Subcellular targeted anion transporters

Ryder, WG; Levina, A; Graziotto, ME; Hawkins, BA; Hibbs, DE; New, EJ; Gale, PA

Subcellular targeted anion transporters

Ryder, WG Levina, A Graziotto, ME Hawkins, BA Hibbs, DE New, EJ Gale, PA

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Publisher:: Elsevier
Publication Type:: Journal Article
Citation:: Chem, 2024
Issue Date:: 2024-01-01

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Field	Value	Language
dc.contributor.author	Ryder, WG
dc.contributor.author	Levina, A
dc.contributor.author	Graziotto, ME
dc.contributor.author	Hawkins, BA
dc.contributor.author	Hibbs, DE
dc.contributor.author	New, EJ
dc.contributor.author	Gale, PA
dc.date.accessioned	2024-12-12T00:07:37Z
dc.date.available	2024-12-12T00:07:37Z
dc.date.issued	2024-01-01
dc.identifier.citation	Chem, 2024
dc.identifier.issn	2451-9308
dc.identifier.issn	2451-9294
dc.identifier.uri	http://hdl.handle.net/10453/182475
dc.description.abstract	Synthetic anion transporters that mediate electroneutral (H+/Cl−) transport have demonstrated anti-cancer activity due to their ability to disrupt subcellular homeostatic environments. Elucidation of the cell death mechanism revealed the transporters’ ability to neutralize lysosomal pH gradients and inhibit autophagy. However, their effects on other subcellular compartments are unknown. Herein, we disclose the first subcellular targeted anionophores that accumulate in various membrane-bound organelles to bias their natural propensity to depolarize lysosomes. Confocal microscopy revealed that the naphthalimide-based transporters effectively localized within their intended organelles. Analogs containing endoplasmic reticulum (ER) and lysosomal targeting motifs showed an enhanced H+/Cl− transport ability and greater cytotoxicity compared with non-targeted analogs. Moreover, lysosomal accumulation improved cancer cell selectivity, while ER and mitochondrial localization enhanced apoptosis in cancer cells. Our work provides an alternative approach to the design of therapeutically focused synthetic anion transporters and an insight into possible subcellular compartment-specific effects on homeostasis.
dc.language	en
dc.publisher	Elsevier
dc.relation	http://purl.org/au-research/grants/arc/DP200100453
dc.relation.ispartof	Chem
dc.relation.isbasedon	10.1016/j.chempr.2024.07.009
dc.rights	info:eu-repo/semantics/embargoedAccess
dc.title	Subcellular targeted anion transporters
dc.type	Journal Article
pubs.organisational-group	University of Technology Sydney
pubs.organisational-group	University of Technology Sydney/Faculty of Science
pubs.organisational-group	University of Technology Sydney/UTS Groups
pubs.organisational-group	University of Technology Sydney/UTS Groups/The Kidman Centre (TKC)
utslib.copyright.status	embargoed	*
utslib.copyright.embargo	2025-08-20T00:00:00+1000Z
dc.date.updated	2024-12-12T00:07:35Z
pubs.publication-status	Published

Abstract:

Synthetic anion transporters that mediate electroneutral (H+/Cl−) transport have demonstrated anti-cancer activity due to their ability to disrupt subcellular homeostatic environments. Elucidation of the cell death mechanism revealed the transporters’ ability to neutralize lysosomal pH gradients and inhibit autophagy. However, their effects on other subcellular compartments are unknown. Herein, we disclose the first subcellular targeted anionophores that accumulate in various membrane-bound organelles to bias their natural propensity to depolarize lysosomes. Confocal microscopy revealed that the naphthalimide-based transporters effectively localized within their intended organelles. Analogs containing endoplasmic reticulum (ER) and lysosomal targeting motifs showed an enhanced H+/Cl− transport ability and greater cytotoxicity compared with non-targeted analogs. Moreover, lysosomal accumulation improved cancer cell selectivity, while ER and mitochondrial localization enhanced apoptosis in cancer cells. Our work provides an alternative approach to the design of therapeutically focused synthetic anion transporters and an insight into possible subcellular compartment-specific effects on homeostasis.

Please use this identifier to cite or link to this item:

http://hdl.handle.net/10453/182475