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Phosphotyrosine prodrugs: design, synthesis and anti-STAT3 activity of ISS-610 aryloxy triester phosphoramidate prodrugs

Miccoli, Ageo, Dhiani, Binar and Mehellou, Youcef 2019. Phosphotyrosine prodrugs: design, synthesis and anti-STAT3 activity of ISS-610 aryloxy triester phosphoramidate prodrugs. MedChemComm 10 (2) , pp. 200-208. 10.1039/C8MD00244D
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Abstract

Unmasked phohate groups of phosphotyrosine-containing molecules carry two negative charges at physiological pH, which compromise their (passive) celular uptake. Also, these phosphate groups are often cleaved off by phosphatases. Together, these ultimately limit the pharmacological efficacy of the phosphotyrosine-containing compounds. To address these drawbacks, we herein present the application of the aryloxy triester phosphoramidate prodrug technology, a monophosphate prodrug technology, to the phosphotyrosine-containing compound ISS-610-Met, an analogue of the anticancer STAT3 dimerization inhibitor ISS-610. Our data shows that the generated ISS-610-Met prodrugs exhibited enhanced pharmacological activity and inhibition of STAT3 downstream signaling compared to the parent compound ISS-610-Met and the known STAT3 dimerization inhibitor ISS-610. These encouraging results provide a compelling proof of concept for the potential of the aryloxy triester phosphoramidate prodrug technology in the discovery of novel therapeutics that contain phosphotyrosine and its phospho mimics.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Pharmacy
Publisher: Royal Society of Chemistry
ISSN: 2040-2503
Date of First Compliant Deposit: 14 November 2018
Date of Acceptance: 6 November 2018
Last Modified: 16 Apr 2019 14:23
URI: http://orca.cf.ac.uk/id/eprint/116803

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