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.

doi:10.1016/j.bioorg.2021.105152

Cited by 10 publications

(14 citation statements)

References 32 publications

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“…As previously reported, non-nitrosylated benzylamines 6a-m possess poor-to-moderate anti-proliferative activity against triple negative breast cancer MDA-MB-231 cells, with the best result being 6h, which reduced growth to 67% of positive control [23]. In contrast, twelve of the thirteen N-nitrosylated benzylamines 7a-m displayed significantly (p-value < 0.05) improved anti-proliferative activity compared to their non-nitrosylated counterparts (Table 1).…”

Section: Anti-proliferative Activity Of N-nitrosylated Benzylaminessupporting

confidence: 57%

“…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%

“…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%

“…The colorectal cancer cell line HCT116 and triple-negative breast cancer cell line MDA-MB-231 were purchased from the ATCC, grown in alpha-MEM containing 5% foetal calf serum (FCS), penicillin/streptomycin (100 U/mL and 100 µg/mL, respectively), and insulin/transferrin/selenium supplement (Roche). Inhibition of cell proliferation for compounds 6a-m has previously been reported [23]. Cell proliferation assays for 7a-m were conducted according to literature methods [23,29].…”

Section: Cell Proliferation Assaymentioning

confidence: 99%

“…It was expected that under physiological conditions, the labile N-NO bond would be cleaved, releasing NO whilst also giving a 2-morpholinobenzoic acid derivative, which we have shown inhibits PC-PLC. The 2-morpholinobenzoic acid derivatives with methyl ester groups were chosen for this study, as they have already been shown to induce moderate anti-proliferative efficacy though PC-PLC inhibition alone [23] and therefore making it possible to elucidate if incorporation of a NO-releasing group provides the desired increase in anti-proliferative activity through increased inhibition of NF-κB in a dual-action mechanism.…”

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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Section: Anti-proliferative Activity Of N-nitrosylated Benzylaminessupporting

confidence: 57%

Section: Synthesis Of N-nitrosylated Benzylaminesmentioning

confidence: 99%

Section: Benzylic Substitutionmentioning

confidence: 99%

Section: Cell Proliferation Assaymentioning

confidence: 99%

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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D609 Suppresses Antituberculosis Response by Regulating Dendritic Cells Antigen Presentation

Liu,

Huang,

Huang

et al. 2024

Immunity Inflam & Disease

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ObjectiveTo elucidate the role of phosphatidylcholine‐specific phospholipase C (PC‐PLC) in the antituberculosis (anti‐TB) immune response mediated by dendritic cells (DCs).MethodsIn vivo, C57BL/6J mice infected with the Mycobacterium tuberculosis strain H37Rv. Before infection, the mice were pretreated with the PC‐PLC inhibitor D609. Bacillary loads in lung and spleen tissues were quantified through colony‐forming unit (CFU) assays. Hematoxylin and eosin (H&E) staining was performed to assess inflammatory infiltration and tissue damage. Levels of inflammatory mediators in peripheral venous blood were quantified using enzyme‐linked immunosorbent assays (ELISAs). Flow cytometry was employed to determine the proportions of conventional DCs (cDCs) and their subsets, cDC1 and cDC2, within lung, spleen, and lymph node tissues. In vitro, mouse bone marrow‐derived dendritic cells (BMDCs) pretreated with D609. The expression levels of chemokines and pro‐inflammatory cytokines were assessed via quantitative polymerase chain reaction (qPCR) and ELISA. BMDCs were loaded with H37Rv expressing red fluorescent protein (RFP‐H37Rv) or DQ‐OVA, and flow cytometry was utilized to analyze the impact of D609 on antigen phagocytosis and processing. Furthermore, flow cytometry was employed to evaluate the effect of D609 pretreatment on the expression levels of costimulatory molecules on BMDCs. The capacity of D609‐treated BMDCs to activate and proliferate T cells, as well as to induce interferon‐gamma (IFN‐γ) secretion, was assessed through a DC‐T cell coculture system.ResultsIn vivo analysis revealed that mice pretreated with D609 exhibited a marked increase in tissue bacterial load, enhanced inflammatory infiltration, and a reduction in pro‐inflammatory mediator expression in peripheral venous blood. There was a notable decrease in the number of cDCs in lung and lymph node tissues, with a pronounced reduction in cDC1 in the lungs and cDC2 in the lymph nodes. In vitro studies demonstrated that D609 pretreated BMDCs displayed a significant decline in inflammatory mediator production, antigen phagocytosis, and antigen processing capabilities, potentially due to altered expression of costimulatory molecules. Coculture experiments indicated that D609 pretreated BMDCs showed a substantial reduction in their ability to stimulate T cell activation, proliferation, and IFN‐γ secretion.ConclusionOur findings suggest that PC‐PLC plays a critical role in the functionality of DCs, including the production of chemokines and pro‐inflammatory cytokines, migration to lymph nodes, and antigen presentation to T cells, which collectively contribute to T cell activation and effective clearance of Mycobacterium tuberculosis. Further investigation into the regulatory mechanisms of PC‐PLC in DCs may uncover novel therapeutic targets for the development of advanced anti‐TB treatments.

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Analyzing the interaction of synthetic inhibitors with phospholipases through in silico methods

Arockiasamy,

Srinivasan,

Pugalendhi

et al. 2023

Phospholipases in Physiology and Pathology

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

Cited by 10 publications

References 32 publications

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

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

D609 Suppresses Antituberculosis Response by Regulating Dendritic Cells Antigen Presentation

Analyzing the interaction of synthetic inhibitors with phospholipases through in silico methods

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