RCAI-17, 22, 24–26, 29, 31, 34–36, 38–40, and 88, the analogs of KRN7000 with a sulfonamide linkage: Their synthesis and bioactivity for mouse natural killer T cells to produce Th2-biased cytokines

Tashiro, Takuya; Hongo, Naomi; Nakagawa, Ryusuke; Seino, K.; Watarai, Hiroshi; Ishii, Yasuyuki; Taniguchi, Masaru; Mori, Kenji

doi:10.1016/j.bmc.2008.08.060

Cited by 31 publications

(16 citation statements)

References 21 publications

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“…In addition, a sulfonamido analog (30) and an ,-difluoroacylated one (31) with an acidic amide NH also showed the Th2-biased cytokine response. 94,95) We also found that an ureido analog (32) induced Th1-type cytokine production.…”

Section: 4886)mentioning

confidence: 69%

Structure-Activity Relationship Studies of Novel Glycosphingolipids That Stimulate Natural Killer T-Cells

Tashiro

2012

Bioscience, Biotechnology, and Biochemistry

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Section: 4886)mentioning

confidence: 69%

Structure-Activity Relationship Studies of Novel Glycosphingolipids That Stimulate Natural Killer T-Cells

Tashiro

2012

Bioscience, Biotechnology, and Biochemistry

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“…The possible molecular mechanisms of OCH-induced Th2 response might be related to its less avidity and stability in binding to CD1d than α-GalCer, leading to a less sustained TCR stimulation on iNKT cells [8, 59, 60]. Other α-GalCer analogues containing sulfonamide linkage to acyl chain induced Th2 response comparable to OCH in mouse splenocytes [61]. Besides, our group has shown that α-GalCer analogues containing a phenyl group in their acyl tail are more effective than α-GalCer in inducing Th1 cytokines/chemokines and human NKT cell expansion.…”

Section: Avidity and Stability Of Tcr-glycolipids-cd1d Complex Dictatmentioning

confidence: 99%

Tailored design of NKT-stimulatory glycolipids for polarization of immune responses

Hung

Huang

2017

J Biomed Sci

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Natural killer T (NKT) cell is a distinct population of T lymphocytes that can rapidly release massive amount of Th1 and Th2 cytokines upon the engagement of their T cell receptor with glycolipids presented by CD1d. The secreted cytokines can promote cell-mediated immunity to kill tumor cells and intracellular pathogens, or suppress autoreactive immune cells in autoimmune diseases. Thus, NKT cell is an attractive target for developing new therapeutics to manipulate immune system. The best-known glycolipid to activate NKT cells is α-galactosylceramide (α-GalCer), which has been used as a prototype for designing new NKT stimulatory glycolipids. Many analogues have been generated by modification of the galactosyl moiety, the acyl chain or the phytosphingosine chain of α-GalCer. Some of the analogues showed greater abilities than α-GalCer in polarizing immune responses toward Th1 or Th2 dominance. Among them, several analogues containing phenyl groups in the lipid tails were more potent in inducing Th1-skewed cytokines and exhibited greater anticancer efficacy than α-GalCer. Analyses of the correlation between structure and activity of various α-GalCer analogues on the activation of iNKT cell revealed that CD1d–glycolipid complexes interacted with the same population of iNKT cell expressing similar T-cell receptor Vβ as α-GalCer. On the other hand, those phenyl glycolipids with propensity for Th1 dominant responses showed greater binding avidity and stability than α-GalCer for iNKT T-cell receptor when complexed with CD1d. Thus, it is the avidity and stability of the ternary complexes of CD1d-glycolipid-iNKT TCR that dictate the polarity and potency of immune responses. These findings provide a key to the rationale design of immune modulating glycolipids with desirable Th1/Th2 polarity for clinical application. In addition, elucidation of α-GalCer-induced anergy, liver damage and accumulation of myeloid derived suppressor cells has offered explanation for its lacklustre anti-cancer activities in clinical trials. On other hand, the lack of such drawbacks in glycolipid analogues containing phenyl groups in the lipid tails of α-GalCer coupled with the greater binding avidity and stability of CD1d-glycolipid complex for iNKT T-cell receptor, account for their superior anti-cancer efficacy in tumor bearing mice. Further clinical development of these phenyl glycolipids is warranted.

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“…They reported that the triazole moiety was tolerated and resulted in a TH1 cytokine release profile. Esters [89], ethers [89,90], sulfonamides [91], and primary amines [90] have also been used as amide replacements. The ether and amine analogs did not induce iNKT cell stimulation, suggesting that the hydrogen bond to the amide nitrogen is essential for iNKT cell stimulation [89,90].…”

Section: α-Galcer Analogsmentioning

confidence: 99%

“…The ester analogs induced a TH2 cytokine response, albeit less potently than α-GalCer [89]. The sulfonamide analogs also biased a TH2 response in vitro , but failed to elicit iNKT cell proliferation in vivo [91] Serine-based ceramide analogs have also been explored [92]; these stimulated iNKT cells similarly to α-GalCer, but were significantly less potent. Recently, Sun et al [90] designed analogs that effectively tested the importance of the positional requirement of the galactose by introducing a short linker in between the ceramide and the glycosidic bond, as well as an analog that attached the saccharide at the 2′-position.…”

Section: α-Galcer Analogsmentioning

confidence: 99%

Stimulation of Natural Killer T Cells by Glycolipids

et al. 2013

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Natural killer T (NKT) cells are a subset of T cells that recognize glycolipid antigens presented by the CD1d protein. The initial discovery of immunostimulatory glycolipids from a marine sponge and the T cells that respond to the compounds has led to extensive research by chemists and immunologists to understand how glycolipids are recognized, possible responses by NKT cells, and the structural features of glycolipids necessary for stimulatory activity. The presence of this cell type in humans and most mammals suggests that it plays critical roles in antigen recognition and the interface between innate and adaptive immunity. Both endogenous and exogenous natural antigens for NKT cells have been identified, and it is likely that glycolipid antigens remain to be discovered. Multiple series of structurally varied glycolipids have been synthesized and tested for stimulatory activity. The structural features of glycolipids necessary for NKT cell stimulation are moderately well understood, and designed compounds have proven to be much more potent antigens than their natural counterparts. Nevertheless, control over NKT cell responses by designed glycolipids has not been optimized, and further research will be required to fully reveal the therapeutic potential of this cell type.

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RCAI-17, 22, 24–26, 29, 31, 34–36, 38–40, and 88, the analogs of KRN7000 with a sulfonamide linkage: Their synthesis and bioactivity for mouse natural killer T cells to produce Th2-biased cytokines

Cited by 31 publications

References 21 publications

Structure-Activity Relationship Studies of Novel Glycosphingolipids That Stimulate Natural Killer T-Cells

Structure-Activity Relationship Studies of Novel Glycosphingolipids That Stimulate Natural Killer T-Cells

Tailored design of NKT-stimulatory glycolipids for polarization of immune responses

Stimulation of Natural Killer T Cells by Glycolipids

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