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J Med Chem. 2015 Oct 22;58(20):8110-27. doi: 10.1021/acs.jmedchem.5b01180. Epub 2015 Oct 9.

Pronounced Inhibition Shift from HIV Reverse Transcriptase to Herpetic DNA Polymerases by Increasing the Flexibility of α-Carboxy Nucleoside Phosphonates.

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Department of Medical Microbiology and Immunology, University of Alberta , 6-020 Katz Group Centre, Edmonton, Alberta T6G 2E1, Canada.
Center for Advanced Biotechnology and Medicine and Department of Chemistry and Chemical Biology, Rutgers University , Piscataway, New Jersey 08901, United States.
Department of Chemistry and School of Pharmacy, Analytical and Biological Chemistry Research Facility, University College Cork , Cork, Ireland.


Alpha-carboxynucleoside phosphonates (α-CNPs) are novel viral DNA polymerase inhibitors that do not need metabolic conversion for enzyme inhibition. The prototype contains a cyclopentyl linker between nucleobase and α-carboxyphosphonate and preferentially (50- to 100-fold) inhibits HIV-1 RT compared with herpetic DNA polymerases. A synthesis methodology involving three steps has been developed for the synthesis of a series of novel α-CNPs, including a Rh(II)-catalyzed O-H insertion that connects the carboxyphosphonate group to a linker moiety and an attachment of a nucleobase to the other end of the linker by a Mitsunobu reaction followed by final deprotection. Replacing the cyclopentyl moiety in the prototype α-CNPs by a more flexible entity results in a selectivity shift of ∼ 100-fold in favor of the herpetic DNA polymerases when compared to selectivity for HIV-1 RT. The nature of the kinetic interaction of the acyclic α-CNPs against the herpetic DNA polymerases differs from the nature of the nucleobase-specific kinetic interaction of the cyclopentyl α-CNPs against HIV RT.

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