Synthesis of 1,4-azaphosphinine pyrimidine nucleosides and their evaluation as inhibitors of human cytidine deaminase and APOBEC3A

Submitting author affiliation:
Massey University, Palmerston North, New Zealand

Beilstein Arch. 2024, 20249.

Published 08 Feb 2024

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This preprint has not been peer-reviewed. When a peer-reviewed version is available, this information will be updated.


Nucleoside and polynucleotide cytidine deaminases (CDA and APOBEC3) share similar mechanism of cytosine to uracil conversion. In 1984 phosphapyrimidine riboside was characterised as the most potent inhibitor of human CDA but its quick degradation in water limited its applicability as a potential therapeutic. To improve stability in water, we synthesised a derivative dPC of phosphapyrimidine nucleoside having CH2 group instead of the N3 atom in the nucleobase. A charge-neutral phosphinamide dPC-NH2 and a negatively-charged phosphinic acid derivative dPC-OH had excellent stability in water at pH 7.4 but only the charge-neutral dPC-NH2 inhibited human CDA similar to previously described 2’-deoxyzebularine (Ki = 8.0 ± 1.9 and 10.7 ± 0.5 µM, respectively). However, at basic conditions the charge-neutral phosphinamide dPC-NH2 was unstable which prevented its incorporation into DNA using conventional DNA chemistry. In contrast, the negatively charged phosphinic acid derivative dPC-OH was incorporated into DNA instead of the target dC using an automated DNA synthesiser but no inhibition of APOBEC3A was observed for modified DNAs. Although this shows that negative charge is poorly accommodated in the active site of CDA and APOBEC3, the synthetic route reported here provides opportunities for the synthesis of other derivatives of phosphapyrimidine riboside for potential development of more potent CDA and APOBEC3 inhibitors.

Keywords: APOBEC3; cytidine deaminase; zebularine; enzyme activity; inhibitor; transition state analogue; nucleoside; nucleotide

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When a peer-reviewed version of this preprint is available, this information will be updated in the information box above. If no peer-reviewed version is available, please cite this preprint using the following information:

Kvach, M. V.; Harjes, S.; Kurup, H. M.; Jameson, G. B.; Harjes, E.; Filichev, V. V. Beilstein Arch. 2024, 20249. doi:10.3762/bxiv.2024.9.v1

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