Synthesis and Antiviral Evaluation of Octadecyloxyethyl Benzyl 9-[(2-Phosphonomethoxy)ethyl]guanine (ODE-Bn-PMEG), a Potent Inhibitor of Transient HPV DNA Amplification

  • J Med Chem. 2016 Dec 8;59(23):10470-10478. doi: 10.1021/acs.jmedchem.6b00659.
James R Beadle  1 ,  Nadejda Valiaeva  1 ,  Guang Yang  2 ,  Jei-Hwa Yu  2 ,  Thomas R Broker  2 ,  Kathy A Aldern  1 ,  Emma A Harden  2 ,  Kathy A Keith  2 ,  Mark N Prichard  2 ,  Tracy Hartman  3 ,  Robert W Buckheit Jr  3 ,  Louise T Chow  2 ,  Karl Y Hostetler  1  4
Affiliations
  • 1. University of California, San Diego , La Jolla, California 92093, United States.
  • 2. University of Alabama at Birmingham , Birmingham, Alabama 35233, United States.
  • 3. ImQuest BioSciences , Frederick, Maryland 21704, United States.
  • 4. Antiva Biosciences, Inc. , South San Francisco, California 94080, United States.
PMID: 27933957 DOI: 10.1021/acs.jmedchem.6b00659
Abstract

Human papillomavirus (HPV) high-risk genotypes such as HPV-16 and HPV-18 cause the majority of anogenital tract carcinomas, including cervical Cancer, the second most common malignancy in women worldwide. Currently there are no approved Antiviral agents that reduce or eliminate HPV and reverse virus-associated pathology. We synthesized and evaluated several alkoxyalkyl acyclic nucleoside phosphonate diesters and identified octadecyloxyethyl benzyl 9-[(2-phosphonomethoxy)ethyl]guanine (ODE-Bn-PMEG) as an active compound which strongly inhibited transient amplification of HPV-11, -16, and -18 origin-containing plasmid DNA in transfected cells at concentrations well below its cytotoxic concentrations. ODE-Bn-PMEG demonstrated increased uptake in human foreskin fibroblast cells and was readily converted in vitro to the active Antiviral metabolite, PMEG diphosphate. The P-chiral enantiomers of ODE-Bn-PMEG were obtained and appeared to have equivalent Antiviral activities against HPV. ODE-Bn-PMEG is a promising candidate for the local treatment of HPV-16 and HPV-18 and Other high-risk types, an important unmet medical need.

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