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.