title: Synthesis of chiral phosphoantigens and their activity in gamma delta T cell stimulation.
abstract: Gammadelta T cells expressing Vgamma2Vdelta2 T cell receptors are activated by a broad range of phosphorus-containing small molecules, termed phosphoantigens, and are of interest in the context of the chemotherapy of B cell malignancies. Here, we report the synthesis of four pairs of chiral phosphoantigens: the bromohydrins of isopentenyl diphosphate (Phosphostim), the epoxides of isopentenyl diphosphate (EIPP); and the corresponding bromohydrin and epoxide analogs of but-3-enyl diphosphate. The ability of each compound to stimulate human Vgamma2Vdelta2 T cells was determined by TNF-alpha release and cell proliferation. In these assays, the (R)-bromohydrin diphosphates were, on average, about twice as active as the (S)-bromohydrin diphosphates. In contrast, the (S)-form of EIPP was about twice as active as (R)-EIPP. The activities of the epoxy but-3-enyl diphosphates were both very low. These results suggest that chiral phosphoantigens, as opposed to racemic mixtures, may have utility in immunotherapy.
authors.affiliation: Department of Chemistry, University of Illinois at Urbana-Champaign, 600 South Mathews Avenue, 61801, USA.
authors.forename: Yongcheng
authors.initials: Y
authors.lastname: Song
authors.forename: Yonghui
authors.initials: Y
authors.lastname: Zhang
authors.forename: Hong
authors.initials: H
authors.lastname: Wang
authors.forename: Amy M
authors.initials: AM
authors.lastname: Raker
authors.forename: John M
authors.initials: JM
authors.lastname: Sanders
authors.forename: Erin
authors.initials: E
authors.lastname: Broderick
authors.forename: Allen
authors.initials: A
authors.lastname: Clark
authors.forename: Craig T
authors.initials: CT
authors.lastname: Morita
authors.forename: Eric
authors.initials: E
authors.lastname: Oldfield
mesh_terms: D000438:Alcohols / Q000138:chemical synthesis* / Q000276:immunology; D000941:Antigens / Q000737:chemistry* / Q000276:immunology; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D045782:Hemiterpenes / Q000138:chemical synthesis* / Q000276:immunology; D006801:Humans; D008213:Lymphocyte Activation; D009943:Organophosphorus Compounds / Q000138:chemical synthesis* / Q000276:immunology; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000378:metabolism*; D013237:Stereoisomerism; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism*
chemical_list: D000438:Alcohols; D000941:Antigens; D045782:Hemiterpenes; D009943:Organophosphorus Compounds; D016692:Receptors, Antigen, T-Cell, gamma-delta; C023963:bromohydrins; C004809:isopentenyl pyrophosphate