title: Structural requirements for TLR7-selective signaling by 9-(4-piperidinylalkyl)-8-oxoadenine derivatives.
abstract: We report the synthesis and biological evaluation of a new series of 8-oxoadenines substituted at the 9-position with a 4-piperidinylalkyl moiety. In vitro evaluation of the piperidinyl-substituted oxoadenines 3a-g in human TLR7- or TLR8-transfected HEK293 cells and in human PBMCs indicated that TLR7/8 selectivity/potency and cytokine induction can be modulated by varying the length of the alkyl linker. Oxoadenine 3f containing a 5-carbon linker was found to be the most potent TLR7 agonist and IFNα inducer in the series whereas 3b possessing a 1-carbon linker was the most potent TLR8 agonist.
authors.affiliation: GlaxoSmithKline Vaccines, 553 Old Corvallis Road, Hamilton, MT 59840, USA.
authors.forename: Hélène G
authors.initials: HG
authors.lastname: Bazin
authors.affiliation: GlaxoSmithKline Vaccines, 553 Old Corvallis Road, Hamilton, MT 59840, USA.
authors.forename: Yufeng
authors.initials: Y
authors.lastname: Li
authors.affiliation: GlaxoSmithKline Vaccines, 553 Old Corvallis Road, Hamilton, MT 59840, USA.
authors.forename: Juhienah K
authors.initials: JK
authors.lastname: Khalaf
authors.affiliation: GlaxoSmithKline Vaccines, 553 Old Corvallis Road, Hamilton, MT 59840, USA.
authors.forename: Sandra
authors.initials: S
authors.lastname: Mwakwari
authors.affiliation: GlaxoSmithKline Vaccines, 553 Old Corvallis Road, Hamilton, MT 59840, USA.
authors.forename: Mark T
authors.initials: MT
authors.lastname: Livesay
authors.affiliation: GlaxoSmithKline Vaccines, 553 Old Corvallis Road, Hamilton, MT 59840, USA.
authors.forename: Jay T
authors.initials: JT
authors.lastname: Evans
authors.affiliation: GlaxoSmithKline Vaccines, 553 Old Corvallis Road, Hamilton, MT 59840, USA.
authors.forename: David A
authors.initials: DA
authors.lastname: Johnson
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D002470:Cell Survival / Q000187:drug effects; D057809:HEK293 Cells; D006801:Humans; D016898:Interferon-alpha / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D051199:Toll-Like Receptor 7 / Q000235:genetics / Q000378:metabolism*; D051200:Toll-Like Receptor 8 / Q000235:genetics / Q000378:metabolism; D014162:Transfection
chemical_list: D016898:Interferon-alpha; D016328:NF-kappa B; D051199:Toll-Like Receptor 7; D051200:Toll-Like Receptor 8; C002992:8-hydroxyadenine; D000225:Adenine
keywords: Immunostimulants; Oxoadenine; TLR7/8 agonist