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Polyfluoroaromatic stavudine (d4T) ProTides exhibit enhanced anti-HIV activity

Kandil, Sahar, Pannecouque, Christophe, Chapman, Fiona M., Westwell, Andrew D. and McGuigan, Christopher 2019. Polyfluoroaromatic stavudine (d4T) ProTides exhibit enhanced anti-HIV activity. Bioorganic and Medicinal Chemistry Letters 29 (24) , 126721. 10.1016/j.bmcl.2019.126721

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Human Immunodeficiency Virus (HIV) damages the immune system and leads to the life-threatening acquired immunodeficiency syndrome (AIDS). Despite the advances in the field of antiretroviral treatment, HIV remains a major public health challenge. Nucleosides represent a prominent chemotherapeutic class for treating viruses, however their cellular uptake, kinase-mediated activation and catabolism are limiting factors. Herein, we report the synthesis and in vitro evaluation of stavudine (d4T) ProTides containing polyfluorinated aryl groups against two strains; HIV-1 (IIIB) and HIV-2 (ROD). ProTide 5d containing a meta-substituted pentafluorosulfanyl (3-SF5) aryl group showed superior antiviral activity over the parent d4T and the nonfluorinated analogue 5a. ProTide 5d has low nanomolar antiviral activity; (IC50 = 30 nM, HIV-1) and (IC50 = 36 nM, HIV-2) which is over tenfold more potent than d4T. Interestingly, ProTide 5d showed a significantly high selectivity indices with SI = 1753 (HIV-1) and 1461 (HIV-2) which is more than twice that of the d4T. All ProTides were screened in wild type as well as thymidine kinase deficient (TK−) cells. Enzymatic activation of ProTide 5d using carboxypeptidase Y enzyme and monitored using both 31P and 19F NMR is presented.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Pharmacy
Publisher: Elsevier
ISSN: 0960-894X
Date of First Compliant Deposit: 5 November 2019
Date of Acceptance: 27 September 2019
Last Modified: 18 Jan 2021 22:27

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