Abstract
Sulfamated 2-ethylestra compounds have demonstrated strong anticancer activity, high bioavailability and an ability to bypass liver metabolism by reversibly binding carbonic anhydrase (CA) II in erythrocytes. Another CA isoform, CA IX, is overexpressed in many cancers. The CA domain of CA IX is oriented extracellularly, which may permit targeting inhibitors to tumors. Presented here is the characterization of three 2-ethylestra compounds bound to both CA II and a CA IX mimic protein. Inhibition by 18O exchange showed that compound 16 demonstrated an approximately 12-fold higher affinity for CA II over CA IX mimic. Structurally, compounds 15 and 16 showed alternate binding modes between CA II and CA IX mimic, apparently due to a water-mediated hydrogen bond to the isozyme-specific residue 67. Though the specificity was demonstrated for CA II over CA IX, this study reveals insights that may be key to developing isozyme specific CA inhibitors for novel anticancer therapies.
Keywords: Carbonic anhydrase, Isozyme specific, Structure based drug design, 2-Ethylestra compounds, Anti-cancer therapy, Steroid sulfatase inhibitors, Sulfamated 2-ethylestra compounds, erythrocytes, liver metabolism, estrogen, colchicine binding site, apoptosis, anti-angiogenic, PISA server, CA isoforms, cancer
Letters in Drug Design & Discovery
Title: Characterization of Carbonic Anhydrase Isozyme Specific Inhibition by Sulfamated 2-Ethylestra Compounds
Volume: 8 Issue: 8
Author(s): Katherine H. Sippel, Andre Stander, Chingkuang Tu, Balasubramanian Venkatakrishnan, Arthur H. Robbins, Mavis Agbandje-McKenna, Fourie Joubert, Annie M. Joubert and Robert McKenna
Affiliation:
Keywords: Carbonic anhydrase, Isozyme specific, Structure based drug design, 2-Ethylestra compounds, Anti-cancer therapy, Steroid sulfatase inhibitors, Sulfamated 2-ethylestra compounds, erythrocytes, liver metabolism, estrogen, colchicine binding site, apoptosis, anti-angiogenic, PISA server, CA isoforms, cancer
Abstract: Sulfamated 2-ethylestra compounds have demonstrated strong anticancer activity, high bioavailability and an ability to bypass liver metabolism by reversibly binding carbonic anhydrase (CA) II in erythrocytes. Another CA isoform, CA IX, is overexpressed in many cancers. The CA domain of CA IX is oriented extracellularly, which may permit targeting inhibitors to tumors. Presented here is the characterization of three 2-ethylestra compounds bound to both CA II and a CA IX mimic protein. Inhibition by 18O exchange showed that compound 16 demonstrated an approximately 12-fold higher affinity for CA II over CA IX mimic. Structurally, compounds 15 and 16 showed alternate binding modes between CA II and CA IX mimic, apparently due to a water-mediated hydrogen bond to the isozyme-specific residue 67. Though the specificity was demonstrated for CA II over CA IX, this study reveals insights that may be key to developing isozyme specific CA inhibitors for novel anticancer therapies.
Export Options
About this article
Cite this article as:
H. Sippel Katherine, Stander Andre, Tu Chingkuang, Venkatakrishnan Balasubramanian, H. Robbins Arthur, Agbandje-McKenna Mavis, Joubert Fourie, M. Joubert Annie and McKenna Robert, Characterization of Carbonic Anhydrase Isozyme Specific Inhibition by Sulfamated 2-Ethylestra Compounds, Letters in Drug Design & Discovery 2011; 8 (8) . https://dx.doi.org/10.2174/157018011796576105
DOI https://dx.doi.org/10.2174/157018011796576105 |
Print ISSN 1570-1808 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-628X |
- 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
-
NAD Precursors, Mitochondria Targeting Compounds and ADP-Ribosylation
Inhibitors in Treatment of Inflammatory Diseases and
Cancer
Current Medicinal Chemistry Review and Research on Feature Selection Methods from NMR Data in Biological Fluids. Presentation of an Original Ensemble Method Applied to Atherosclerosis Field
Current Drug Metabolism Effects of the Novel Non-Peptidyl Low Molecular Weight Radical Scavenger IAC in Different Models of Inflammation: A New Perspective in Anti-Inflammatory Therapy
Current Medicinal Chemistry Carotenoids as Modulators of Intracellular Signaling Pathways
Current Signal Transduction Therapy Alpha9Alpha10 Nicotinic Acetylcholine Receptors as Target for the Treatment of Chronic Pain
Current Pharmaceutical Design Targeting the Akt Kinase to Modulate Survival, Invasiveness and Drug Resistance of Cancer Cells
Current Medicinal Chemistry Nanoparticles in Melanoma
Current Medicinal Chemistry Discovery of Hedgehog Antagonists for Cancer Therapy
Current Medicinal Chemistry Parallel Solid-Phase Synthesis using a New Diethylsilylacetylenic Linker and Leading to Mestranol Derivatives with Potent Antiproliferative Activities on Multiple Cancer Cell Lines
Anti-Cancer Agents in Medicinal Chemistry Inhibitors of Fatty Acid Amide Hydrolase and Monoacylglycerol Lipase: New Targets for Future Antidepressants
Current Neuropharmacology Metabolomics
Current Drug Metabolism Green Tea Catechins: Proposed Mechanisms of Action in Breast Cancer Focusing on the Interplay Between Survival and Apoptosis
Anti-Cancer Agents in Medicinal Chemistry Influence of Aldo-keto Reductase 1C3 in Prostate Cancer - A Mini Review
Current Cancer Drug Targets Relationship Between Metal Transcription Factor-1 and Zinc in Resistance to Metals Producing Free Radicals
Current Chemical Biology Design, Synthesis, and Evaluation of Heat Shock Protein 90 Inhibitors in Human Breast Cancer and Its Metastasis
Current Pharmaceutical Biotechnology Absorption, Pharmacokinetics and Disposition of Biodegradable Nanoscale Preparations
Current Drug Metabolism Tumor Markers: The Potential of “Omics” Approach
Current Molecular Medicine Cardioprotective Effects of Natural Products <i>via</i> the Nrf2 Signaling Pathway
Current Vascular Pharmacology Recent Advances in Radiation Therapy of Cancer Cells: A Step towards an Experimental and Systems Biology Framework
Current Radiopharmaceuticals The Chemosensitizing Role of Metformin in Anti-Cancer Therapy
Anti-Cancer Agents in Medicinal Chemistry