title: Synthesis and Antiviral Evaluation of Octadecyloxyethyl Benzyl 9-[(2-Phosphonomethoxy)ethyl]guanine (ODE-Bn-PMEG), a Potent Inhibitor of Transient HPV DNA Amplification.
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.
authors.affiliation: University of California, San Diego , La Jolla, California 92093, United States.
authors.forename: James R
authors.initials: JR
authors.lastname: Beadle
authors.affiliation: University of California, San Diego , La Jolla, California 92093, United States.
authors.forename: Nadejda
authors.initials: N
authors.lastname: Valiaeva
authors.affiliation: University of Alabama at Birmingham , Birmingham, Alabama 35233, United States.
authors.forename: Guang
authors.initials: G
authors.lastname: Yang
authors.affiliation: University of Alabama at Birmingham , Birmingham, Alabama 35233, United States.
authors.forename: Jei-Hwa
authors.initials: JH
authors.lastname: Yu
authors.affiliation: University of Alabama at Birmingham , Birmingham, Alabama 35233, United States.
authors.forename: Thomas R
authors.initials: TR
authors.lastname: Broker
authors.affiliation: University of California, San Diego , La Jolla, California 92093, United States.
authors.forename: Kathy A
authors.initials: KA
authors.lastname: Aldern
authors.affiliation: University of Alabama at Birmingham , Birmingham, Alabama 35233, United States.
authors.forename: Emma A
authors.initials: EA
authors.lastname: Harden
authors.affiliation: University of Alabama at Birmingham , Birmingham, Alabama 35233, United States.
authors.forename: Kathy A
authors.initials: KA
authors.lastname: Keith
authors.affiliation: University of Alabama at Birmingham , Birmingham, Alabama 35233, United States.
authors.forename: Mark N
authors.initials: MN
authors.lastname: Prichard
authors.affiliation: ImQuest BioSciences , Frederick, Maryland 21704, United States.
authors.forename: Tracy
authors.initials: T
authors.lastname: Hartman
authors.affiliation: ImQuest BioSciences , Frederick, Maryland 21704, United States.
authors.forename: Robert W
authors.initials: RW
authors.lastname: Buckheit
authors.affiliation: University of Alabama at Birmingham , Birmingham, Alabama 35233, United States.
authors.forename: Louise T
authors.initials: LT
authors.lastname: Chow
authors.affiliation: University of California, San Diego , La Jolla, California 92093, United States.|Antiva Biosciences, Inc. , South San Francisco, California 94080, United States.
authors.forename: Karl Y
authors.initials: KY
authors.lastname: Hostetler
mesh_terms: D000998:Antiviral Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004279:DNA, Viral / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D006147:Guanine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D057809:HEK293 Cells; D006678:HIV / Q000187:drug effects; D018258:Herpesvirus 2, Human / Q000187:drug effects; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000821:virology; D015394:Molecular Structure; D021141:Nucleic Acid Amplification Techniques; D063065:Organophosphonates / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D027383:Papillomaviridae / Q000187:drug effects* / Q000235:genetics; D013329:Structure-Activity Relationship; D014779:Virus Replication / Q000187:drug effects
chemical_list: D000998:Antiviral Agents; D004279:DNA, Viral; D063065:Organophosphonates; C550608:octadecyloxyethyl 9-(2-(phosphonomethoxy)ethyl)guanine; D006147:Guanine