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

Autor: Rees SWP; School of Chemical Sciences, University of Auckland, Auckland 1010, New Zealand., Leung E; Auckland Cancer Society Research Centre, University of Auckland, Grafton, Auckland 1023, New Zealand., Reynisson J; School of Pharmacy and Bioengineering, Keele University, Hornbeam Building, Staffordshire ST5 5BG, United Kingdom., Barker D; School of Chemical Sciences, University of Auckland, Auckland 1010, New Zealand; MacDiarmid Institute for Advanced Materials and Nanotechnology, Wellington, New Zealand. Electronic address: d.barker@auckland.ac.nz., Pilkington LI; School of Chemical Sciences, University of Auckland, Auckland 1010, New Zealand. Electronic address: lisa.pikington@auckland.ac.nz.
Jazyk: angličtina
Zdroj: Bioorganic chemistry [Bioorg Chem] 2021 Sep; Vol. 114, pp. 105152. Date of Electronic Publication: 2021 Jul 07.
DOI: 10.1016/j.bioorg.2021.105152
Abstrakt: 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 Zn 2+ 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 Zn 2+ 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.
(Copyright © 2021. Published by Elsevier Inc.)
Databáze: MEDLINE
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