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Synthesis and biological evaluation of EGFR/HER-2 inhibitors: analogs of 5-substituted-4-anilinoquinazoline and 6,7-disubstituted-4-anilinoquinoline-3-carbonitrile: screening for development of novel PET tracers

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Defense Thèse de doctorat : Univ. Genève, 2014 - Sc. 4726 - 2014/08/26
Abstract The aim of this project was to synthesize new PET tracers for the imaging of the EGFR/HER-2 expressing tumors and to explore PET-assisted drug discovery approach for novel EGFR/HER-2 inhibitors. To achieve this aim, several research aspects such as design, synthesis, in vitro-in vivo biological evaluation and preliminary PET studies had to be performed. We chose two classes of commercially available anticancer compounds, 5-substitued-anilinoquinazolines (reversible inhibitors) and 6,7-disubstituted-4-anilinoquinoline-3-carbonitrile (irreversible inhibitor). Their analogs were synthesized by different synthetic routes in quantitative yields and characterized by proton NMR and MS. The final compounds were purified > 95% and used for in vitro biological evaluations. The various assays were developed and validated to analyse EGFR and HER-2 kinase inhibitory activities, autophosphorylation inhibition, and cell growth inhibition on a variety of cancer cell lines harboring different EGFR or HER-2 expression levels or mutational status. The results obtained for the two series of compounds were compared with clinical leads (Gefitinib, Erlotinib and EKB-569). The compounds 43 and 47 were found to be the most potent inhibitors among all and compounds 9, 42 and 43 were selected as potential PET tracers. After selection of leads for radiochemistry, the conditions were set up for the different steps involved in the radiochemical synthesis of 18F-labelled radiotracers. The method developed needs further optimization for production of [18F]-9 to maximize the radiochemical yield. Modifications are also required to minimize synthesis time as less as possible. Also, radiochemistry for rest of the compounds remains to be explored. We also intend to use the PET nuclear modality for the therapeutic efficacy analysis of potent promising compounds such as compound 43 and 47.
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URN: urn:nbn:ch:unige-458723
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PIMPLE, Surekha. Synthesis and biological evaluation of EGFR/HER-2 inhibitors: analogs of 5-substituted-4-anilinoquinazoline and 6,7-disubstituted-4-anilinoquinoline-3-carbonitrile: screening for development of novel PET tracers. Université de Genève. Thèse, 2014. https://archive-ouverte.unige.ch/unige:45872

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Deposited on : 2015-01-26

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