Design, Synthesis and Evaluation of FPR-1 Antagonists in the Treatment of Glioma

High expression of FPR-1 and its ligands are known to contribute to glioblastoma development. It was hypothesised that antagonists that inhibit FPR-1 may effectively treat glioblastoma. The previously synthesised antagonist, ICT12035, was potent but only exhibited a moderate ability to penetrate the BBB. Therefore, this project aimed to design and synthesise new antagonists with better lipophilicity whilst maintaining potency based on the structure of ICT12035. Apart from ICT13376 (3) being synthesised from ICT13362 (1), all novel antagonists were synthesised following a similar synthetic route. FPR-1 expression was confirmed in a panel of cell lines using flow cytometry, and these lines were then utilised to assess potency and the ability to inhibit cell migration for the antagonists using calcium flux assays and scratch assays, respectively. MTT assays confirmed that the antagonists would be non-toxic to cells. Most novel antagonists showed improved lipophilicity, but none showed higher potency or migratory inhibition than ICT12035. From studying the SAR of the novel series, it could be concluded that introducing an H-bond acceptor at the para-position of the cyclohexane ring is desirable in enhancing the lipophilicity and potency of antagonists. It is also important to avoid introducing any groups to the paraposition of the benzenesulfonyl group that would generate an inductive effect to weaken the molecular binding with surrounding residues. Additionally, introducing bulky groups should be avoided due to the spatial constraints of the binding pocket. Thus, this should be the template for further studies on improving the anticancer potency of this series of compounds.

URI

https://bradscholars.brad.ac.uk/handle/10454/20830

Type

Thesis

Qualification name

PhD