothecin analog and the impact on nuclear and mitochondrial mechanism(s) of action. This example illustrates the importance of integrating tumor physiology and charge dynamics into anticancer drug development.
Keywords: Camptothecin, charge dynamics, glycolytic phenotype, hypoxia, pKa, topoisomerase I, tumor pH gradient, Anticancer, ionization, receptor
Current Medicinal Chemistry
Title: Tumor Physiology and Charge Dynamics of Anticancer Drugs: Implications for Camptothecin-based Drug Development
Volume: 18 Issue: 9
Author(s): D. J. Adams and L. R. Morgan
Affiliation:
Keywords: Camptothecin, charge dynamics, glycolytic phenotype, hypoxia, pKa, topoisomerase I, tumor pH gradient, Anticancer, ionization, receptor
Abstract: Charge is an important characteristic of drug molecules, since ionization sites determine the pKa at a particular pH. The pKa in turn can affect many parameters, including solubility, dissolution rate, reaction kinetics, formulation, cell permeability, tissue distribution, renal elimination, metabolism, protein binding and receptor interactions. The impact of charge dynamics is amplified in human solid tumors that exhibit the glycolytic phenotype and associated acidic extracellular microenvironment. This phenotype is driven by hypoxia and creates a pH gradient in tumors that favors uptake of weak acids and exclusion of weak bases. Established anticancer drugs exhibit a range of pKa's and thus variable ability to exploit the tumor pH gradient. The camptothecins are a prime example as they represent a diverse class of approved anticancer drugs and drug candidates whose charge distribution varies with pH. An in silico method was used to predict charge distribution of camptothecins at physiological versus acidic pH in both the lactone and carboxylate forms. A significant amount of uncharged carboxylate was predicted at acidic pH that could enter tumor cells and accumulate in mitochondria to inhibit mitochondrial topoisomerase I. A model is presented to describe the charge dynamics of a new camptothecin analog and the impact on nuclear and mitochondrial mechanism(s) of action. This example illustrates the importance of integrating tumor physiology and charge dynamics into anticancer drug development.
Export Options
About this article
Cite this article as:
J. Adams D. and R. Morgan L., Tumor Physiology and Charge Dynamics of Anticancer Drugs: Implications for Camptothecin-based Drug Development, Current Medicinal Chemistry 2011; 18 (9) . https://dx.doi.org/10.2174/092986711795029609
DOI https://dx.doi.org/10.2174/092986711795029609 |
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
-
Gallic Acid and Gallic Acid Derivatives: Effects on Drug Metabolizing Enzymes
Current Drug Metabolism Consumption of Cooked Navy Bean Powders Modulate the Canine Fecal and Urine Metabolome
Current Metabolomics Potential Role of miRNA in Metastatic Cascade of Triple-Negative Breast Cancer
Current Cancer Drug Targets Breast Cancer Resistance Protein and P-Glycoprotein in Brain Cancer: Two Gatekeepers Team Up
Current Pharmaceutical Design Laminin-332-Integrin Interaction: A Target For Cancer Therapy?
Current Medicinal Chemistry Fibroblast Growth Factor 2: From Laboratory Evidence to Clinical Application
Current Vascular Pharmacology Lymphocyte Homing to the Liver
Current Medicinal Chemistry - Anti-Inflammatory & Anti-Allergy Agents Computational Analysis of Drug Resistance Network in Lung Adenocarcinoma
Anti-Cancer Agents in Medicinal Chemistry Mevalonate Kinase Deficiency: Disclosing the Role of Mevalonate Pathway Modulation in Inflammation
Current Pharmaceutical Design Recent Advances in Hematopoietic Stem Cell-Mediated Regeneration
Recent Patents on Regenerative Medicine Thioredoxin, Glutathione and Related Molecules in Tumors of the Nervous System
Current Medicinal Chemistry Clinical and <i>In Silico</i> Outcomes of the Expression of miR-130a-5p and miR-615-3p in Tumor Compared with Non-Tumor Adjacent Tissues of Patients with BC
Anti-Cancer Agents in Medicinal Chemistry Promises of Apoptosis-Inducing Peptides in Cancer Therapeutics
Current Pharmaceutical Biotechnology Recent Progress in Synthesis and Applications of Fluorinated Carbohydrates
Current Organic Chemistry Percutaneous Radiofrequency Ablation of Hepatocellular Carcinoma on Cirrhosis: State of the Art and Future Perspectives
Recent Patents on Anti-Cancer Drug Discovery Mutant Cell Surface Receptors as Targets for Individualized Cancer Diagnosis and Therapy
Current Cancer Drug Targets MUC1 Story: Great Expectations, Disappointments and the Renaissance
Current Medicinal Chemistry Effect of Pinocembrin Isolated from Boesenbergia pandurata on Xenobiotic-Metabolizing Enzymes in Rat Liver
Drug Metabolism Letters Macrophages in Immunopathology of Atherosclerosis: A Target for Diagnostics and Therapy
Current Pharmaceutical Design Gene Polymorphisms and Pharmacogenetics in Rheumatoid Arthritis
Current Genomics