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
-
Paris polyphylla: Chemical and Biological Prospectives
Anti-Cancer Agents in Medicinal Chemistry Tracking Stem Cell Therapy in the Myocardium: Applications of Positron Emission Tomography
Current Pharmaceutical Design Structure Conversion and Structure Separation of G-Quadruplexes Investigated by Carbazole Derivatives
Current Pharmaceutical Design Development of Vitamin D Analogs Modulating the Pocket Structure of Vitamin D Receptor
Current Topics in Medicinal Chemistry Extraction Methods for Obtaining Carotenoids from Vegetables - Review
Current Analytical Chemistry 1,4-Diazabicyclo[2.2.2]octanium Diacetate under Grinding: Efficient and Eco-Friendly Process for the Synthesis of Symmetric, Unsymmetric and New Bis di(indolyl)indolin-2-one
Letters in Organic Chemistry Synthesis and Antioxidant Activity of 1,2,4-Triazole linked Thieno[2,3- d]pyrimidine Derivatives
Letters in Drug Design & Discovery QSAR Study on a Series of Aryl Carboxylic Acid Amide Derivatives as Potential Inhibitors of Dihydroorotate Dehydrogenase (DHODH)
Medicinal Chemistry Green Synthesis of Silver Nanoparticle using Sechium edule Aqueous Extract and Study of Antimicrobial and Catalytic Activity
Current Nanomaterials Natural Naphthoquinones with Great Importance in Medicinal Chemistry
Current Organic Synthesis Polyisoprenylation Potentiates the Inhibition of Polyisoprenylated Methylated Protein Methyl Esterase and the Cell Degenerative Effects of Sulfonyl Fluorides
Current Cancer Drug Targets MicroRNAs in Cancer: Small Molecules, Big Chances
Anti-Cancer Agents in Medicinal Chemistry Novel 4- Aryl-2(1H)-phthalazinone Derivatives as Cyclooxygenase-2 Inhibitors: Synthesis, Molecular Modeling Study and Evaluation as Promising Anti-inflammatory Agents
Anti-Inflammatory & Anti-Allergy Agents in Medicinal Chemistry iPGK-PseAAC: Identify Lysine Phosphoglycerylation Sites in Proteins by Incorporating Four Different Tiers of Amino Acid Pairwise Coupling Information into the General PseAAC
Medicinal Chemistry Deep Neck Infections: Decisional Algorithm for Patients with Multiple Spaces Involvement
Reviews on Recent Clinical Trials Somatic Genomic Variations in Extra-Embryonic Tissues
Current Genomics Chemically Modified Nano Crystalline Diamond Layer as Material Enhanced Laser Desorption Ionisation (MELDI) Surface in Protein Profiling
Current Nanoscience The Importance of Bioactivation in Computer-Guided Drug Repositioning. Why the Parent Drug is Not Always Enough
Current Topics in Medicinal Chemistry Recent Developments of Melatonin Related Antioxidant Compounds
Combinatorial Chemistry & High Throughput Screening Synthesis and Pharmacological Evaluation of Maleopimaric N-arylimides: Identification of Novel Proapoptotic Agents
Anti-Cancer Agents in Medicinal Chemistry