Synthesis and evaluation of acyl-chain- and galactose-6''-modified analogues of α-GalCer for NKT cell activation.
α-GalCer is an immunostimulating glycolipid that binds to CD1d molecules and activates invariant natural killer T (iNKT) cells. Here we report a scaled-up synthesis of α-GalCer analogues with modifications in the acyl side chain and/or at the galactose 6''-position, together with their evaluation in vitro and in vivo. Analogues containing 11-phenylundecanoyl acyl side chains with aromatic substitutions (14, 16-21) and Gal-6''-phenylacetamide-substituted α-GalCer analogues bearing p-nitro- (32), p-tert-butyl (34), or o-, m-, or p-methyl groups (40-42) displayed higher IFN-γ/IL-4 secretion ratios than α-GalCer in vitro. In mice, compound 16, with an 11-(3,4-difluorophenyl)undecanoyl acyl chain, induced significant proliferation of NK and DC cells, which should be beneficial in killing tumors and priming the immune response. These new glycolipids might prove useful as adjuvants or anticancer agents.
School of Pharmacy, College of Medicine, National Taiwan University, 1, Jen-Ai Road, Section 1, Taipei 100, Taiwan.
Ming-Han
MH
Hsieh
Jung-Tung
JT
Hung
Ya-Wen
YW
Liw
Yin-Jen
YJ
Lu
Chi-Huey
CH
Wong
Alice L
AL
Yu
Pi-Hui
PH
Liang
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D016207:Cytokines / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D005260:Female; D005699:Galactosylceramides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D008213:Lymphocyte Activation / Q000187:drug effects*; D051379:Mice; D008810:Mice, Inbred C57BL; D008968:Molecular Conformation; D055611:Natural Killer T-Cells / Q000166:cytology / Q000187:drug effects* / Q000276:immunology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D000970:Antineoplastic Agents; D016207:Cytokines; D005699:Galactosylceramides; C493154:alpha-galactosylceramide