The development of S-trityl L-cysteine based inhibitors of Eg5 as anticancer chemotherapeutics.

QD Chemistry;RM Therapeutics. Pharmacology

Good, James Arthur Dudley ; Kozielski, Frank

University:University of Glasgow

Department:Institute of Cancer Sciences

关键词: cancer, chemotherapy, anti-mitotic, kinesins, Eg5, S-trityl L-cysteine, drug discovery, medicinal chemistry;   

Others  :  http://theses.gla.ac.uk/3748/1/2012goodphd.pdf

来源: University of Glasgow

【 摘 要 】

The kinesins are a class of microtubule based motor proteins which have extensive involvement in the orchestration of the mechanics of mitosis. The most studied of these is the kinesin spindle protein Eg5, which is crucially involved in the establishment of the bipolar spindle in prometaphase. Inhibition of this protein results in monopolar mitotic spindles and subsequently mitotic arrest, which can lead to apoptosis in cancer cell lines.S-Trityl L-cysteine (STLC) was identified as a selective small molecule inhibitor of Eg5 which binds to an allosteric pocket formed by the loop L5 of Eg5. In this thesis, I present the structure based design and development and optimisation of the STLC scaffold to produce orally available potential drug candidates. This was accomplished by optimising the lipophilic binding interactions of the trityl group, and investigating a number of hydrophilic optimisation vectors from the same moiety. The L-cysteine tail was optimised to improve the potency and metabolic stability, and fluorination as a means of altering the lead candidates’ drug like properties investigated. In order to improve efficacy in multi-drug resistant (MDR) cell lines overexpressing the P-glycoprotein transporter, I also investigated a number of strategies related modifying to the terminal α-carboxylic acid.The optimised candidates display growth inhibition ≤ 50 nM across multiple tumour cell lines, and possess favourable metabolic, toxicological and physicochemical attributes. Evaluation in vivo confirms their anti tumour activity, and finally strategies for the further progression and development of the lead series in targeting haematological malignancies are discussed.