Abstract
Background: One of the most studied anti-cancer compounds of the last several decades is the microtubule targeting agent and cis-stilbene, combretastatin A4 (CA4). Despite promising results at the pre-clinical level, future clinical use of CA4 as a monotherapy is in question due to metabolic vulnerability and conformational instability.
Objective: Thus, medicinal chemists have focused on synthesizing derivatives with improved pharmokinetic profile. One common strategy has been the incorporation of the ethylene linker into a ring system, thus preventing the isomerization of CA4 into the virtually inactive trans-isomer. Although many structurally stable and potent analogues of CA4 have been designed and synthesized, several analogues have been discovered to possess anti-proliferative properties seemingly independent of microtubule targeting. The presence of such analogues suggests that CA4 may also possess nonmicrotubule targets, which reveals the necessity for future structure activity relationship studies and optimization of any non-microtubule targeting. Furthermore, analogues of CA4 not inhibiting microtubule polymerization can no longer be assumed to be inactive.
Conclusion: Future clinical development of the CA4 pharmacophore requires that attention should be paid to abnormal CA4 analogues, which appear to retain cytotoxicity independent of canonical microtubule inhibition.
Keywords: Anticancer, antivascular, combretastatin A4 phosphate, combretastatin A4, microtubule targeting agent, polymerization.
Mini-Reviews in Medicinal Chemistry
Title:Review of Cytotoxic CA4 Analogues that Do Not Target Microtubules: Implications for CA4 Development
Volume: 17 Issue: 16
Author(s): Daniel Tarade, Siyaram Pandey*James McNulty
Affiliation:
- Department of Chemistry and Biochemistry, Faculty of Science, University of Windsor, Windsor,Canada
Keywords: Anticancer, antivascular, combretastatin A4 phosphate, combretastatin A4, microtubule targeting agent, polymerization.
Abstract: Background: One of the most studied anti-cancer compounds of the last several decades is the microtubule targeting agent and cis-stilbene, combretastatin A4 (CA4). Despite promising results at the pre-clinical level, future clinical use of CA4 as a monotherapy is in question due to metabolic vulnerability and conformational instability.
Objective: Thus, medicinal chemists have focused on synthesizing derivatives with improved pharmokinetic profile. One common strategy has been the incorporation of the ethylene linker into a ring system, thus preventing the isomerization of CA4 into the virtually inactive trans-isomer. Although many structurally stable and potent analogues of CA4 have been designed and synthesized, several analogues have been discovered to possess anti-proliferative properties seemingly independent of microtubule targeting. The presence of such analogues suggests that CA4 may also possess nonmicrotubule targets, which reveals the necessity for future structure activity relationship studies and optimization of any non-microtubule targeting. Furthermore, analogues of CA4 not inhibiting microtubule polymerization can no longer be assumed to be inactive.
Conclusion: Future clinical development of the CA4 pharmacophore requires that attention should be paid to abnormal CA4 analogues, which appear to retain cytotoxicity independent of canonical microtubule inhibition.
Export Options
About this article
Cite this article as:
Tarade Daniel , Pandey Siyaram *, McNulty James , Review of Cytotoxic CA4 Analogues that Do Not Target Microtubules: Implications for CA4 Development, Mini-Reviews in Medicinal Chemistry 2017; 17 (16) . https://dx.doi.org/10.2174/1389557515666160509125829
DOI https://dx.doi.org/10.2174/1389557515666160509125829 |
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
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
Natural Products in Drug Discovery
Natural products have always been one of the important ways of drug discovery due to their novel skeleton and diverse functional group characteristics. According to statistics, between 1981 and 2019, the FDA approved a total of 1,394 small molecule drugs for marketing, of which 930 marketed drugs originated from the ...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
-
Detection of COVID-19 Incidentally in <sup>68</sup>Ga-PSMA PET/CT for Restaging
of Prostate Cancer
Current Medical Imaging Nitrogen Containing Privileged Structures and their Solid Phase Combinatorial Synthesis
Combinatorial Chemistry & High Throughput Screening Maximum Temperature Through a Yttrium Stabilized Zirconia Ceramic After Er,Cr:YSGG Laser Irradiation
Current Dentistry Challenges and Perspectives in the Discovery of Dengue Virus Entry Inhibitors
Current Medicinal Chemistry Demographic, Clinical and Laboratory Profiles of HIV Infected Patients Admitted into Imam Khomeini Hospital of Tehran, Iran
Infectious Disorders - Drug Targets Discovery of AX8312, an N-alkyl-Gly-boro-Pro Derivative that Accelerates Recovery from Neutropenia in the Mouse
Letters in Drug Design & Discovery Recent Advances in the Medicinal Chemistry of Sodium Channel Blockers and their Therapeutic Potential
Current Topics in Medicinal Chemistry Small Molecule Inhibitors of Human Adipocyte Fatty Acid Binding Protein (FABP4)
Medicinal Chemistry Gut Microbiota and Cardiovascular Disease: Symbiosis Versus Dysbiosis
Current Medicinal Chemistry Rhodanine as a Privileged Scaffold in Drug Discovery
Current Medicinal Chemistry Lopinavir-Loaded Self-Nanoemulsifying Drug Delivery System for Enhanced Solubility: Development, Characterisation and Caco-2 Cell Uptake
Current Drug Delivery Diverse Peptidyl Privileged Structures as Potent Somatostatin Receptor Ligands
Letters in Drug Design & Discovery Internal Ribosome Entry Site Elements in Eukaryotic Genomes
Current Genomics Heteroaromatization with 4-Phenyldiazenyl-1-naphthol. Part IV: Synthesis of Some New Heterocyclic Compounds with Potential Biological Activity
Current Organic Synthesis The Discovery of Epidepride and Its Analogs as High-Affinity Radioligands for Imaging Extrastriatal Dopamine D2 Receptors in Human Brain
Current Pharmaceutical Design The Impact of Crystallographic Data for the Development of Machine Learning Models to Predict Protein-Ligand Binding Affinity
Current Medicinal Chemistry Preventing and Treating Anthracycline-Related Cardiotoxicity in Survivors of Childhood Cancer
Current Cancer Therapy Reviews Cryopreservation of Orchids – A Review
Recent Patents on Biotechnology Design, Synthesis and Interaction at the Vesicular Monoamine Transporter-2 of Lobeline Analogs: Potential Pharmacotherapies for the Treatment of Psychostimulant Abuse
Current Topics in Medicinal Chemistry Glycogen Phosphorylase Inhibitors
Mini-Reviews in Medicinal Chemistry