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

Bioorg Med Chem. 2024 Mar 25;103:117696. doi: 10.1016/j.bmc.2024.117696. Online ahead of print.ABSTRACTAryloxy 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 PS analogues of three ProTides that have reached the clinic as anticancer agents. These novel PS 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 PO with a PS 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 PS aminoacyl product but the corresponding PO aminoacyl compound.PMID:38547648 | DOI:10.1016/j.bmc.2024.117696

Source: Bioorganic and Medicinal Chemistry - March 28, 2024 Category: Chemistry Authors: Michaela Serpi Samule di Ciano Fabrizio Pertusati Source Type: research