William J. Sanders

Synthetic ligands point to cell surface strategies

Protein shedding, the proteolytic release of a cell surface protein, can serve a regulatory role by liberating soluble molecules into circulation while decreasing their concentration on the cell surface. We have created a new class of multivalent ligands, ‘neoglycopolymers’, which are designed to promote the proteolytic cleavage of a cell adhesion molecule involved in the inflammatory response, L-selectin. These synthetic ligands induce the release of the extracellular portion of L-selectin by appropriating an endogenous protease; such activities suggest new strategies to generate anti-inflammatory agents and regulate the cell surface.

Inhibition of L-selectin-mediated Leukocyte Rolling by Synthetic Glycoprotein Mimics*

Synthetic carbohydrate and glycoprotein mimics displaying sulfated saccharide residues have been assayed for their L-selectin inhibitory properties under static and flow conditions. Polymers displaying the L-selectin recognition epitopes 3′,6-disulfo Lewis x(Glc) (3-O-SO3-Galβ1α4(Fucα1α3)-6-O-SO3-Glcβ-OR) and 3′,6′-disulfo Lewis x(Glc) (3,6-di-O-SO3-Galβ1α4(Fucα1α3)Glcβ-OR) both inhibit L-selectin binding to heparin under static, cell-free binding conditions with similar efficacies. Under conditions of shear flow, however, only the polymer displaying 3′,6-disulfo Lewis x(Glc) inhibits the rolling of L-selectin-transfected cells on the glycoprotein ligand GlyCAM-1. Although it has been shown to more effective than sialyl Lewis x at blocking the L-selectin–GlyCAM-1 interaction in static binding studies, the corresponding monomer had no effect in the dynamic assay. These data indicate that multivalent ligands are far more effective inhibitors of L-selectin-mediated rolling than their monovalent counterparts and that the inhibitory activities are dependent on the specific sulfation pattern of the recognition epitope. Importantly, our results indicate the L-selectin specificity for one ligand over another found in static, cell-free binding assays is not necessarily retained under the conditions of shear flow. The results suggest that monovalent or polyvalent carbohydrate or glycoprotein mimetics that inhibit selectin binding in static assays may not block the more physiologically relevant process of selectin-mediated rolling.

New Oligocene primate from Saudi Arabia and the divergence of apes and Old World monkeys

It is widely understood that Hominoidea (apes and humans) and Cercopithecoidea (Old World monkeys) have a common ancestry as Catarrhini deeply rooted in Afro-Arabia. The oldest stem Catarrhini in the fossil record are Propliopithecoidea, known from the late Eocene to early Oligocene epochs (roughly 35–30 Myr ago) of Egypt, Oman and possibly Angola. Genome-based estimates for divergence of hominoids and cercopithecoids range into the early Oligocene; however, the mid-to-late Oligocene interval from 30 to 23 Myr ago has yielded little fossil evidence documenting the morphology of the last common ancestor of hominoids and cercopithecoids, the timing of their divergence, or the relationship of early stem and crown catarrhines. Here we describe the partial cranium of a new medium-sized (about 15–20 kg) fossil catarrhine, Saadanius hijazensis, dated to 29–28 Myr ago. Comparative anatomy and cladistic analysis shows that Saadanius is an advanced stem catarrhine close to the base of the hominoid–cercopithecoid clade. Saadanius is important for assessing competing hypotheses about the ancestral morphotype for crown catarrhines, early catarrhine phylogeny and the age of hominoid–cercopithecoid divergence. Saadanius has a tubular ectotympanic but lacks synapomorphies of either group of crown Catarrhini, and we infer that the hominoid–cercopithecoid split happened later, between 29–28 and 24 Myr ago.

Stereoselective, Lewis acid-catalyzed glycosylation of alcohols by glucose 1,2-cyclic sulfites

Abstract α- d -Glucopyranose-1,2-cyclic sulfites ( 1a–c ) have been prepared by reaction of a suitably protected glucose residue and thionyl diimidazole. Reaction of these compounds with alcohols in the presence of Yb(OTf) 3 or Ho(OTf) 3 stereoselectively affords β-O-glycosides.

SYNTHESIS OF SULFATED TRISACCHARIDE LIGANDS FOR THE SELECTINS

Abstract In a directed effort to elucidate the molecular factors responsible for selectin-mediated cell adhesion events as a basis for the generation of potent and specific inhibitors of these processes, we have synthesized a variety of sulfated analogs of the trisaccharide recognition epitopes Lewis a [Le a : Galβ1→3(Fucα1→4)GlcNAc] and Lewis x [Le x : Galβ1→4(Fucα1→3)GlcNAc]. Our divergent synthetic route allows for the synthesis of gram quantities of these sulfated trisaccharides from common intermediates in 10–20% overall yields and in no more than 15 linear steps. In addition, we have anchored the reducing end of the Le a and Le x trisaccharide precursors with a β-allyl aglycone, providing a single anomer of each final product and allowing for further modification into multivalent derivatives.

Evolution of locomotion in Anthropoidea: the semicircular canal evidence

Our understanding of locomotor evolution in anthropoid primates has been limited to those taxa for which good postcranial fossil material and appropriate modern analogues are available. We report the results of an analysis of semicircular canal size variation in 16 fossil anthropoid species dating from the Late Eocene to the Late Miocene, and use these data to reconstruct evolutionary changes in locomotor adaptations in anthropoid primates over the last 35 Ma. Phylogenetically informed regression analyses of semicircular canal size reveal three important aspects of anthropoid locomotor evolution: (i) the earliest anthropoid primates engaged in relatively slow locomotor behaviours, suggesting that this was the basal anthropoid pattern; (ii) platyrrhines from the Miocene of South America were relatively agile compared with earlier anthropoids; and (iii) while the last common ancestor of cercopithecoids and hominoids likely was relatively slow like earlier stem catarrhines, the results suggest that the basal crown catarrhine may have been a relatively agile animal. The latter scenario would indicate that hominoids of the later Miocene secondarily derived their relatively slow locomotor repertoires.