Pilkington, LI, Sparrow, K, Rees, SWP, Paulin, EK, van Rensburg, M, Xu, CS, Langley, RJ, Leung, IKH, Reynisson, J, Leung, E and Barker, D (2020) Development, synthesis and biological investigation of a novel class of potent PC-PLC inhibitors. European Journal of Medicinal Chemistry, 191. ISSN 1768-3254

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Phospholipases are enzymes that are involved in the hydrolysis of acyl and phosphate esters of phospholipids, generating secondary messengers that have implications in various cellular processes including proliferation, differentiation and motility. As such inhibitors of phospholipases have been widely studied for their use as anti-cancer therapeutics. Phosphatidylcholine-specific phospholipase C (PC-PLC) is implicated in the progression of a number of cancer cell lines including aggressing triple-negative breast cancers. Most current studies on PC-PLC have utilised D609 as the standard inhibitor however it is known to have multiple failings, including poor stability in aqueous media. 2-Morpholinobenzoic acids were recently identified using vHTS as a potential class of lead compounds, with improvements over D609. In this work 129 analogues in this class were prepared and their PC-PLC inhibitory activity was assessed. It was found that the majority of these novel compounds had improved activity when compared to D609 with the most potent inhibitors completely inhibiting enzyme activity. It was determined that the best compound/s contained a morpholino and 2-substituted N-benzyl moieties with these findings explained using molecular modelling. The compounds reported here will allow for improved study of PC-PLC activity.

Item Type: Article
Additional Information: The final accepted manuscript and additional information can be found at; https://www.sciencedirect.com/science/article/pii/S022352342030129X?via%3Dihub
Uncontrolled Keywords: synthesis, biological investigation, PC-PLC inhibitors.
Subjects: Q Science > Q Science (General)
Q Science > QM Human anatomy
R Medicine > R Medicine (General)
Divisions: Faculty of Medicine and Health Sciences > School of Pharmacy and Bioengineering
Related URLs:
Depositing User: Symplectic
Date Deposited: 03 Mar 2020 16:10
Last Modified: 19 Feb 2021 01:30
URI: https://eprints.keele.ac.uk/id/eprint/7749

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