Development, synthesis and biological investigation of a novel class of potent PC-PLC inhibitors

Pilkington, Lisa I.; Sparrow, Kevin; Rees, Shaun W. P.; Paulin, Emily K.; Rensburg, Michelle van; Xu, Chris; Langley, Ries J.; Leung, Ivanhoe K. H.; Reynisson, Jóhannes; Leung, Euphemia; Barker, David

doi:10.1016/j.ejmech.2020.112162

Cited by 9 publications

(10 citation statements)

References 42 publications

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“…One of the key findings of the present study is that SMS1 and SMS2 have PC-PLC activity. PC-PLC is an important member of PLC family to catalyze the hydrolysis of the ester linkage between glycerol and phosphate in PC, producing DAG and P-choline ( 17 ). Since the 1990s, a growing body of evidence has pointed to the implication of PC-PLC in metabolism, growth, differentiation, senescence, and apoptosis of mammalian cells ( 18 , 19 , 20 , 21 ).…”

Section: Discussionmentioning

confidence: 99%

Sphingomyelin synthases 1 and 2 exhibit phosphatidylcholine phospholipase C activity

Chiang

Chen

et al. 2021

Journal of Biological Chemistry

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Many studies have confirmed the enzymatic activity of a mammalian phosphatidylcholine (PC) phospholipase C (PLC) (PC-PLC), which produces diacylglycerol (DAG) and phosphocholine through the hydrolysis of PC in the absence of ceramide. However, the protein(s) responsible for this activity have never yet been identified. Based on the fact that tricyclodecan-9-yl-potassium xanthate can inhibit both PC-PLC and sphingomyelin synthase (SMS) activities, and SMS1 and SMS2 have a conserved catalytic domain that could mediate a nucleophilic attack on the phosphodiester bond of PC, we hypothesized that both SMS1 and SMS2 might have PC-PLC activity. In the present study, we found that purified recombinant SMS1 and SMS2 but not SMS-related protein have PC-PLC activity. Moreover, we prepared liver-specific Sms1 /global Sms2 double-KO mice. We found that liver PC-PLC activity was significantly reduced and steady-state levels of PC and DAG in the liver were regulated by the deficiency, in comparison with control mice. Using adenovirus, we expressed Sms 1 and Sms 2 genes in the liver of the double-KO mice, respectively, and found that expressed SMS1 and SMS2 can hydrolyze PC to produce DAG and phosphocholine. Thus, SMS1 and SMS2 exhibit PC-PLC activity in vitro and in vivo .

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Section: Discussionmentioning

confidence: 99%

Sphingomyelin synthases 1 and 2 exhibit phosphatidylcholine phospholipase C activity

Chiang

Chen

et al. 2021

Journal of Biological Chemistry

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“…In order to synthesize the desired N-nitrosylated compounds, we first had to synthesize benzylamines 6a-m from 2-chloro-5-nitrobenzoic acid, 1. This was achieved using previously reported methods (Scheme 1) [22,23]. First, the carboxylic acid motif on compound 1 was converted into the methyl ester on compound 2, and then, the 2-Cl group was substituted with a morpholine ring affording 3.…”

Section: Synthesis Of N-nitrosylated Benzylaminesmentioning

confidence: 99%

“…Next, the 5-nitro group was reduced via catalytic hydrogenation to an amine, yielding aniline 4. Following this, aniline 4 was subjected to a two-pot reductive amination with various benzaldehydes 5a-m, producing aforementioned benzylamines 6a-m. A range of benzaldehydes 5a-m with F, Cl, Br, and OMe substitution at the 2-, 3-and 4-positions around the aromatic ring were selected, as these substituents provided the best PC-PLC inhibitory activity for the carboxylic acid series [22]. Benzylamines 6a-m were then nitrosylated using sodium nitrite and p-toluenesulfonic acid in dichloromethane affording the desired novel N-nitrosylated benzylamines 7a-m in good to excellent yields [24].…”

Section: Synthesis Of N-nitrosylated Benzylaminesmentioning

confidence: 99%

“…These results suggests that both the NO releasing and PC-PLC inhibitory mechanisms are working together, potentially through a dual-action inhibition of the PC-PLC/PKC/NF-κB pathway in order to enhance the overall anti-proliferative ability of this class of compounds. Compounds 2-6a-m were synthesized in accordance with our previously reported procedures [22,23].…”

Section: Benzylic Substitutionmentioning

confidence: 99%

“…Despite this link between PC-PLC inhibition and exogenous NO, a single molecule with both functionalities has yet to be reported in the literature. We have, however, recently reported the discovery of a novel class of PC-PLC inhibitors, the 2-morpholinobenzoic acids, which are able to inhibit PC-PLC at superior levels to the aforementioned literature standard D609 (Figure 1) [22]. Furthermore, these molecules possess a secondary benzylamine group, which has the ability to act as a substrate for N-nitrosylation, allowing possible incorporation of an NO group into this class of potent PC-PLC inhibitors.…”

Section: Introductionmentioning

confidence: 99%

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Incorporation of a Nitric Oxide Donating Motif into Novel PC-PLC Inhibitors Provides Enhanced Anti-Proliferative Activity

Rees

Leung

et al. 2021

IJMS

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Inhibition of phosphatidylcholine-specific phospholipase C (PC-PLC) has previously been shown to be a potential target for novel cancer therapeutics. One downstream consequence of PC-PLC activity is the activation of NF-κB, a nuclear transcription factor responsible for transcribing genes related to oncogenic traits, such as proliferation, angiogenesis, metastasis, and cancer cell survival. Another biological pathway linked to NF-κB is the exogenous delivery of nitric oxide (NO), which decreases NF-κB activity through an apparent negative-feedback loop. In this study, we designed and synthesised 13 novel NO-releasing derivatives of our previously reported class of PC-PLC inhibitors, 2-morpholinobenzoic acids. These molecules contained a secondary benzylamine group, which was readily nitrosylated and subsequently confirmed to release NO in vitro using a DAF-FM fluorescence-based assay. It was then discovered that these NO-releasing derivatives possessed significantly improved anti-proliferative activity in both MDA-MB-231 and HCT116 cancer cell lines compared to their non-nitrosylated parent compounds. These results confirmed that the inclusion of an exogenous NO-releasing functional group onto a known PC-PLC inhibitor enhances anti-proliferative activity and that this relationship can be exploited in order to further improve the anti-proliferative activity of current/future PC-PLC inhibitors.

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

Rees

Leung

Reynisson

et al. 2021

Bioorganic Chemistry

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Development, synthesis and biological investigation of a novel class of potent PC-PLC inhibitors

Cited by 9 publications

References 42 publications

Sphingomyelin synthases 1 and 2 exhibit phosphatidylcholine phospholipase C activity

Sphingomyelin synthases 1 and 2 exhibit phosphatidylcholine phospholipase C activity

Incorporation of a Nitric Oxide Donating Motif into Novel PC-PLC Inhibitors Provides Enhanced Anti-Proliferative Activity

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

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