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Design and synthesis of inhibitors of critical target proteins implicated in cellular proliferation

Carpenter, Nicholas 2005. Design and synthesis of inhibitors of critical target proteins implicated in cellular proliferation. PhD Thesis, Cardiff University.

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Cyclin-Dependent Kinases (CDKs) are a family of protein kinases that control progression through the eukaryotic cell cycle. CDKs become activated when they form a complex with the appropriate cyclin protein, and are fully activated by phosphorylation. CDK inhibitors regulate the activity of CDK/cyclin complexes through competitive inhibition with ATP for the active site. This inhibition prevents the CDK/cyclin complex phosphorylating its substrates and cell cycle progression stops. Alterations in CDK control through cyclin overexpression, CDK inhibitor underexpression or CDK mutation are responsible for tumour development Therefore CDK inhibition has become a novel therapeutic approach to cancer treatment. Hymenialdisine and Kenpaullone have recently been identified as potent CDK inhibitors. The crystal structures of these two compounds as inhibitors of CDK2 show that Kenpaullone can form two hydrogen bonds to residue Leu83, while Hymenialdisine forms these two hydrogen bonds and a third to Glu81. These hydrogen bonds have been shown to be significant towards their potency, and are formed from the azepinone fused to a heterocycle feature of both structures. The aim of this thesis is to explore the structure activity relationship associated with the novel azepinone motif of the two CDK inhibitors Kenpaullone and Hymenialdisine via analogues of the lead structure 3,4-d%ydoazepino 3,4-indole-l,5(2//,10//)-dione, trivially named indoloazepinone. These analogues focus on alterations to the hydrogen bonding pattern, the size of the azepinone ring, extensions from the ketone functional group and bromination at the 7-posititon. The compounds synthesized in the study were assayed against MCF-7 breast cancer and A549 non small cell lung cancer (NSCLC) cell lines showing good growth inhibition. An accumulation of proliferating cancer cells in the GQ/Gl stage was demonstrated for a selected compound. Further assays against CDK2/cyclin A showed generally moderate inhibition, with good inhibition for one compound, while assays against CDK2 showed no inhibition.

Item Type: Thesis (PhD)
Status: Unpublished
Schools: Pharmacy
Subjects: R Medicine > RM Therapeutics. Pharmacology
ISBN: 9781303181658
Date of First Compliant Deposit: 30 March 2016
Last Modified: 10 Oct 2017 15:28

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