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

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.