Abstract
Bryostatin 1 represents a novel and potent therapeutic lead with a unique activity profile. Its natural and synthetic availability is severely limited. Function oriented synthesis provides a means to address this supply problem through the design of synthetically more accessible simplified structures that at the same time incorporate improved functional activity. Pharmacophore searching and a new computer aided visualization of a possible binding mode are combined with an understanding of function and knowledge of synthesis to design and prepare a new and simplified compound with bryostatin-like function in biological systems. This new compound is a potent ligand for protein kinase C in vitro (Ki = 8.0 nM). More significantly, the described molecule retains the functional ability to translocate a PKCδ-GFP fusion protein in RBL cells. The extent of protein translocation and the sub-cellular localization induced by this new compound is similar to that seen in response to bryostatin 1, indicating that the new molecule retains the functional activity of the natural product but is simpler and can be synthesized in a practical fashion.
Keywords: Bryostatin, Pharmacophore, RBL cells
Current Drug Discovery Technologies
Title: Function Oriented Synthesis: The Design, Synthesis, PKC Binding and Translocation Activity of a New Bryostatin Analog
Volume: 1 Issue: 1
Author(s): Paul A. Wender, Jeremy L. Baryza, Stacey E. Brenner, Michael O. Clarke, Madeleine L. Craske, Joshua C. Horan and Tobias Meyer
Affiliation:
Keywords: Bryostatin, Pharmacophore, RBL cells
Abstract: Bryostatin 1 represents a novel and potent therapeutic lead with a unique activity profile. Its natural and synthetic availability is severely limited. Function oriented synthesis provides a means to address this supply problem through the design of synthetically more accessible simplified structures that at the same time incorporate improved functional activity. Pharmacophore searching and a new computer aided visualization of a possible binding mode are combined with an understanding of function and knowledge of synthesis to design and prepare a new and simplified compound with bryostatin-like function in biological systems. This new compound is a potent ligand for protein kinase C in vitro (Ki = 8.0 nM). More significantly, the described molecule retains the functional ability to translocate a PKCδ-GFP fusion protein in RBL cells. The extent of protein translocation and the sub-cellular localization induced by this new compound is similar to that seen in response to bryostatin 1, indicating that the new molecule retains the functional activity of the natural product but is simpler and can be synthesized in a practical fashion.
Export Options
About this article
Cite this article as:
Wender A. Paul, Baryza L. Jeremy, Brenner E. Stacey, Clarke O. Michael, Craske L. Madeleine, Horan C. Joshua and Meyer Tobias, Function Oriented Synthesis: The Design, Synthesis, PKC Binding and Translocation Activity of a New Bryostatin Analog, Current Drug Discovery Technologies 2004; 1 (1) . https://dx.doi.org/10.2174/1570163043484888
DOI https://dx.doi.org/10.2174/1570163043484888 |
Print ISSN 1570-1638 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-6220 |
- 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
-
Silver Based Materials for Biomedical Applications
Current Organic Chemistry Application of Nanotechnology in Miniaturized Systems and its Use for Advanced Analytics and Diagnostics – an Updated Review
Recent Patents on Food, Nutrition & Agriculture Established and In-trial GPCR Families in Clinical Trials: A Review for Target Selection
Current Drug Targets Interactions Between Proteins and Platinum-Containing Anti-Cancer Drugs
Mini-Reviews in Medicinal Chemistry Meta Analysis of Advanced Cancer Survival Data Using Lognormal Parametric Fitting: A Statistical Method to Identify Effective Treatment Protocols
Current Pharmaceutical Design Simultaneous Separation, Quantitation, and Determination of the Dissociation Constant of Five Components of Ixeris sonchifolia by Microemulsion Electrokinetic Chromatography
Current Pharmaceutical Analysis Protein Bioinformatics Applied to Virology
Current Protein & Peptide Science Pollutants in Organic Chemistry and Medicinal Chemistry Education Laboratory. Experimental and Machine Learning Studies
Current Topics in Medicinal Chemistry From Amino Acids to Proteins as Targets for Metal-based Drugs
Current Drug Metabolism Prodrug Strategy for Enhancing Drug Delivery via Skin
Current Drug Discovery Technologies Unfolding During Urea Denaturation of a Low Molecular Weight Phytocystatin (Thiol Protease Inhibitor) Purified from Phaseolus mungo (Urd)
Protein & Peptide Letters Review of Noscapine and its Analogues as Potential Anti-Cancer Drugs
Mini-Reviews in Organic Chemistry Molecular Recognition Mechanisms for Detecting Cell Death In Vivo
Current Pharmaceutical Biotechnology Aptamers: Potential Applications to Pancreatic Cancer Therapy
Anti-Cancer Agents in Medicinal Chemistry Lipoprotein (a) Evolution: Possible Benefits and Harm. Genetic and Non-Genetic Factors Influencing its Plasma Levels
Current Medicinal Chemistry Vitamin D Insufficiency and Diabetes Risks
Current Drug Targets Polyphenols Can Inhibit Furin In Vitro As A Result of the Reactivity of their Auto-oxidation Products to Proteins
Current Medicinal Chemistry The Role of Anti-LeY Antibody in the Downregulation of MAPKs/COX-2 Pathway in Gastric Cancer
Current Drug Targets Chondroitin Sulfate and Glucosamine as Disease Modifying Anti- Osteoarthritis Dru gs (DMOADs)
Current Medicinal Chemistry Meet Our Editorial Board Member:
Reviews on Recent Clinical Trials