Issue 44, 2023

N-Acyloxymethyl-phthalimides deliver genotoxic formaldehyde to human cells

Abstract

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 N-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 N-acyloxymethyl-phthalimides and control compounds provide an accessible and broadly applicable chemical toolkit for formaldehyde biological research and have potential as cancer therapeutics.

Graphical abstract: N-Acyloxymethyl-phthalimides deliver genotoxic formaldehyde to human cells

Supplementary files

Article information

Article type
Edge Article
Submitted
05 jun 2023
Accepted
13 sep 2023
First published
15 sep 2023
This article is Open Access

All publication charges for this article have been paid for by the Royal Society of Chemistry
Creative Commons BY license

Chem. Sci., 2023,14, 12498-12505

N-Acyloxymethyl-phthalimides deliver genotoxic formaldehyde to human cells

V. L. Emms, L. A. Lewis, L. Beja, N. F. A. Bulman, E. Pires, F. W. Muskett, J. S. O. McCullagh, Lonnie. P. Swift, P. J. McHugh and R. J. Hopkinson, Chem. Sci., 2023, 14, 12498 DOI: 10.1039/D3SC02867D

This article is licensed under a Creative Commons Attribution 3.0 Unported Licence. You can use material from this article in other publications without requesting further permissions from the RSC, provided that the correct acknowledgement is given.

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