Design and development of a synthetic process for the preparation of new analogues of Imatinib as inhibitors of protein kinases for the treatment of neoplasms (Doctoral thesis)
Protein kinases are enzymes that catalyze the transfer of the γ-phosphate group of ATP onto a substrate, mediate most signal transductions, and regulate various cellular activities, including proliferation, survival, apoptosis, metabolism, transcription, differentiation, and a wide array of other cellular processes. Accumulating pharmacological and pathological evidence has revealed that kinases are promising drug targets for the treatment of numerous diseases such as cancers. In the search for low-molecular weight therapeutic agents to treat cancers and other diseases, protein kinases have become attractive targets. Imatinib, a clinically important ATP analogue inhibitor that targets the tyrosine kinase domain of the intracellular Abl-Bcr, has revolutionized the treatment of chronic myeloid leukaemia, which is caused by the oncogene Bcr–Abl. As a leading kinase inhibitor, imatinib also provides an excellent model system to investigate how changes in drug design impact biological activity. In the present PhD thesis we describe the design, synthesis, and biological evaluation of a new series of phenylaminopyrimidines, structurally related to imatinib with modifications such as: a) lack of the N-methylpiperazine group, b) repositioning of the amide function at the phenyl ring and the incorporation of different groups at the final phenyl ring, c). replacement of the amide bond with the urea moiety and incorporation of different groups at the final phenyl ring. Another objective of the present PhD thesis was to provide an improved process for the preparation of the imatinib analogues, overcoming the difficulties of the synthetic process described in patents of the Novartis Company. By our synthetic method the inhibitors were isolated much easier and also obtained in higher yields compared to the Novartis synthetic method. All the 22 new inhibitors described herein were fully characterized by IR, 1H NMR, 13C NMR spectroscopy, as well as by high resolution mass spectrometry. The new compounds provide a platform for further drug development against the therapeutically important receptor family PDGF, and they also provide insight into alternative ways of engineering drugs with altered biological activity.
|Institution and School/Department of submitter:||Πανεπιστήμιο Ιωαννίνων. Σχολή Θετικών Επιστημών. Τμήμα Χημείας|
|Subject classification:||Πρωτεϊνικές κινάσες|
|Keywords:||Πρωτεϊνικές κινάσες,Καρκίνος,Χρόνια Μυελογενή Λευχαιμία,Ιματινίβη,Aναστολείς πρωτεϊνικών κνασών,Θεραπευτική στρατηγική,Protein kinases,Cancer,Chronic Myelogenous Leukemia,Imatinib,Protein kinase inhibitor,Therapeutic strategy|
|Appears in Collections:||Διδακτορικές Διατριβές|
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|Δ.Δ. ΓΙΑΝΝΟΥΣΗ ΑΙΜΙΛΙΑ 2018.pdf||12.67 MB||Adobe PDF||View/Open|
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