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

• Published in: Bioorganic chemistry Vol. 114; p. 105152
• Main Authors: Rees, Shaun W.P., Leung, Euphemia, Reynisson, Jóhannes, Barker, David, Pilkington, Lisa I.
• Format: Journal Article
• Language: English
• Published: SAN DIEGO Elsevier Inc 01.09.2021; Elsevier
• Subjects: 2-Morpholinobenzoic acids; Anti-proliferative activity; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Benzamides - chemical synthesis; Benzamides - chemistry; Benzamides - pharmacology; Biochemistry & Molecular Biology; Cell Line, Tumor; Cell Proliferation - drug effects; Chemistry; Chemistry, Organic; D609; Dose-Response Relationship, Drug; Drug Development; Drug Screening Assays, Antitumor; Humans; Hydroxamic acids; Life Sciences & Biomedicine; Molecular Structure; Morpholinos - chemical synthesis; Morpholinos - chemistry; Morpholinos - pharmacology; PC-PLC; Physical Sciences; Science & Technology; Structure-Activity Relationship; Hydroxamic acids; PC-PLC; D609; 2-Morpholinobenzoic acids; Anti-proliferative activity; METABOLISM; PHOSPHOLIPASE-C; CELL-CYCLE; PROLIFERATION; PHOSPHATIDYLCHOLINE
• ISSN: 0045-2068; 1090-2120
• DOI: 10.1016/j.bioorg.2021.105152

[Display omitted] •New class 2-morpholino-N-hydroxybenzamides synthesised in high yields.•Analogues demonstrated equivalent or better PC-PLC inhibition than D609.•Compounds induced potent anti-proliferative effects, far superior to D609. 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.