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Synthesis and characterization of nuc-7738, an aryloxy phosphoramidate of 3?-deoxyadenosine, as a potential anticancer agent

Serpi, Michaela ORCID: https://orcid.org/0000-0002-6162-7910, Ferrari, Valentina ORCID: https://orcid.org/0000-0003-1895-8906, McGuigan, Christopher ORCID: https://orcid.org/0000-0001-8409-710X, Ghazaly, Essam and Pepper, Chris 2022. Synthesis and characterization of nuc-7738, an aryloxy phosphoramidate of 3?-deoxyadenosine, as a potential anticancer agent. Journal of Medicinal Chemistry 65 (23) , pp. 15789-15804. 10.1021/acs.jmedchem.2c01348

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Abstract

3′-Deoxyadenosine (3′-dA, Cordycepin, 1) is a nucleoside analogue with anticancer properties, but its clinical development has been hampered due to its deactivation by adenosine deaminase (ADA) and poor cellular uptake due to low expression of the human equilibrative transporter (hENT1). Here, we describe the synthesis and characterization of NUC-7738 (7a), a 5′-aryloxy phosphoramidate prodrug of 3′-dA. We show in vitro evidence that 7a is an effective anticancer drug in a panel of solid and hematological cancer cell lines, showing its preferential cytotoxic effects on leukemic stem cells. We found that unlike 3′-dA, the activity of 7a was independent of hENT1 and kinase activity. Furthermore, it was resistant to ADA metabolic deactivation. Consistent with these findings, 7a showed increased levels of intracellular 3′-deoxyadenosine triphosphate (3′-dATP), the active metabolite. Mechanistically, levels of intracellular 3′-dATP were strongly associated with in vitro potency. NUC-7738 is now in Phase II, dose-escalation study in patients with advanced solid tumors

Item Type: Article
Date Type: Publication
Status: Published
Schools: Chemistry
Pharmacy
Publisher: American Chemical Society
ISSN: 0022-2623
Funders: NuCana plc
Date of First Compliant Deposit: 2 December 2022
Date of Acceptance: 9 November 2022
Last Modified: 28 Feb 2024 07:39
URI: https://orca.cardiff.ac.uk/id/eprint/154616

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