title: Pronounced Inhibition Shift from HIV Reverse Transcriptase to Herpetic DNA Polymerases by Increasing the Flexibility of α-Carboxy Nucleoside Phosphonates.
abstract: 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.
authors.forename: Jubi
authors.initials: J
authors.lastname: John
authors.forename: Youngju
authors.initials: Y
authors.lastname: Kim
authors.affiliation: Department of Medical Microbiology and Immunology, University of Alberta , 6-020 Katz Group Centre, Edmonton, Alberta T6G 2E1, Canada.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Bennett
authors.affiliation: Center for Advanced Biotechnology and Medicine and Department of Chemistry and Chemical Biology, Rutgers University , Piscataway, New Jersey 08901, United States.
authors.forename: Kalyan
authors.initials: K
authors.lastname: Das
authors.forename: Sandra
authors.initials: S
authors.lastname: Liekens
authors.forename: Lieve
authors.initials: L
authors.lastname: Naesens
authors.affiliation: Center for Advanced Biotechnology and Medicine and Department of Chemistry and Chemical Biology, Rutgers University , Piscataway, New Jersey 08901, United States.
authors.forename: Eddy
authors.initials: E
authors.lastname: Arnold
authors.affiliation: Department of Chemistry and School of Pharmacy, Analytical and Biological Chemistry Research Facility, University College Cork , Cork, Ireland.
authors.forename: Anita R
authors.initials: AR
authors.lastname: Maguire
authors.affiliation: Department of Medical Microbiology and Immunology, University of Alberta , 6-020 Katz Group Centre, Edmonton, Alberta T6G 2E1, Canada.
authors.forename: Matthias
authors.initials: M
authors.lastname: Götte
authors.forename: Wim
authors.initials: W
authors.lastname: Dehaen
authors.forename: Jan
authors.initials: J
authors.lastname: Balzarini
mesh_terms: D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D004256:DNA Polymerase I / Q000037:antagonists & inhibitors; D019951:DNA Polymerase beta / Q000037:antagonists & inhibitors; D017931:DNA Primers; D015195:Drug Design; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors*; D015497:HIV-1 / Q000187:drug effects / Q000201:enzymology; D014645:Herpesvirus 3, Human / Q000187:drug effects / Q000201:enzymology; D006801:Humans; D008968:Molecular Conformation; D019384:Nucleic Acid Synthesis Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D063065:Organophosphonates / Q000138:chemical synthesis* / Q000494:pharmacology*; D010957:Plasmids / Q000235:genetics; D018894:Reverse Transcriptase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D018139:Simplexvirus / Q000187:drug effects / Q000201:enzymology*; D013329:Structure-Activity Relationship
chemical_list: D000998:Antiviral Agents; D017931:DNA Primers; D019384:Nucleic Acid Synthesis Inhibitors; D063065:Organophosphonates; D018894:Reverse Transcriptase Inhibitors; D054303:HIV Reverse Transcriptase; D004256:DNA Polymerase I; D019951:DNA Polymerase beta