Design, synthesis and biological evaluation of aryloxy thiophosphoramidate triesters of anticancer nucleoside analogues

Serpi, Michaela ORCID: https://orcid.org/0000-0002-6162-7910, di Ciano, Samule and Pertusati, Fabrizio ORCID: https://orcid.org/0000-0003-4532-9101 2024. Design, synthesis and biological evaluation of aryloxy thiophosphoramidate triesters of anticancer nucleoside analogues. Bioorganic and Medicinal Chemistry 103 , 117696. 10.1016/j.bmc.2024.117696

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Abstract

Aryloxy phosphoroamidate triesters, known as ProTides, are a class of prodrugs developed to enhance the physicochemical and pharmacological properties of therapeutic nucleosides. This approach has been extensively investigated in the antiviral and anticancer areas leading to three prodrugs on the market and several others in clinical stage. In this article we have prepared the Pdouble bondS analogues of three ProTides that have reached the clinic as anticancer agents. These novel Pdouble bondS ProTides were tested for their capacity in enzymatic activation and for their cytotoxic properties against a panel of solid and liquid tumor cell lines. As expected, the replacement of the Pdouble bondO with a Pdouble bondS bond led to increased metabolic stability albeit concomitant to a decrease in potency. Surprisingly, the intermediate formed after the first activation step of a thiophosphoramidate with carboxypeptidase Y is not the expected Pdouble bondS aminoacyl product but the corresponding Pdouble bondO aminoacyl compound.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Chemistry
Publisher:	Elsevier
ISSN:	0968-0896
Funders:	NuCana plc.
Date of First Compliant Deposit:	8 May 2024
Date of Acceptance:	20 March 2024
Last Modified:	10 May 2024 14:45
URI:	https://orca.cardiff.ac.uk/id/eprint/168786

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