N -Acyloxymethyl-phthalimides deliver genotoxic formaldehyde to human cells

Formaldehyde is a pollutant and human metabolite that is toxic at high concentrations. Biological studies on formaldehyde are hindered by its high reactivity and volatility, which make it challenging to deliver quantitatively to cells. Here, we describe the development and validation of a set of -ac...

Full description

Saved in:
Bibliographic Details
Published in:Chemical science (Cambridge) 2023-11, Vol.14 (44), p.12498-12505
Main Authors: Emms, Vicki L, Lewis, Liam A, Beja, Lilla, Bulman, Natasha F A, Pires, Elisabete, Muskett, Frederick W, McCullagh, James S O, Swift, Lonnie P, McHugh, Peter J, Hopkinson, Richard J
Format: Article
Language:English
Subjects:
Cancer
Cell death
Formaldehyde
Genotoxicity
Lead compounds
Metabolites
Phthalimides
Thymidine
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:Formaldehyde is a pollutant and human metabolite that is toxic at high concentrations. Biological studies on formaldehyde are hindered by its high reactivity and volatility, which make it challenging to deliver quantitatively to cells. Here, we describe the development and validation of a set of -acyloxymethyl-phthalimides as cell-relevant formaldehyde delivery agents. These esterase-sensitive compounds were similarly or less inhibitory to human cancer cell growth than free formaldehyde but the lead compound increased intracellular formaldehyde concentrations, increased cellular levels of thymidine derivatives (implying increased formaldehyde-mediated carbon metabolism), induced formation of cellular DNA-protein cross-links and induced cell death in pancreatic cancer cells. Overall, our -acyloxymethyl-phthalimides and control compounds provide an accessible and broadly applicable chemical toolkit for formaldehyde biological research and have potential as cancer therapeutics.
ISSN:2041-6520
2041-6539
DOI:10.1039/d3sc02867d