Development of 2-Morpholino-N-hydroxybenzamides as anti-proliferative PC-PLC inhibitors

Rees, Shaun W.P.; Leung, Euphemia; Reynisson, Jóhannes; Barker, David; Pilkington, Lisa I.

Abstract

Phosphatidylcholine-specific phospholipase C (PC-PLC) is a key enzyme involved in the metabolism of the mammalian phospholipid phosphatidylcholine into secondary messengers diacylglycerol (DAG) and phosphocholine. DAG and phosphocholine have been identified to amplify various cellular processes involved in oncogenesis such as proliferation, cell-cycle activation, differentiation and motility, therefore making PC-PLC a potential target for novel anti-cancer treatments. The current literature standard for PC-PLC inhibition, tricyclodecan-9-yl-potassium xanthate (D609), has been shown to arrest proliferation in multiple cancer cell lines, however, it is not drug-like resulting in low aqueous stability, making it a poor drug candidate. 2-Morpholinobenzoic acids have been shown to have improved PC-PLC inhibitory activity compared to D609, with molecular modelling identifying chelation of the carboxylic acid to catalytic Zn2+ ions in the PC-PLC active site being a key interaction. In this study, the carboxylic acid motif was replaced with a hydroxamic acid to strengthen the Zn2+ interaction. It was found that the hydroxamic acid derivatives displayed PC-PLC inhibitory activity similar, or better, than D609. Furthermore, these novel inhibitors had potent anti-proliferative activity in MDA-MB-231 and HCT-116 cancer cell lines, far greater than D609 and previous 2-morpholinobenzoic acids.

Citation

Rees, S. W., Leung, E., Reynisson, J., Barker, D., & Pilkington, L. I. (2021). Development of 2-Morpholino-N-hydroxybenzamides as anti-proliferative PC-PLC inhibitors. Bioorganic Chemistry, 114, 105152. https://doi.org/10.1016/j.bioorg.2021.105152

• Journal Article Type: Article
• Acceptance Date: Jul 2, 2021
• Online Publication Date: Jul 7, 2021
• Publication Date: 2021-09
• Deposit Date: Jun 2, 2023
• Journal: Bioorganic Chemistry
• Print ISSN: 0045-2068
• Publisher: Elsevier
• Peer Reviewed: Peer Reviewed
• Volume: 114
• Pages: 105152
• DOI: https://doi.org/10.1016/j.bioorg.2021.105152
• Keywords: Organic Chemistry; Drug Discovery; Molecular Biology; Biochemistry
• Additional Information: This article is maintained by: Elsevier; Article Title: Development of 2-Morpholino-N-hydroxybenzamides as anti-proliferative PC-PLC inhibitors; Journal Title: Bioorganic Chemistry; CrossRef DOI link to publisher maintained version: https://doi.org/10.1016/j.bioorg.2021.105152; Content Type: article; Copyright: © 2021 Published by Elsevier Inc.