title: Synthesis and evaluation of 8-oxoadenine derivatives as potent Toll-like receptor 7 agonists with high water solubility.
abstract: We report the discovery of novel series of highly potent TLR7 agonists based on 8-oxoadenines, 1 and 2 by introducing and optimizing various tertiary amines onto the N(9)-position of the adenine moiety. The introduction of the amino group resulted in not only improved water solubility but also enhanced TLR7 agonistic activity. In particular compound 20 (DSR-6434) indicated an optimal balance between the agonistic potency and high water solubility. It also demonstrated a strong antitumor effect in vivo by intravenous administration in a tumor bearing mice model.
authors.affiliation: Chemistry Research Laboratories, Dainippon Sumitomo Pharma. Co., Ltd, 3-1-98 Kasagade-naka, Osaka-city, Osaka 554-0022, Japan.
authors.forename: Tomoaki
authors.initials: T
authors.lastname: Nakamura
authors.forename: Hiroki
authors.initials: H
authors.lastname: Wada
authors.forename: Hirotaka
authors.initials: H
authors.lastname: Kurebayashi
authors.forename: Tom
authors.initials: T
authors.lastname: McInally
authors.forename: Roger
authors.initials: R
authors.lastname: Bonnert
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Isobe
mesh_terms: D000225:Adenine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D061605:Administration, Intravenous; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D015394:Molecular Structure; D012995:Solubility; D051199:Toll-Like Receptor 7 / Q000819:agonists*; D014867:Water / Q000737:chemistry*
chemical_list: D000970:Antineoplastic Agents; C581841:DSR-6434; D051199:Toll-Like Receptor 7; D014867:Water; C002992:8-hydroxyadenine; D000225:Adenine