{'fraction_non_alphanumeric': 0.04361370716510903, 'fraction_numerical': 0.02232606438213915, 'mean_word_length': 5.2564935064935066, 'pattern_counts': {'":': 0, '<': 0, '<?xml version=': 0, '>': 0, 'https://': 0, 'lorem ipsum': 0, 'www.': 0, 'xml': 0}, 'pii_count': 0, 'substrings_counts': 0, 'word_list_counts': {'cursed_substrings.json': 0, 'profanity_word_list.json': 0, 'sexual_word_list.json': 0, 'zh_pornsignals.json': 0}}
C‐Glycosphingolipids with an exo‐Methylene Substituent: Stereocontrolled Synthesis and Immunostimulation of Mouse and Human Natural Killer T Lymphocytes

Glycosphingolipids (GSLs) are a diverse group of lipids that control a myriad of biological and physiological processes, including stimulation of the immune system.[1] The invariant Natural Killer T (iNKT) cells are an evolutionary conserved sub-lineage of T cells that are characterized by the expression of an invariant T cell receptor (TCR) α-chain (Vα24-Jα18 in human and Vα14-Jα18 in mouse) and reactivity to self- and microbial-derived glycolipids presented by monomorphic HLA class-I-like molecule. CD1d iNKT cells specifically recognize α-galactosylceramide (1, commonly referred to as α-galactosylceramide C26:0 or α-GalCer; see Scheme 1) and its analogues.[2] When NKT cells are activated by GSL antigens presented by CD1d, they rapidly produce large amounts of immunoregulatory cytokines. The ternary complex formed by 1, CD1d, and the iNKT cell TCR has a long half-life,[3] which leads to unselective production of T-helper 1 (Th1) and T-helper 2 (Th2) cytokines; furthermore, overstimulation of iNKT cells by 1 results in a long-term unresponsiveness of iNKT cells.[4] These effects have impeded therapeutic applications of 1 and have led to efforts to prepare various structural analogues that (a) selectively stimulate iNKT cells to secrete either Th1 or Th2 cytokines and (b) have a reduced affinity for the TCR to minimize iNKT cell overactivation.[4] α-GalCer derivatives bearing a truncated phytosphingosine chain (denoted as OCH, 2a)[5] or a C20:2 amide chain (2b)[6] have been identified as ligands that polarize iNKT cells to produce Th2 cytokines. On the other hand, Th1-polarizing ligands have been found by installation of an aromatic group at the terminus of the amide chain (such as 3)[7] or derivatization of the galactosyl 6-hydroxyl group.[8]