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

摘要

Alpha-carboxynudeoside phosphonates (alpha-CNPs) are novel viral DNA polymerase inhibitors that do not need metabolic conversion for enzyme inhibition. The prototype contains a cydopentyl linker between nucleobase and alpha-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 alpha-CNPs, including a Rh(II)-catalyzed O-H insertion that connects the carboxyphosphonate group to a linker moiety and an attachment of a nudeobase to the other end of the linker by a Mitsunobu reaction followed by final deprotection. Replacing the cydopentyl moiety in the prototype alpha-CNPs by a more flexible entity results in a selectivity shift of similar to 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 alpha-CNPs against the herpetic DNA polymerases differs from the nature of the nudeobase-specific kinetic interaction of the cyclopentyl alpha-CNPs against HIV RT.