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Title: Structure-activity relationships for alkoxypirimidine inhibitors of cyclin-dependent kinases (CDK’s)
Author: Marchetti, Francesco
ISNI:       0000 0004 2720 4847
Awarding Body: University of Newcastle Upon Tyne
Current Institution: University of Newcastle upon Tyne
Date of Award: 2009
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Cyclin-dependent kinases (CDKs) are a family of serine/threonine protein kinases that play a fundamental role in the regulation of eukaryotic cell-cycle progression, particularly at cell- cycle checkpoints. Cell-cycle alterations result in a loss of checkpoint function, which correlates with increased or aberrant CDK activity in human tumours. CDK inhibitors are therefore recognised to have potential therapeutic effects in the treatment of cancer and other proliferative diseases. This research project centres on the medicinal chemistry of a new class of CDK inhibitors, based on the 2,6-diamino-4-alkoxy- 5-nitrosopyrimidine pharmacophore (77). Previous studies, employing a structure-based inhibitor design approach, have resulted in the identification of 2-arylamino-06- alkylguanines exhibiting potent inhibitory activity against CDK2, and exemplified by NU6102 (31; IC50 = 5 nM). Structure-activity relationship studies revealed that the purine pharmacophore is not a prerequisite for CDK-inhibitory activity. Thus, comparable activity resides in the corresponding pyrimidines, where an intramolecular hydrogen bond between a 5-nitroso substituent and a 6-amino group confers a 'purine-mimetic' structure (164; CDK2/A, IC50 = 1 nM). Guided by results obtained previously for the corresponding 06-alkylguanines, systematic structural modifications have been made at the pyrimidine 2-, 4- and 5- positions, via the development and optimisation of efficient synthetic pathways Replacement of the 5-nitroso substituent of the parent inhibitors (77, 164) by groups that are more acceptable from a toxicological standpoint has been a prominent target of this work. Formyl, ketone and oxime functionalities have been successfully introduced at the pyrimidine 5-position, while different alkoxy and arylamino substituents were introduced at the pyrimidine 4-position and 2-position, respectively, to probe additional potential interactions within the ATP ribose-binding domain and CDK2 specificity pocket. The synthesis and structure-activity relationships for this new series of CDK inhibitors have been investigated, as exemplified by (220) (CDK2/A, IC50 = 49 nM), (239) (CDK2/A, IC50 = 7.4 nM) and (109) (CDK2/A, IC50 = 23.3 μM). These studies have resulted in the identification of novel compounds, such as (225), exhibiting improved potency against CDKs, with sub-nanomolar inhibitory activity versus CDK2/A (IC5o = 0.77 nM) and good cell growth inhibition properties (G150 = 0.57 μM).
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available