Marc d'Alarcao

Synthesis of cyclitols via ring-closing metathesis

A convenient synthesis of enantiomerically pure and differentially protected L-chiro -a ndmyo-inositols as well as conduritols B and F from 2,3,4-tri-O-benzyl-D-xylopyranose via ring-closing metathesis is reported. The facile synthesis of conduritol B constitutes a short formal synthesis of ()-cyclophellitol.

Synthesis of a potentially insulin-mimetic phosphodisaccharide

The synthesis of phosphodisaccharide 1 from myo-inositol and D-glucosamine has been accomplished. This compound is the terminal (and presumably essential) portion of both the putative insulin second messenger and the phosphatidylinositol glycan protein membrane anchor.

Fluorination of mammalian cell surfaces via the sialic acid biosynthetic pathway

Metabolic oligosaccharide engineering has been employed to introduce fluorine-containing groups onto mammalian cell surfaces. Incubation of HeLa, Jurkat, and HL60 cells in culture with fluorinated sialic acid and mannosamine analogues resulted in cell-surface presentation of fluorinated glycans. Metabolic conversion of fluorinated precursors was detected and quantified by DMB-derivatization and HPLC ESI-MS analysis. Between 7% and 72% of total membrane-associated sialosides were fluorinated, depending on the precursor used and the cell type. Fluorination of mammalian cell surfaces provides a means for introducing a bioorthogonal surface for modulating noncovalent interactions such as those involved in cell adhesion.

A new irreversible inhibitor of soybean lipoxygenase; relevance to mechanism

Abstract The mechanism of the oxidation of arachidonic acid by soybean lipoxygenase has been studied kinetically with the help of a newly designed inhibitor. It is proposed that olefin complexation with Fe(III) activates arachidonic acid for deprotonation by a basic group on the enzyme leading to an intermediate which then combines with dioxygen.

Enantiospecific synthesis of a differentially protected L-chiro-inositol from D-xylose

Abstract A convenient synthesis of differentially protected L- chiro -inositol 7 from 2,3,4-tri- O -benzyl-D-xylopyranose is described. The structure of 7 was confirmed by its transformation to the pentabenzylated derivative of (−)-quebrachitol.

Synthesis of inositol 2-phosphate-quercetin conjugates

The antiproliferative flavonoid, quercetin, is limited in its pharmacological utility by its low water solubility. In this paper, we describe the synthesis of two quercetin analogues prepared by linking the hydroxyl group at the 3- or 5-position of the flavonoid to the 1-hydroxyl group of myo-inositol-2-phosphate via a succinate diester linkage. The resulting conjugates were found to have dramatically enhanced water solubility relative to quercetin; the 5-linked quercetin analogue 2 had a water solubility of > 300 mg/mL at 20 degrees C. Comparison of the in vitro cytotoxicity and antiproliferative activity of conjugate 2 with those of quercetin toward cultured human colon adenocarcinoma (SW480) and human glioblastoma (U87MG) cells indicated that this modification of quercetin does not significantly diminish its activity in these assays.

Synthesis of new lipoxygenase inhibitors 13-Thia- and 10-Thiaarachidonic acids

Abstract Short, efficient and stereocontrolled syntheses are reported for 13-thiaarachidonic acid (11) and 10-thiaarachidonic acid (17), valuable substrates for the study of the mechanisms of enzymatic lipoxygenation of polyunsaturated fatty acids.

Synthesis of inositol glycan cyclic phosphates

An efficient synthesis of tri-, tetra-, and pentasaccharide cyclic phosphates 1-5, structurally related to natural inositol phosphate glycans, is reported. The title compounds were assembled by PhSeOTf-promoted glycosylation of the known glucosamine precursor, t-butyldimethylsilyl 2-azido-3,6-di-O-benzyl-2-deoxy-beta-D-glucopyranoside (8) with protected 1-methylthio mono-, di-, and trimannosides 7a-c, and, after conversion into glycosyl fluorides, Cp2ZrCl2- AgOTf-promoted glycosylation of differentially protected optically pure 1D-myo-inositol 11. The syntheses were completed by installing the cyclic phosphate moieties with methylpyridinium dichlorophosphate and finally, removal of all protecting groups by dissolving-metal reduction.

Formation and cell-medium partitioning of autoinhibitory free fatty acids and cyclodextrin's effect in the cultivation of Bordetella pertussis

Palmitic, palmitoleic and stearic acids were found in the extracted cellular lipids of virulent Bordetella pertussis as unesterified acids in confirmation of earlier taxonomic analyses. The same free fatty acids (FFAs) were found in the spent culture supernatant in concentrations higher than in the uninoculated medium, indicating that they are released into the extracellular medium. These long-chain fatty acids are known to inhibit the growth of B. pertussis at concentrations as low as 1 ppm. Measurement of palmitate cell-medium partitioning demonstrated a strong tendency of FFAs for cellular adsorption. Inhibition kinetics indicated that the cell-bound FFA was responsible for inhibition and that the specific cellular FFA concentrations actually found during growth were similar to those determined to be inhibitory. Autoinhibition by these endogenous FFAs provides an explanation of the low maximum cell concentrations currently attainable in liquid media. Addition of soluble dimethyl-beta-cyclodextrin (MebetaCD) to FFA-inhibited cultures resulted in a rapid reversal of the inhibition. A corresponding shift in the distribution of FFAs from the cells to the extracellular medium demonstrated that MebetaCD sequesters FFAs. Although MebetaCD did not increase final cell concentrations and even had an adverse effect on growth at concentrations above 1 g l-1, it did (at 1 g l-1 extend the initial period of high growth rate leading to shorter cultivation times.

12-methylidene-10(Z), 13(Z)-nonadecadienoic acid, a new irreversible inhibitor of soybean lipoxygenase

Abstract Aerobic incubation of soybean lipoxygenase with 12-methylidene-10(Z, 13(Z-nonadecadienoic acid results in irreversible deactivation of the enzyme in a manner consistent with a recently proposed mechanism for lipoxygenation.