William Keun Chan Park

Synthesis of novel dendritic glycosides

Abstract Dendritic thiolated glycosides, with and without a spacer moiety, exhibiting valencies of two, four and eight were synthesized using L-lysine as a divalent core structure via solid-phase chemistry.

Synthesis of hyper-branched dendritic lactosides

Abstract Hyper-branched dendritic lactosides with a valency of three ( 16 ) and nine ( 21 ) residues were synthesized using gallic acid ( 6 ) as trivalent core structure and tetraethyleneglycol as hydrophilic spacer.

Combined glycomimetic and multivalent strategies for the design of potent selectin antagonists

Abstract Stepwise large scale synthesis of 3′-sulfo-Lewis x -Glc mimetic of the lead anti-inflammatory agent sialyl Lewis x in a form suitable for copolymerization with acrylamide has been achieved. The resulting watersoluble copolyacrylamide showed inhibition of binding of both L-and E-selectins in the μMolar range.

Synthesis of sialyl Lewis X mimetics using the Ugi four-component reaction

Application of the Ugi four-component condensation to rapidly synthesize a library of glycopeptide mimics of the tetrasaccharide SLe(x) as inhibitors of E- and P-selectin, and to study the effect of varied functionality in mimics on the inhibition is described.

SINGLE STEP SYNTHESES OF LACTOSYLATED CLUSTERS BY TELOMERIZATIONS

Abstract N-Acryloylated lactoside derivatives containing spacer arms of different length were polymerized in the presence of thiols acting as radical scavengers to provide small oligomeric clusters (telomers) in a single step. t -Butyl mercaptan and methyl 3-mercaptopropionate chosen as chain transfer reagents, were used for further attachment to L-lysine methyl ester.

[27] Syntheses of clustered lactosides by telomerization

Publisher Summary Carbohydrate-containing polymers—glycopolymers—have been specifically designed to access the multivalent properties of clusters. However, such glycopolymers constitute poorly defined chemical entities, thus representing mediocre therapeutic agents. This chapter describes a single-step synthesis of a family of clusters derived from quenching polymer growth by chain transfer reagents—telogens. This process, called “telomerization (TM),” has given access to small size polymers— telomers— of 1-6 residues depending on the concentration and nature of the chain transfer reagent used. Lactosylated telomers with and without a spacer arm have been synthesized to provide access to carbohydrate clusters that are useful in the studies of carbohydrate–lectin interactions. Thus, lactosyl azide is readily prepared from peracetylated lactosyl bromide under phase-transfer catalysis (PTC). Reduction of the azide group in lactosyl azide by Raney nickel followed by N -acryloylation and Zemplen de-O-acetylation provides the required monomer (taxogen) in high yield.

Chemical libraries towards protein kinase inhibitors.

Over 500 human protein kinases identified to date are susceptible to play crucial roles in the regulation of many signal transduction pathways, making them significant drug discovery targets. However, their active sites share a high level of similarity, which constitutes a major challenge in the finding of selective and safe inhibitors. In order to meet this challenge, whether via traditional or alternative approaches, the use of chemical libraries to find either unknown natural ligands or specific inhibitors of particular kinases is more important than ever. This review briefly summarizes the recent literature on such libraries of peptides, natural product analogues, and small molecules. Significant chemical scaffolds, some synthetic routes particularly on solid-phase support, and computational tools employed for the efficient design of both selective and bioavailable inhibitors are highlighted.

Evaluation of a Novel Thermal Accelerant for Augmentation of Microwave Energy during Image-guided Tumor Ablation

The primary challenge in thermal ablation of liver tumors (e.g. hepatocellular carcinoma and hepatic colorectal cancer) is the relatively high recurrence rate (~30%) for which incomplete ablation at the periphery of the tumor is the most common reason. In an attempt to overcome this, we have developed a novel thermal accelerant (TA) agent capable of augmenting microwave energy from a distance normally unattainable by a single microwave ablation antenna. This cesium-based block co-polymer compound transforms from a liquid to a gel at body temperature and is intrinsically visible by computed tomography. Using an agarose phantom model, herein we demonstrate that both the rate and magnitude of temperature increase during microwave ablation were significantly greater in the presence of TA when compared with controls. These results suggest robust augmentation of microwave energy, and may translate into larger ablation zone volumes within biologic tissues. Further work using in vivo techniques is necessary to confirm these findings.

The in vivo performance of a novel thermal accelerant agent used for augmentation of microwave energy delivery within biologic tissues during image-guided thermal ablation: a porcine study

Abstract Objectives: To investigate the effects of a novel caesium-based thermal accelerant (TA) agent on ablation zone volumes following in vivo microwave ablation of porcine liver and skeletal muscle, and to correlate the effects of TA with target organ perfusion. Materials and methods: This prospective study was performed following institutional animal care and use committee approval. Microwave ablation was performed in liver and resting skeletal muscle in eight Sus scrofa domesticus swine following administration of TA at concentrations of 0 mg/mL (control), 100 mg/mL and 250 mg/mL. Treated tissues were explanted and stained with triphenyltetrazolium chloride (TTC) for quantification of ablation zone volumes, which were compared between TA and control conditions. Hematoxylin and eosin (H&E) staining was also performed for histologic analysis. General mixed modelling with a log-normal distribution was used for all quantitative comparisons (p = 0.05). Results: A total of 28 ablations were performed in the liver and 18 in the skeletal muscle. The use of TA significantly increased ablation zone volumes in a dose-dependent manner in both the porcine muscle and liver (p < 0.01). Both the absolute mean ablation zone volume and percentage increase in ablation zone volume were greater in the resting skeletal muscle than in the liver. In one swine, a qualitative mitigation of heat sink effects was observed by TTC and H&E staining. Non-lethal polymorphic ventricular tachycardia was identified in one swine, treated with intravenous amiodarone. Conclusions: The use of a novel TA agent significantly increased mean ablation zone volumes following microwave ablation using a porcine model. The relationship between TA administration and ablation size was dose-dependent and inversely proportional to the degree of target organ perfusion, and a qualitative reduction in heat-sink effects was observed.

Solvent independent transition-state structures. Part III. Sulfonyl transfer reactions

A kinetic spectrophotometric study has been performed on the reactions of p-nitrophenyl benzenesulfonate (PNPBS) with m-chlorophenoxide, p-chlorophenoxide, phenoxide, p-methylphenoxide and p-methoxyphenoxide ions in DMSO–H2O mixtures at 25.0 °C. Systematic variation of the DMSO content showed that the second-order rate constants (k2) changed only moderately upon addition of DMSO up to 20 mol% for reaction of p-chlorophenoxide, phenoxide and p-methylphenoxide. On the other hand, the rates of reaction for all of the phenoxide ions studied increased markedly in solvent compositions greater than 40 mol% DMSO. The nature of the transition state (TS) for these reactions was probed via Bronsted-type linear free energy relationships (LFERs). Traditional Bronsted-type plots (method ‘A’), in which the remote substituent on the aryloxide was varied and the solvent composition was held constant, were constructed for the reactions of the phenoxides with PNPBS in each of the following solvent compositions: 40%, 50%, 70% and 90% DMSO by mole. Novel Bronsted-type plots (method ‘B’), in which variation in phenoxide pKa, was imparted through solvent changes while the remote substituent was held constant, were also constructed for the reactions of each of the five phenoxide nucleophiles. Method A yielded a set of lines whose slopes (βnuc values) decreased steadily from 0.75 in 40 mol% DMSO to 0.60 in 90 mol% DMSO. Method B yielded a single straight line, βnuc= 0.60, with satisfactory linearity for all data points (r2= 0.995, 95% Cl =±0.021 ), although closer examination suggested slight curvature with βnuc varying from 0.54 for p-CH3O to 0.66 for m-Cl. These results point to a discrepancy in the traditional view that Bronsted-type LFERs can be directly translated into a TS structure. Considerations based on the Marcus equation suggest that linearity in a Bronsted-type plot may result for a set of reaction series with differing intrinsic barriers provided that ΔG#0 varies linearly with ΔG0.