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Short Communication

Synthesis of ortho-formylphenylphosphonic acids as covalent probes of active site lysines

, , , &
Pages 313-314 | Received 11 Sep 2018, Accepted 19 Oct 2018, Published online: 13 Feb 2019
 

Abstract

During the course of an investigation of targeted inhibition of DNA polymerase beta (pol β) lyase activity using small molecules, we observed the formation of an aldimine between (2-formyl)phenylphosphonic acid (2FPP) and butylamine under basic aqueous conditions; complete deprotonation of the phosphonate group was required to stabilize the imine product. Results of computational docking studies suggested that the reaction of Lys-72 on the lyase active site with an aldehyde group could be facilitated by a proximal phosphonate, not only because of the phosphonate’s ability to mimic phosphate interacting with the DNA binding site, but also because of its ability to shield the imine against hydrolysis. Novel pol β lyase inhibitors were thus prepared using a 2FPP analogue with an amine linker; P-C bond formation in synthesis of this intermediate was possible with an unprotected aldehyde using palladium-catalyzed, microwave-assisted Michaelis–Arbuzov chemistry. These compounds, and structurally related derivatives lacking the aldehyde or phosphonate, were evaluated in an assay for pol β to assess their potential for inhibition.

Graphical Abstract

Additional information

Funding

This research was supported by a grant from the NIH-NCI, U19CA177547.

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