Synthesis of pyranobenzopyrans from D-glucal using ionic liquids.

Imidazolium room temperature ionic liquids (RTILs) were used as solvents in the Lewis acid-catalyzed cycloaddition reactions of D-glucal with substituted salicylaldehydes. These reactions selectively led to various, novel, cis-pyrano [4,3-b]benzopyrans in modest yields, different products than those isolated from analogous solution studies. Furan diol was isolated as the major byproduct from all the reactions. The use of RTILs facilitated the use of unprotected sugars in these reactions.

Inverse-electron demand Diels Alder Reactions between glycals and tetrazines.

The inverse-electron demand Diels Alder reaction (IEDDA) of substituted tetrazines with 2,3-unsaturated sugars (glycals) has been investigated to prepare novel carbohydrate-based heterocycles. The cycloaddition reactions occurred in moderate to good, isolated yields and gave acyclic, C-linked pyranose diazines as the major products (33-90%). The effects of variations in sugars, sugar protecting groups, and reaction solvents on the yields and products obtained in these reactions were studied. Lower yields of adducts were isolated for TBDMS-protected glucals and for 4,6-O-benzylidene protected glucals. When unprotected sugars were used, the reactions failed to give the desired cycloadducts. A range of substituted tetrazines were also evaluated in these reactions. For comparison, HOMO-[LUMO + 1] gaps for glycal-tetrazine pairs were calculated using Density Functional (DFT) calculations at the B3LYP/631G+ level.

Small-Molecule Carbohydrate-Based Immunostimulants.

In this review, we discuss small-molecule, carbohydrate-based immunostimulants that target Toll-like receptor 4 (TLR-4) and cluster of differentiation 1D (CD1d) receptors. The design and use of these molecules in immunotherapy as well as results from their use in clinical trials are described. How these molecules work and their utilization as vaccine adjuvants are also discussed. Future applications and extensions for the use of these analogues as therapeutic agents will be outlined.

Synthesis and immunological evaluation of a low molecular weight saccharide with TLR-4 agonist activity.

The paucity of FDA approved adjuvants renders the synthesis, characterization, and use of new compounds as vaccine adjuvants, a necessity. For this purpose, a novel saccharide analog has been synthesized from glucosamine, pyruvylated galactose and 1,4-cyclohexanediol and its biological efficacy was determined in innate immune cells. More specifically, we assessed the production of pro-inflammatory cytokines from the murine monocyte cell line, Raw 264.7 and from C57 BL/6 mouse peritoneal macrophages following exposure to the saccharide analog. Our data conclude that the novel saccharide has immunostimulatory activity on mouse macrophages as indicated by the elevated levels of IL-6 and TNF-α in culture supernatants. This effect was TLR-4-dependent but TLR-2-independent. Our data, suggest TLR-4 agonism; a key feature of vaccine adjuvants.

An improved synthesis of 3,6-anhydro-D-glucal and a study of its unusual chemical reactivity.

6-O-Tosyl-d-glucal 1 upon treatment with excess LiAlH4 unexpectedly gave 3,6-anhydro-d-glucal 2 as a major product in good yield. A crystal structure was obtained. Reaction of the anhydride 2 with N-iodosuccinimide (NIS) in excess methanol resulted in the formation of diastereomeric 2-deoxy-2-iodoglycosides. Addition of ceric (IV) ammonium nitrate and thiophenol to a solution of 2 in acetonitrile gave a mixture of 2-deoxy and 2,3-unsaturated thioglycosides. Reaction of 1,2:3,4-di-O-isopropylidine-α-d-galactopyranose with the anhydro sugar 2 in the presence of N-iodosuccinimide did not give the expected iodoglycoside mixture, but instead gave an unusual 1,4:3,6-dianhydride 7 as the major product.

Synthesis, DNA binding and anti-leukemic activity of an aminoacyl nucleolipid.

The synthesis and characterization of a new class of DNA binding molecule exhibiting potent and selective anti-leukemic activity is described. The synthesis of an aminoacyl nucleolipid was developed from an efficient EEDQ coupling strategy, in which a series of seven bioconjugates were synthesized in yields of 53-78%. Guanosine bioconjugate 7, was used as building block for the synthesis of a target aminoacyl nucleolipid 14. Its GRP78 DNA binding affinity was confirmed by gel shift assay, CD spectroscopy, Tm measurements and dynamic light scattering experiments. Moreover, in a single dose (10 µM) screen against a panel of 60 cancer cell lines, aminoacyl nucleolipid 14 was found to selectively trigger greater than 90% cell death in a SR human leukemia cancer cell line. The reported aminoacyl nucleolipid represents a useful model for a new class of DNA binding molecules for the development of potent and selective anti-cancer agents.

Synthesis of chiral mesoporous silicas with oligo(saccharide) surfaces and their use in separation of stereoisomers.

Novel chiral mesoporous silicas (SBA-15 motif) with chemically bonded oligo(saccharides) (1, 3, and 7 glucose units) were obtained through the cocondensation of organosilicon derivatives of the oligo(saccharides) and silica precursors in the presence of polymer surfactant template under mild acidic conditions. The pore order and structure of the materials prepared were characterized by transmission electron microscopy and nitrogen adsorption. The direct application of the oligo(saccharide)-grafted SBA-15 stationary phases in the HPLC separations of stereoisomers was demonstrated for the first time.

Carbohydrate-based drugs in the treatment of epilepsy, depression and other affective disorders.

Mental illness affects a quarter of the US population. Recently, it has been shown that new, carbohydrate-based drugs hold promise in the treatment of central nervous system (CNS) disorders. A variety of ways in which drugs of this sort may reduce the symptoms of epilepsy, depression and other affective disorders have been proposed, including: targeting the immune system, disrupting glycolysis, acting at different sites in the hypothalamic-pituitary-adrenal (HPA) axis, and targeting specific biochemical pathways such as the inositol pathway. In the present review, the structure-activity relationships (SARs) of a wide variety of CNS-active carbohydrates are presented.

Why are silyl ethers conformationally different from alkyl ethers? Chair-chair conformational equilibria in silyloxycyclohexanes and their dependence on the substituents on silicon. The wider roles of eclipsing, of 1,3-repulsive steric interactions, and of attractive steric interactions.

An NMR study of the diaxial/diequatorial chair equilibrium in a range of silylated derivatives of trans-1,4- and trans-1,2-dihydroxycyclohexane is reported and discussed with a view to explaining unusually large populations of chair conformations with axial substituents, noted previously for some monosilyloxycyclohexanes and in some silylated sugars. X-ray diffraction studies of three bis-triphenylsilyloxycyclohexanes are reported and show both axial and equatorial silyloxy groups with the exocyclic bonds eclipsed. Eclipsing is also suggested by molecular mechanics (MM3) calculations on such derivatives. Both axial and equatorial tertiary silyl groups have 1,3-repulsive interactions with whatever substituents or hydrogen atoms are at the two adjacent equatorial positions, and these are relieved by rotation toward the eclipsed conformation of the exocyclic C-O bond. The three substituents on silicon interact attractively with the nine atoms at the 3, 4, and 5-positions of the cyclohexane ring and calculations suggest that these stabilizing interactions are significantly greater in the axial than in the equatorial conformation. An equatorial C-OSiR(3) bond with one or two equatorial neighbors has a restricted potential energy well that becomes much broader when the bond is axial without any equatorial neighbors in the alternative chair. Adjacent silyl groups in the 1,2-disubstituted series interact in a stabilizing way overall in all conformations, this being particularly marked in the diaxial conformation of the more complex ethers. These factors lead to unusually large axial populations.

The synthesis and biological evaluation of novel bridging nucleoside analogues.

Novel bridging nucleoside analogues were prepared by cycloaddition reactions between pyranose glycals and barbiturate-derived, reactive thionoimides in modest yields. In all of the reactions conducted, the major cycloadducts obtained were the bottom faced adducts resulting from endo addition to the glycal. The adducts were stable to a variety of acidic reaction conditions and several of the compounds showed moderate activities against HIV-1 in primary human lymphocytes. One compound displayed anti-herpes simplex virus type-1 activity in Vero cells. Cytotoxicity measurements were also obtained.