Abstract
Epothilones A and B are naturally occurring microtubule-stabilizers, which inhibit the growth of human cancer cells in vitro at nM or even sub-nM concentrations. In contrast to paclitaxel (Taxol®) epothilones are also active against different types of multidrug-resistant cancer cell lines in vitro and against multidrug-resistant tumors in vivo (epothilone B). Their attractive preclinical profile has made epothilones important lead structures in the search for improved cytotoxic anticancer drugs and epothilone B is currently undergoing phase II clinical trials. Numerous synthetic and semi-synthetic analogs have been prepared since the absolute stereochemistry of epothilone B was first disclosed in mid-1996 and their in vitro biological activity has been determined. Apart from generating a wealth of SAR information, these efforts have led to the identification of at least four compounds (in addition to epothilone B), which are currently at various stages of clinical evaluation in humans. This review is first intended to provide a summary of the basic features of the in vitro biological profile of epothilone B, with particular emphasis on recent developments in this area. A second part will outline the most relevant aspects of the epothilone SAR with regard to effects on tubulin polymerization, in vitro antiproliferative activity, and in vivo antitumor activity. This will include a brief discussion of research directed at the determination of the bioactive conformation of epothilones. In a final section, the preclinical profile of those epothilone analogs currently in clinical development will be discussed in greater detail.
Keywords: epothilone, microtubule stabilizer, anticancer, drug discovery, structure-activity relationship, natural products, antiproliferative, medicinal chemistry
Current Pharmaceutical Design
Title: Recent Developments in the Chemical Biology of Epothilones
Volume: 11 Issue: 13
Author(s): Karl Heinz Altmann
Affiliation:
Keywords: epothilone, microtubule stabilizer, anticancer, drug discovery, structure-activity relationship, natural products, antiproliferative, medicinal chemistry
Abstract: Epothilones A and B are naturally occurring microtubule-stabilizers, which inhibit the growth of human cancer cells in vitro at nM or even sub-nM concentrations. In contrast to paclitaxel (Taxol®) epothilones are also active against different types of multidrug-resistant cancer cell lines in vitro and against multidrug-resistant tumors in vivo (epothilone B). Their attractive preclinical profile has made epothilones important lead structures in the search for improved cytotoxic anticancer drugs and epothilone B is currently undergoing phase II clinical trials. Numerous synthetic and semi-synthetic analogs have been prepared since the absolute stereochemistry of epothilone B was first disclosed in mid-1996 and their in vitro biological activity has been determined. Apart from generating a wealth of SAR information, these efforts have led to the identification of at least four compounds (in addition to epothilone B), which are currently at various stages of clinical evaluation in humans. This review is first intended to provide a summary of the basic features of the in vitro biological profile of epothilone B, with particular emphasis on recent developments in this area. A second part will outline the most relevant aspects of the epothilone SAR with regard to effects on tubulin polymerization, in vitro antiproliferative activity, and in vivo antitumor activity. This will include a brief discussion of research directed at the determination of the bioactive conformation of epothilones. In a final section, the preclinical profile of those epothilone analogs currently in clinical development will be discussed in greater detail.
Export Options
About this article
Cite this article as:
Altmann Heinz Karl, Recent Developments in the Chemical Biology of Epothilones, Current Pharmaceutical Design 2005; 11 (13) . https://dx.doi.org/10.2174/1381612053764715
DOI https://dx.doi.org/10.2174/1381612053764715 |
Print ISSN 1381-6128 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-4286 |
Call for Papers in Thematic Issues
"Tuberculosis Prevention, Diagnosis and Drug Discovery"
The Nobel Prize-winning discoveries of Mycobacterium tuberculosis and streptomycin have enabled an appropriate diagnosis and an effective treatment of tuberculosis (TB). Since then, many newer diagnosis methods and drugs have been saving millions of lives. Despite advances in the past, TB is still a leading cause of infectious disease mortality ...read more
Current Pharmaceutical challenges in the treatment and diagnosis of neurological dysfunctions
Neurological dysfunctions (MND, ALS, MS, PD, AD, HD, ALS, Autism, OCD etc..) present significant challenges in both diagnosis and treatment, often necessitating innovative approaches and therapeutic interventions. This thematic issue aims to explore the current pharmaceutical landscape surrounding neurological disorders, shedding light on the challenges faced by researchers, clinicians, and ...read more
Emerging and re-emerging diseases
Faced with a possible endemic situation of COVID-19, the world has experienced two important phenomena, the emergence of new infectious diseases and/or the resurgence of previously eradicated infectious diseases. Furthermore, the geographic distribution of such diseases has also undergone changes. This context, in turn, may have a strong relationship with ...read more
Melanoma and Non-Melanoma Skin Cancer Treatment: Standard of Care and Recent Advances
In this thematic issue, we aim to provide a standard of care of the diagnosis and treatment of melanoma and non-melanoma skin cancer. The editor will invite authors from different countries who will write review articles of melanoma and non-melanoma skin cancers. The Diagnosis, Staging, Surgical Treatment, Non-Surgical Treatment all ...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
-
Toward a Discipline of Pharmacoepigenomics
Current Pharmacogenomics Insight γ-Secretase: Structure, Function, and Role in Alzheimer’s Disease
Current Drug Targets Iron Chelators: Development of Novel Compounds with High and Selective Anti-Tumour Activity
Current Drug Delivery Cancer Molecular Imaging: Radionuclide-Based Biomarkers of the Epidermal Growth Factor Receptor (EGFR)
Current Topics in Medicinal Chemistry Recently Patented Applications of Homologous Cellular and Extracellular Agents as Therapeutics or Targets for the Prevention of Restenosis Post- Angioplasty
Recent Patents on Cardiovascular Drug Discovery Diffuse Intrinsic Pontine Glioma (DIPG): Breakthrough and Clinical Perspective
Current Medicinal Chemistry Design, Synthesis, Computational and Biological Evaluation of Two New Series of 1, 3- and 1,6-dihydroxy Xanthone Derivatives as Selective COX-2 Inhibitors
Letters in Drug Design & Discovery Inhibitory Effect of Ebselen on Cerebral Acetylcholinesterase Activity In Vitro: Kinetics and Reversibility of Inhibition
Current Pharmaceutical Design Emerging Roles of microRNAs in Neural Stem Cells
Current Stem Cell Research & Therapy Topoisomerases and Tubulin Inhibitors: A Promising Combination for Cancer Treatment
Current Medicinal Chemistry - Anti-Cancer Agents Pioglitazone Prevents Smoking Carcinogen-Induced Lung Tumor Development in Mice
Current Cancer Drug Targets Molecular Biology of Nucleoside Transporters and their Distributions and Functions in the Brain
Current Topics in Medicinal Chemistry Assessment In Vitro of a Novel Therapeutic Strategy for Glioma, Combining Herpes Simplex Virus HSV1716-mediated Oncolysis with Gene Transfer and Targeted Radiotherapy
Medicinal Chemistry Targeting SKCa Channels in Cancer: Potential New Therapeutic Approaches
Current Medicinal Chemistry Radiolabeled Compounds in the Development of Cytotoxic Agents
Current Pharmaceutical Design RAGE: A Multi-Ligand Receptor Unveiling Novel Insights in Health and Disease
Current Medicinal Chemistry Improvement of Nonviral Gene Therapy by Epstein-Barr Virus (EBV)-based Plasmid Vectors
Current Gene Therapy Genetic Risk Factors in Cerebrovascular Disorders and Cognitive Deterioration
Current Genomics Cancer Stem Cells in Pediatric Brain Tumors
Current Stem Cell Research & Therapy Pharmacology of Rhein and Advancement in the Synthesis of Its Derivatives
Current Traditional Medicine