sp2-Iminosugar glycolipids as inhibitors of lipopolysaccharide-mediated human dendritic cell activation in vitro and of acute inflammation in mice in vivo

Abstract

Glycolipid mimetics consisting of a bicyclic polyhydroxypiperidine-cyclic carbamate core and a pseudoanomeric hydrophobic tail, termed sp 2 -iminosugar glycolipids (sp 2 -IGLs), target microglia during neuroinflammatory processes. Here we have synthesized and investigated new variants of sp 2 -IGLs for their ability to suppress the activation of human monocyte-derived dendritic cells (DCs) by lipopolysaccharide (LPS) signaling through Toll-like receptor 4. We report that the best lead was (1R)-1dodecylsulfonyl-5N,6O-oxomethylidenenojirimycin (DSO 2 -ONJ), able to inhibit LPS-induced TNFa production and maturation of DCs. Immunovisualization experiments, using a mannoside glycolipid conjugate (MGC) that also suppress LPS-mediated DC activation as control, evidenced a distinct mode of action for the sp 2 -IGLs: unlike MGCs, DSO 2 -ONJ did not elicit internalization of the LPS co-receptor CD14 or induce its co-localization with the Toll-like receptor 4. In a mouse model of LPS-induced acute inflammation, DSO 2 -ONJ demonstrated anti-inflammatory activity by inhibiting the production of the pro-inflammatory interleukin-6. The ensemble of the data highlights sp 2 -IGLs as a promising new class of molecules against inflammation by interfering in Toll-like receptor intracellular signaling.

Thiol-ene "Click" Synthesis and Pharmacological Evaluation of C-Glycoside sp2-Iminosugar Glycolipids

“…The fact that both cancer and parasite infection lead to subversion of the innate immune system suggests that the compounds act as immunoregulators, as reported for other drugs displaying anticancer and antileishmanial behaviors, e.g., the alkyl lipid ethers miltefosine and perifosine [67]. Indeed, the sp 2 -IGL representative DSO 2 -ONJ (Figure 1), which also displayed antiproliferative and antileishmanial activities [43,53], was found to behave as a toll-like receptor-4 (TLR4) antagonist in LPS-induced inflammation models in microglia and dendritic cells, as well as in a mouse model of acute inflammation, displaying potent anti-inflammatory activity [49]. Biochemical and computational data pointed at the p38 mitogen activated protein kinase (MAPK), a master regulator of the immune response, as the putative target.…”

“…The compatibility of the synthetic methodologies for the preparation of sp 2 -iminosugar conjugates with structural diversity-oriented strategies has contributed decisively to expand their range of biological activities. Notably, sp 2 -IGLs have shown to be potent antitumor, antileishmanial, and anti-inflammatory agents [49,50] depending on the nature of the aglycone moiety. For instance, the C -octyl pseudo-α-glycoside 5 N ,6 O -oxomethylidenenojirimycin (ONJ) derivative OC-ONJ (Figure 1) exhibited selective antimitotic, proapoptotic, and antimetastatic activities against breast carcinoma in vitro (noninvasive MCF-7 and invasive MDA-MB-231 cell lines) and in vivo (mice) [51,52].…”

Stereoselective Synthesis of Iminosugar 2-Deoxy(thio)glycosides from Bicyclic Iminoglycal Carbamates Promoted by Cerium(IV) Ammonium Nitrate and Cooperative Brønsted Acid-Type Organocatalysis

“…( (d,1H,J1,2 = 2.1 Hz,5.12 (t,1H,J3,4 = J4,5 = 9.5 Hz,4.46 (dd,1H,J6a,6b = 9.0 Hz,J5,6a = 8.0 Hz,4.34 (dd,1H,J5,6b = 6.6 Hz, (13). Yield: 43 mg (33%, two steps).…”

“…[α]D +36.3 (c 1.4 in MeOH). 1 H NMR (300 MHz, CD3OD) δ 5.09 (d,1 H,J1,2a = 3.6 Hz,J1,2b = 1.5 Hz,4.54 (t,1 H,J6a,6b = J5,6a = 9.0 Hz,4.26 (dd,1 H,J5,6b = 6.0 Hz,3.79 (ddd,1 H,J2a,3 = 11.7 Hz,J3,4 = 9.0 Hz,J2b,3 = 4.5 Hz, General Glycosylation/Thioglycosylation Procedure by Cooperative Organocatalysis. The benzylated iminoglycal donor 5 (20 mg, 57 mol) and the corresponding acceptor (86 mol, 1.5 eq) were placed into a microwave vial under vacuum for 1 h under N2 atmosphere.…”

“…ESI-HRMS Calcd for C33H41NNaO10 [M + Na] + 634.2623, found 634.2610. Data for 30: 1 H NMR (500 MHz, CDCl3) δ 7.37-7.26 (m, 10 H, Ph), 5.83 (d,1 H,J1,2 = 5.6 Hz,5.39 (m,1 H,4.96,4.65 (2 d,2 H,2 JH,H = 11.5 Hz,CHPh),4.70,4.65 (2 d,1 H,2 JH,H = 11.6 Hz,CHPh),4.43 (d,1 H,J1,2 = 3.40 Hz,4.40 (t,1 H,J5,'6a' = J6a',6b' = 7.1 Hz, H-6a'), 4.33 (t, 1 H, H-6b'), 4.14 (d,1 H,J3,4 = 2.9 Hz,4.11 (dd,1 H,J6a,6b = 5.8 Hz,J5,6a = 8.3 Hz,4.07 (dd,1 H,J4,3 = 8.9 Hz,J4,5 = 3.0 Hz, H-4), 4.00 (dd, 1 H, J5,6b = 4.9 Hz, H-6b), 3.98-3.91 (m, 1 H, H-3'), 3.98-3.91 (m, 1 H, H-3), 3.82-3.77 (m, 1 H, H-5'), 3.34 (t, 1 H, J4',5' = 8.9 Hz, H-4'), 2.40 (ddd,1 H J2a',2b' = 13.5 Hz,J2a',3' = 4.8 Hz, H-2a'), 1.60 (ddd, 1 H, H-2b'). 13 C NMR (125.7 MHz, CDCl3) δ 155.9 (CO), 138. , 112. , 105.4 (C-1), 83.8 (C-2), 81.2 (C-4'), 80.4 (C-1'), 79.8 (C-4), 77.5 (C-3'), 74.8-72.3 (CH2Ph), 72.3 (C-3), 67.7 (C-6), 67.0 (C-6'), 53.6 (C-5'), 34.0 (C-2').…”