Synthesis and Th1-immunostimulatory activity of α-galactosylceramide analogues bearing a halogen-containing or selenium-containing acyl chain

Abstract

A novel series of CD1d ligand α-galactosylceramides (α-GalCers) were synthesized by incorporation of the heavy atoms Br and Se in the acyl chain backbone of α-galactosyl-N-cerotoylphytosphingosine. The synthetic analogues are potent CD1d ligands and stimulate mouse invariant natural killer T (iNKT) cells to selectively enhance Th1 cytokine production. These synthetic analogues would be efficient X-ray crystallographic probes to disclose precise atomic positions of alkyl carbons and lipid-protein interactions in KRN7000/CD1d complexes.

An efficient synthetic route to l-γ-methyleneglutamine and its amide derivatives, and their selective anticancer activity

“…The cyclic amide ring was selectively opened with LiOH 28 to afford the common intermediate 19 in 70% yield. Amide was then installed to 19 from ammonium chloride using a published amide coupling protocol, 29 resulting in 20 in 85% yield. Treatment of 20 with TFA removed both the tert-butyl and Boc protecting groups, affording the desired L-g-methyleneglutamine 1 in 80% yield.…”

Synthesis and Biological Evaluation of tert-Butyl Ester and Ethyl Ester Prodrugs of L-γ-Methyleneglutamic Acid Amides for Cancer

“…The cyclic amide ring in 33 was selectively opened with LiOH 16 to afford 44 in 67% yield (the tert-butyl ester remained intact). Finally, an amide-coupling reaction 17 of 44 with ammonium chloride or various amines produced the tert-butyl ester prodrugs 11 and 13-20 of the corresponding L-γ-methyleneglutamic acid amides in 40-75% yield.…”

“…Scheme 1. Syntheses of tert-butyl ester prodrugs of the L-γ-methyleneglutamic acid amides (11)(12)(13)(14)(15)(16)(17)(18)(19)(20). Reagents and conditions: a) AcO t Bu, HClO4, 23 °C, 18h, 70%; b) (Boc)2O, DMAP, Et3N, CH2Cl2, 23 °C, 18 h, 87%; c) i. LiHMDS, CF3CO2CH2CF3, THF, -78 °C, 4 h, ii.…”

“…The capacity for the tert-butyl ester and ethyl ester prodrugs of the L-γ-methyleneglutamic acid amides (11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30) and the cyclic metabolite and its tert-butyl ester and ethyl ester prodrugs (31 -35) to inhibit the growth of the three breast cancer cell lines MCF-7, SK-BR-3, and MDA-MB-231 and the non-malignant MCF-10A breast cell line was assessed after 72 h of treatment (Figure 8). The potencies of all compounds on MCF-7 or SK-BR-3 cell lines were markedly reduced compared to those of previously identified leads (5, 6, or 9; Figure 2), and none exhibited a significant increase in potency compared to positive controls or were equipotent to compounds 5, 6, or 9.…”

Heavy Atom Detergent/Lipid Combined X-ray Crystallography for Elucidating the Structure-Function Relationships of Membrane Proteins

“…Lipidic ligands carrying a heavy atom moiety are also useful for revealing lipid-protein interactions, not only for phase determination but by making the heavy atom position conspicuous with the anomalous difference map. Recently, we developed a heavy atom derivative of α-galactosylceramide (α-GalCer) known as KRN7000, which activates immune responses by inducing cytokine production upon binding to the protein CD1d (Figure 6) [59]. Selenium was incorporated into the fatty acid chain of α-GalCer by substitution of a methylene group through chemical synthesis.…”