SYNTHESIS OF NEW PROTEIN KINASE INHIBITORS WITH POTENTIAL INFLUENCE OF eEF-2K TITLE OF THE THESIS

Diğer hastalıklara göre daha fazla ölüme neden olan kanser; geçmişten günümüze kadar gelen en önemli sağlık sorunlarındandır ve vakalarında her geçen yıl artış görülmektedir. Meme, akciğer, pankreas ve mide gibi farklı kanser türleri arasında en çok meme ve akciğer kanserleri görülmektedir. En ölümcül çeşitlerinden olan ve her yıl yaklaşık 1,2 milyona yakın kadına teşhisi konulan meme kanseri 400 bine yakın kadının yaşamını yitirme sebebidir. Bir diğer ölümcül kanser türü olan pankreas kanserinde ise; spesifik belirtilerin olmaması ve erken tanı konulamaması tedaviyi zorlaştıran nedenlerdendir. Proteinlere fosfat bağlayan enzim yapıları olan protein kinazlar; sinyal iletiminde önemli rol oynarlar. Hücreler arası ve hücre içindeki sinyal iletimi hücrenin gelişme, çoğalma, farklılaşma ve yaşamını sürdürebilmesi için oldukça önemlidir. Sinyal iletim yolaklarında yaşanan problemler başta kanser olmak üzere birçok hastalığa neden olmaktadır. eEF-2K enzimi bir protein kinaz enzimidir ve polipeptit zincirinin uzamasının düzenlenmesinde görev alır. Bu enziminin düzensiz aktivitesi meme ve pankreas kanserine sebep olmaktadır. Bu tez kapsamında eEF-2K enzimini inhibe edebilecek, yeni heterohalkalı bileşiklerin sentezlenmesi amaçlanmıştır. Sentezlenen bu maddeler; akrilamit, izoindolin, pirimidin karboksilat ve benzamit sınıfı bileşik türevlerini i?erir. Daha önce sentezi yapılmamış bu bileşiklerin yapıları; infrared spektroskopisi, 1H-NMR ve 13C-NMR spektroskopileri, HRMS spektrometresi ve erime noktası teknikleri kullanılarak aydınlatıldı.Cancer; causes more death than other diseases, is one of the most important health problems from past to present and there is an increase in cancer cases every year. Breast, lung, pancreas and stomach cancers are among the most common types of cancer. Breast cancer, one of the most deadly varieties and diagnosed with approximately 1.2 million women every year, is the cause of the death of nearly 400 thousand women. The lack of specific symptoms and early diagnosis of pancreatic cancer, another deadly cancer, are among the reasons that make treatment difficult. Protein kinases with phosphate binding enzyme structures to proteins play an important role in signal transmission. Intercellular and intracellular signal transduction are important for cell growth, proliferation, differentiation and survival. Problems in signal transduction pathways cause many diseases, especially cancer. eEF-2K is a protein kinase enzyme involved in the regulation of the elongation of the polypeptide chain. The irregular activity of this enzyme causes breast and pancreatic cancer. Within the scope of this project, it is aimed to synthesize new heterocyclic compounds that can inhibit the eEF-2K enzyme. The aim of this project is to synthesize novel heterocycle compounds which can inhibit eEF-2K enzyme. These substances to be synthesized include acrylamide, isoindoline, pyrimidine carboxylate and benzamide class compound derivatives. The structures of the novel compounds were identified by infrared spectroscopy, 1H-NMR and 13C-NMR spectroscopy, HRMS spectrometer and melting point techniques

Novel Inhibitors of Eukaryotic Elongation Factor 2 Kinase: In Silico, Synthesis, and in Vitro Studies

Eukaryotic elongation factor 2 kinase (eEF2K) is an unusual alpha kinase whose expression is highly upregulated in various cancers and contributes to tumor growth, metastasis, and progression. More importantly, expression of eEF2K is associated with poor clinical outcome and shorter patient survival triple negative breast cancer (TNBC). Therefore, eEF2K is an emerging molecular target for development of novel targeted therapeutics and precision medicine in solid cancers. However, currently potent, and specific inhibitors of eEF2K are not available for clinical translation. In the current study, we investigated the effects of various newly designed and synthesized a series of compounds with coumarin scaffold substitutions in inhibiting eEF2K activity using in silico approaches and in vitro studies in TNBC cells. We utilized an amide substitution at 3-position on the coumarin ring with their pharmacologically active groups containing pyrrolidine, piperidine, morpholine and piperazine groups with –(CH2)2– bridged for aliphatic amides. To evaluate substituent effects on coumarin scaffold, boronic acid pinacol ester and boronic acids on phenyl rings were investigated using in silico and in vitro analyses. Due to their ability to form covalent binding to the target enzyme, we investigated the effects of boron containing groups on functionalized coumarin ring (3 compounds) and designed novel aliphatic and aromatic derivatives of coumarin scaffolds (10 compounds) and phenyl ring with boron groups (4 compounds). In silico analysis and molecular docking studies were performed using the Glide/SP module of Maestro molecular modeling package. According to obtained results, structure activity relationship (SAR) was carried out. Among the newly designed, synthesized, and tested compounds, our in vitro findings revealed that several compounds displayed a highly effective eEF2K inhibition at submicromolar concentration in in vitro breast cancer cells. In conclusion, we identified novel eEF2K inhibitors as promising anticancer drug substance candidates which should be further evaluated by in vivo studies, preclinical and clinical studies.<br /