Tulay Polat

Structural basis for activation of fibroblast growth factor signaling by sucrose octasulfate.

ABSTRACT Sucrose octasulfate (SOS) is believed to stimulate fibroblast growth factor (FGF) signaling by binding and stabilizing FGFs. In this report, we show that SOS induces FGF-dependent dimerization of FGF receptors (FGFRs). The crystal structure of the dimeric FGF2-FGFR1-SOS complex at 2.6-Å resolution reveals a symmetric assemblage of two 1:1:1 FGF2-FGFR1-SOS ternary complexes. Within each ternary complex SOS binds to FGF and FGFR and thereby increases FGF-FGFR affinity. SOS also interacts with the adjoining FGFR and thereby promotes protein-protein interactions that stabilize dimerization. This structural finding is supported by the inability of selectively desulfated SOS molecules to promote receptor dimerization. Thus, we propose that SOS potentiates FGF signaling by imitating the dual role of heparin in increasing FGF-FGFR affinity and promoting receptor dimerization. Hence, the dimeric FGF-FGFR-SOS structure substantiates the recently proposed “two-end” model, by which heparin induces FGF-FGFR dimerization. Moreover, the FGF-FGFR-SOS structure provides an attractive template for the development of easily synthesized SOS-related heparin agonists and antagonists that may hold therapeutic potential.

Enzyme Catalyzed Regioselective Synthesis of Sucrose Fatty Acid Ester Surfactants

Abstract A commercial subtilisin preparation was used in pyridine to catalyze the regioselective conversion of sucrose and fatty acid vinyl esters into the 1′-O-acyl sucrose derivatives. The 1′-O-laury sucrose, 1′-O-myristyl sucrose and 1′-O-stearyl sucrose were obtained as the major products of these reactions. The 1′,6-di-O-acyl sucrose derivatives were also obtained as minor products. The critical micellar concentration (CMC) of each of these sucrose monoesters was determined.

SYNTHESIS OF SUCROSE-BASED SURFACTANTS THROUGH REGIOSELECTIVE SULFONATION OF ACYLSUCROSE AND THE NUCLEOPHILIC OPENING OF A SUCROSE CYCLIC SULFATE

Synthesis of a new class of anionic and amphoteric sucrose-based surfactants is described. Direct sulfonation of 6-O-acylsucrose using the pyridine‐sulfur trioxide complex led to a mixture of the regioisomeric monosulfates, 6-O-acyl-4 0 ‐O-sulfosucrose and 6-O-acyl-1 0 -O-sulfosucrose, while sulfonation of 1 0 -O-acylsucrose aAorded a mixture of 1 0 -O-acyl-6 0 -O-sulfosucrose and 1 0 -O-acyl-6O-sulfosucrose. The ratio of regioisomers ranged from 4.7:1.0 to 7.5:1.0, depending on reaction time and the size of the fatty acyl chain. The regiospecific synthesis of 6-O-acyl-4-O-sulfosucrose derivatives was accomplished by nucleophilic substitution of the sucrose 4,6-cyclic sulfate using various fatty acids. The amphoteric 6-alkylamino-6-deoxy-4-O-sulfosucrose surfactants were also synthesized by nucleophilic substitution of the sucrose cyclic sulfate by diAerent fatty amines. All the newly synthesized sucrose-based surfactants displayed excellent surface-active properties. # 1998 Elsevier Science Ltd. All rights reserved

The stereospecific synthesis of KDN α-C-glycosides by Samarium mediated reductive desulfonylation of glycosyl phenylsulfone

Abstract Samarium-mediated KDN C -glycoside formation under Barbier conditions is described. The α-selectivity at C-2′ and the S-configuration of C-3″ in the C -disaccharide 15 are confirmed by empirical rules, molecular modeling and IRMA calculation based on NMR data (2D ROESY and 13 C NMR).

Tissue Distribution of [14C]Sucrose Octasulfate following Oral Administration to Rats

AbstractPurpose. Aluminum sucrose octasulfate (SOS) is used clinically to prevent ulcers. Under physiologic conditions, the sodium salt of this drug can be formed. Our objective was to determine whether sodium SOS was absorbed when administered orally. In addition to furthering our understanding of aluminum SOS, this study also aimed to clarify how other polyanionic drugs, such as heparin and low-molecular-weight heparins, are absorbed. Methods. [14C]-labeled and cold sodium SOS (60 mg/kg) were given to rats by stomach tube. Radioactivity was counted in gut tissue, gut washes, and nongut tissue (i.e., lung, liver, kidney, spleen, endothelial, and plasma samples) at 3 min, 6 min, 15 min, 30 min, 60 min, 4 h, and 24 h, and in urine and feces accumulated over 4 h and 24 h. Results. Peak radioactivity was found in the tissue and washes of the stomach, ileum, and colon at 6 min, 60 min, and 4 h, respectively, showing progression through the gut. Gut recovery accounted for 84% of the dose at 6 min but only 12% of the dose at 24 h, including counts from feces. Radioactivity was recovered from nongut tissue (averaging 8.6% of the dose) and accumulated urine (18% of the dose at 24 h). When total body distribution was considered, the recovery of radioactivity was greater for the endothelium than for plasma (peak percentage of the dose was 65% at 15 min, 20% at 3 min, 5% from 20 to 240 min for the vena cava, aortic endothelium, and plasma, respectively). Conclusions. Results indicate that sodium SOS is absorbed, agreeing with previous studies demonstrating the oral absorption of other sulfated polyanions. Endothelial concentrations must be considered when assessing the pharmacokinetics of these compounds. The measured plasma drug concentrations reflect the much greater amounts of drug residing with the endothelium.

Zinc triflate-benzoyl bromide: a versatile reagent for the conversion of ether into benzoate protecting groups and ether glycosides into glycosyl bromides

A simple and efficient method is developed for the chemoselective one-pot conversion of ethers (benzyl, TBDMS and acetal) to the corresponding benzoates by zinc triflate-catalyzed deprotection and benzoylation by benzoyl bromide. In the same reaction, methyl or p-methoxyphenyl glycosides are converted into glycosyl bromides that are useful in glycosylation reactions.

Synthesis of sulfosucrose derivatives for evaluation as regulators of fibroblast growth factor activity

Abstract Based on X-ray crystallographic studies on sucrose octasulfate in complex with fibroblast growth factor and its receptor, three analogs of sucrose octasulfate were regioselectively synthesized for biological evaluation as regulations of cell proliferation and differentiation.