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

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...

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Autores principales:	Shaun W. P. Rees, Tayla A. Rees, Euphemia Leung, Christopher S. Walker, David Barker, Lisa I. Pilkington
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	2-morpholinobenzoic acids anti-proliferative activity DAF-FM NF-κB nitric oxide donors PC-PLC Biology (General) QH301-705.5 Chemistry QD1-999
Acceso en línea:	https://doaj.org/article/bbb885a4388a45739df8c7fe2316f4e3
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spelling	oai:doaj.org-article:bbb885a4388a45739df8c7fe2316f4e32021-11-11T16:58:40ZIncorporation of a Nitric Oxide Donating Motif into Novel PC-PLC Inhibitors Provides Enhanced Anti-Proliferative Activity10.3390/ijms2221115181422-00671661-6596https://doaj.org/article/bbb885a4388a45739df8c7fe2316f4e32021-10-01T00:00:00Zhttps://www.mdpi.com/1422-0067/22/21/11518https://doaj.org/toc/1661-6596https://doaj.org/toc/1422-0067Inhibition 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.Shaun W. P. ReesTayla A. ReesEuphemia LeungChristopher S. WalkerDavid BarkerLisa I. PilkingtonMDPI AGarticle2-morpholinobenzoic acidsanti-proliferative activityDAF-FMNF-κBnitric oxide donorsPC-PLCBiology (General)QH301-705.5ChemistryQD1-999ENInternational Journal of Molecular Sciences, Vol 22, Iss 11518, p 11518 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	2-morpholinobenzoic acids anti-proliferative activity DAF-FM NF-κB nitric oxide donors PC-PLC Biology (General) QH301-705.5 Chemistry QD1-999
spellingShingle	2-morpholinobenzoic acids anti-proliferative activity DAF-FM NF-κB nitric oxide donors PC-PLC Biology (General) QH301-705.5 Chemistry QD1-999 Shaun W. P. Rees Tayla A. Rees Euphemia Leung Christopher S. Walker David Barker Lisa I. Pilkington Incorporation of a Nitric Oxide Donating Motif into Novel PC-PLC Inhibitors Provides Enhanced Anti-Proliferative Activity
description	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.
format	article
author	Shaun W. P. Rees Tayla A. Rees Euphemia Leung Christopher S. Walker David Barker Lisa I. Pilkington
author_facet	Shaun W. P. Rees Tayla A. Rees Euphemia Leung Christopher S. Walker David Barker Lisa I. Pilkington
author_sort	Shaun W. P. Rees
title	Incorporation of a Nitric Oxide Donating Motif into Novel PC-PLC Inhibitors Provides Enhanced Anti-Proliferative Activity
title_short	Incorporation of a Nitric Oxide Donating Motif into Novel PC-PLC Inhibitors Provides Enhanced Anti-Proliferative Activity
title_full	Incorporation of a Nitric Oxide Donating Motif into Novel PC-PLC Inhibitors Provides Enhanced Anti-Proliferative Activity
title_fullStr	Incorporation of a Nitric Oxide Donating Motif into Novel PC-PLC Inhibitors Provides Enhanced Anti-Proliferative Activity
title_full_unstemmed	Incorporation of a Nitric Oxide Donating Motif into Novel PC-PLC Inhibitors Provides Enhanced Anti-Proliferative Activity
title_sort	incorporation of a nitric oxide donating motif into novel pc-plc inhibitors provides enhanced anti-proliferative activity
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/bbb885a4388a45739df8c7fe2316f4e3
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Incorporation of a Nitric Oxide Donating Motif into Novel PC-PLC Inhibitors Provides Enhanced Anti-Proliferative Activity

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