Synthesis of novel PROTEIN KINASE C C1 domain targeted compounds

Protein kinase C (PKC) belongs to the AGC family of serine/threonine kinases and plays a critical role in the regulation of various aspects of cell functions, including growth, differentiation, metabolism and apoptosis. PKC isoenzymes, as one of the main mediator to convert the extracellular stimuli into biological responses, are activated by phospholipid-derived second messengers and transmit their signal by phosphorylating specific protein substrates. Since protein kinase C is involved in a wide range of signal transduction networks, it represents an interesting and extensively studied molecular target for the treatment of several diseases, such as cancer, and Alzheimer’s disease. Prof. Jari Yli-Kauhaluoma and his team of researchers have been interested in developing simple hydrophobic isophthalic acid derivatives able to modify PKC functions by targeting the C1 domain of the enzyme. A set of small derivatives have been rationally designed and synthesized with a structure-based approach, using the crystal structure of the PKCδ C1B domain. The aims of the thesis were to design and synthesize a compound library based on the hit compound targeted to the C1 domain of PKC using sevaral alcohols, to design and synthesize the “exotic compound” based on the hit compound targeted to the C1 domain using a malonic group and an alcohol and in the end to design and synthetize compounds based on the scaffold of pyrimidine. Affinity studies are going to be performed to evaluate the ability of these new copounds to bind C1 domain and to achieve reliable knowledge on other potential target(s) than PKCs, which could be found in the cell lysate. The work was carried out in the Medicinal Chemistry group of the Division of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Helsinki (Finland).