Design and Synthesis of Esters as Protein Kinase C(PKC)-CI Domain Regulators

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The contents of my thesis have been divided into six chapters based on the results of experimental work performed during the complete course of research period. The introductory chapter (chapter 1) of the thesis presents the structure, activation and C1 domain of protein kinase C (PKC). In addition, C1 domain targeted ligands including natural products, synthetic compounds and the synthesis of biological active ester molecules using different approaches. Chapter 2 describes design, synthesis and protein binding properties of diacyltetrol (DATs) lipids. Chapter 3 illustrates development of diacyltetrol based anionic hybrid lipids as protein kinase C-C1 domain regulators. Chapter 4 presents (hydroxylmethyl)phenyl ester analogues as C1 domain regulators. In chapter 5, C1 domain targeted alkyl cinnamates synthesis is described. Chapter 6 describes Zn(OTf)2 catalyzed chemoselective esterification of carboxylic acids. Protein kinase C (PKC) family of serine/threonine kinases are the major cellular receptor for diacylglycerol (DAG)/phorbol esters. DAG depended PKC activation controls several cellular pathways by phosphorylating the target proteins. Dysregulation of these cellular pathways causes numerous diseases including cancer, diabetes, stroke, heart failure and Alzheimer disease. Therefore, PKC isoenzymes particularly in the cancer field have been a subject of intensive research and drug development. PKC isoforms can be activated by natural products such as phorbol esters, prostratin, ingenol, indolactam V, iridal, bryostatin and their derivatives. However, except bryostatin most of them act as tumor promoters, due to their higher binding affinity. In addition, synthesis and structural modifications of these natural products are laborious for the specific and selectivity among the C1 domains of PKC isoforms. Therefore, there is a clear and unmet need to design simple surrogates, whose structure can be easily modified to achieve higher specificity and selectivity among the C1 domains of the PKC isoenzymes. Most of the reported PKC-C1 domain ligands have ester subunits, as an essential pharmacophore within their complex structure. However, only few methods can be used for synthesis of bioactive esters. In this regard, we developed esters as PKC-C1 domain regulators as well as Zn(OTf)2 catalyzed selective esterification method in this thesis.
Supervisor: Debasis Manna