title: An Enzyme-Directed Imidazoquinoline for Cancer Immunotherapy.
abstract: Herein we report the synthesis and activity of an enzyme-directed immunostimulant with immune cell activation mediated by β-galactosidase, either exogenously added, or on B16 melanoma cells. Covalent attachment of a β-galactopyranoside to an imidazoquinoline immunostimulant at a position critical for activity resulted in a pro-immunostimulant that could be selectively converted by β-galactosidase into an active immunostimulant. The pro-immunostimulant exhibited β-galactosidase-directed immune cell activation as measured by NF-κB transcription in RAW-Blue macrophages or cytokine production (TNF, IL-6, IL-12) in JAWSII monocytes. Conversion of the pro-immunostimulant into an active immunostimulant was also found to occur using β-galactosidase-enriched B16 melanoma cells. In co-culture experiments with either immune cell line, β-galactosidase-enriched B16 cells effected activation of bystander immune cells.
authors.affiliation: Department of Chemistry, Washington State University, 100 Dairy Road, Pullman, WA, 99164, USA.
authors.forename: Joseph D
authors.initials: JD
authors.lastname: Hantho
authors.affiliation: Department of Chemistry, Washington State University, 100 Dairy Road, Pullman, WA, 99164, USA.
authors.forename: Timothy A
authors.initials: TA
authors.lastname: Strayer
authors.affiliation: Department of Chemistry, Washington State University, 100 Dairy Road, Pullman, WA, 99164, USA.
authors.forename: Amy E
authors.identifier: 0000-0002-7393-4846
authors.initials: AE
authors.lastname: Nielsen
authors.affiliation: Department of Chemistry, Washington State University, 100 Dairy Road, Pullman, WA, 99164, USA.
authors.forename: Rock J
authors.identifier: 0000-0002-3557-8123
authors.initials: RJ
authors.lastname: Mancini
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000378:metabolism / Q000627:therapeutic use*; D006801:Humans; D007093:Imidazoles / Q000378:metabolism / Q000627:therapeutic use*; D007167:Immunotherapy; D008546:Melanoma, Experimental / Q000276:immunology / Q000378:metabolism / Q000628:therapy*; D008968:Molecular Conformation; D011804:Quinolines / Q000378:metabolism / Q000627:therapeutic use*; D001616:beta-Galactosidase / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D007093:Imidazoles; D011804:Quinolines; D001616:beta-Galactosidase
keywords: cancer; directed-enzyme prodrug therapy; galactosidase; imidazoquinoline; immunology