Abstract
This review presents an overview of Choline Kinase (ChoK) inhibitors with antiproliferative activity. The consideration of ChoK as a novel target for the development of new anticancer drugs is justified. The synthesis of several derivatives based on structural modifications of hemicholinium-3 (HC-3) is not accompanied by potentiation of the neurological toxicity of HC-3. The increment of both ChoK inhibitory and antiproliferative activities was successfully obtained by the two following changes: a) substitution of the oxazonium moiety of HC-3 by several aromatic heterocycles, and b) using the 1,2-ethylene(bisbenzyl) moiety instead of the 4,4-biphenyl fragment. In an attempt to understand the ChoK inhibitory activity, a quantitative structure-activity relationship was developed. The QSAR equations have described the forces involved in quantitative terms. The electron characteristic of the substituent at position 4 of the heterocycle and the lipophilic character of the whole molecule were found to significantly affect the antitumour activity in compounds 17-95. Trispyridinium compounds 91-95 are more potent than the bispyridinium ones 87-89 as ChoK inhibitors. Nevertheless, 91-95 are less active than 87-89 as antiproliferative agents because the latter show better lipophilicities to cross the cytosolic membranes. Inhibition of the growth of human tumours in nude mice has been demonstrated: Antitumour activity of compound 64 against human HT-29 produced a decrease of up to 70% in the size of the tumour in nude mice. These results indicate that ChoK can be used as a general target for anticancer drug design against Ras-dependent tumourigenesis.
Keywords: choline kinase inhibitors, antitumour drugs, bisquaternary heterocyclic compounds, hammett parameters, lipophilicity, qsar, frontier orbitals
Current Medicinal Chemistry
Title: QSAR-Derived Choline Kinase Inhibitors: How Rational can Antiproliferative Drug Design Be?
Volume: 10 Issue: 13
Author(s): J. Campos, M. C. Nunez, A. Conejo-Garcia, R. M. Sanchez-Martin, R. Hernandez-Alcoceba, A. Rodriguez-Gonzalez, J. C. Lacal, M. A. Gallo and A. Espinosa
Affiliation:
Keywords: choline kinase inhibitors, antitumour drugs, bisquaternary heterocyclic compounds, hammett parameters, lipophilicity, qsar, frontier orbitals
Abstract: This review presents an overview of Choline Kinase (ChoK) inhibitors with antiproliferative activity. The consideration of ChoK as a novel target for the development of new anticancer drugs is justified. The synthesis of several derivatives based on structural modifications of hemicholinium-3 (HC-3) is not accompanied by potentiation of the neurological toxicity of HC-3. The increment of both ChoK inhibitory and antiproliferative activities was successfully obtained by the two following changes: a) substitution of the oxazonium moiety of HC-3 by several aromatic heterocycles, and b) using the 1,2-ethylene(bisbenzyl) moiety instead of the 4,4-biphenyl fragment. In an attempt to understand the ChoK inhibitory activity, a quantitative structure-activity relationship was developed. The QSAR equations have described the forces involved in quantitative terms. The electron characteristic of the substituent at position 4 of the heterocycle and the lipophilic character of the whole molecule were found to significantly affect the antitumour activity in compounds 17-95. Trispyridinium compounds 91-95 are more potent than the bispyridinium ones 87-89 as ChoK inhibitors. Nevertheless, 91-95 are less active than 87-89 as antiproliferative agents because the latter show better lipophilicities to cross the cytosolic membranes. Inhibition of the growth of human tumours in nude mice has been demonstrated: Antitumour activity of compound 64 against human HT-29 produced a decrease of up to 70% in the size of the tumour in nude mice. These results indicate that ChoK can be used as a general target for anticancer drug design against Ras-dependent tumourigenesis.
Export Options
About this article
Cite this article as:
Campos J., Nunez C. M., Conejo-Garcia A., Sanchez-Martin M. R., Hernandez-Alcoceba R., Rodriguez-Gonzalez A., Lacal C. J., Gallo A. M. and Espinosa A., QSAR-Derived Choline Kinase Inhibitors: How Rational can Antiproliferative Drug Design Be?, Current Medicinal Chemistry 2003; 10 (13) . https://dx.doi.org/10.2174/0929867033457539
DOI https://dx.doi.org/10.2174/0929867033457539 |
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
-
Cationic Polymer Optimization for Efficient Gene Delivery
Mini-Reviews in Medicinal Chemistry The Use of Computational Methods in the Discovery and Design of Kinase Inhibitors
Current Pharmaceutical Design Graphical Abstracts
Letters in Drug Design & Discovery Review of Estrone Sulfatase and its Inhibitors - An Important New Target Against Hormone Dependent Breast Cancer
Current Medicinal Chemistry Molecular Modeling of Cytochrome P450 and Drug Metabolism
Current Drug Metabolism Anti-IgE Monoclonal Antibody (Omalizumab) in the Treatment of Atopic Asthma and Allergic Respiratory Diseases
Current Drug Targets - Inflammation & Allergy Novel Marine and Microbial Natural Product Inhibitors of Vacuolar ATPase
Current Medicinal Chemistry Drug Repurposing: An Emerging Tool for Drug Reuse, Recycling and Discovery
Current Drug Research Reviews Meet the Editorial Board
Combinatorial Chemistry & High Throughput Screening Self Assembling Polymers as Polymersomes for Drug Delivery
Current Pharmaceutical Design Medicinal Importance, Pharmacological Activities, and Analytical Aspects of Engeletin in Medicine: Therapeutic Benefit Through Scientific Data Analysis
Endocrine, Metabolic & Immune Disorders - Drug Targets Mechanistic Aspects of Medicinal Plants and Secondary Metabolites against Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2)
Current Pharmaceutical Design Coagulation Disorders in Acute Lung Injury
Current Respiratory Medicine Reviews Recent Advances in the Design and Synthesis of c-Met Inhibitors as Anticancer Agents (2014-Present)
Current Medicinal Chemistry Meet the Editorial Board Member
Current Medicinal Chemistry Cluster Analysis of Coronavirus Sequences using Computational Sequence Descriptors: With Applications to SARS, MERS and SARS-CoV-2 (CoVID-19)
Current Computer-Aided Drug Design Guided Docking Approaches to Structure-Based Design and Screening
Current Topics in Medicinal Chemistry RNA Interference and Potential Applications
Current Topics in Medicinal Chemistry The Role of Transcription Factors in the Formation of an Arrhythmogenic Substrate in Congestive Human Heart Failure
Current Medicinal Chemistry Strategies in the Rational Drug Design
Current Medicinal Chemistry