Synthesis of diacyl glycerol lactone-based bryostatin analogs: progress towards a simplified binding domain that retains the biological properties of the natural product

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Title Synthesis of diacyl glycerol lactone-based bryostatin analogs: progress towards a simplified binding domain that retains the biological properties of the natural product
Publication Type dissertation
School or College College of Science
Department Chemistry
Author Baumann, David Owen
Date 2016
Description Bryostatin 1 is a large macrocyclic polyketide natural product that was isolated from the marine bryozoan Bugula neritina. Bryostatin was found to have many interesting biological properties stemming from its extremely high affinity for protein kinase C (PKC) isozymes. Bryostatin 1 has attracted increased attention due to its anticancer and immune system stimulating properties. In recent years, bryostatin 1 has been found to have properties that may lead to effective treatments for Alzheimer’s disease and HIV. Several high affinity PKC ligands are potent tumor promoters; however, bryostatin 1 does not display any of these properties and even antagonizes the effects of phorbol esters, which are potent tumor promoters. Due to the continued interest in bryostatin 1, attention has been focused on the synthesis of simplified analogs in order to study structure-function relationships. Most of this work has focused on the synthesis of analogs with simplified AB top-halfs, while very little attention has been applied towards the synthesis of analogs with simplified C-ring binding domains. Extensive work has been conducted on the synthesis of diacylglycerol (DAG) lactone analogs, which are simple high affinity PKC ligands. The focus of this work involves the substitution of a DAG lactone for the C-ring in a bryostatin analog, resulting in the synthesis of 3 bryostatin analogs. Biological evaluation indicates that significant binding affinity in the first analog was lost as compared to the natural product even though all structural elements were present that are thought to be required for good affinity. Molecular modeling studies indicate that the planer conformation of the top-half of the natural product was lost in these new analogs, resulting in a conformation unfavorable for effective binding. The binding domain orientation of the analog was reversed, resulting in a slight increase in affinity, but at the cost of lower stability under biological conditions, due to the diester linkage used to assemble the first two analogs. Building upon these results, a third-generation analog with increased lipophilicity and lacking the diester linker was synthesized. The third-generation analog had a much higher affinity for PKC as well as an improved biological profile as compared to the first 2 analogs.
Type Text
Publisher University of Utah
Subject Bryostatins; Diacylglycerol Lactones; Medicinal Chemistry; Organic Synthesis; PKC Activators
Dissertation Name Doctor of Philosophy
Language eng
Rights Management ¬©David Owen Baumann
Format application/pdf
Format Medium application/pdf
ARK ark:/87278/s6hm9d8b
Setname ir_etd
ID 1341636
Reference URL https://collections.lib.utah.edu/ark:/87278/s6hm9d8b
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