Timothy P. Kogan

The Synthesis of Substituted Methoxy-Poly(Ethyleneglycol) Derivatives Suitable for Selective Protein Modification

Abstract The syntheses of methoxypoly(ethyleneglycol) derivatives, functionalized either as hydrazides for the selective attachment of methoxypoly(ethyleneglycol) to carbohydrate domains of glycoproteins, or as iodoacetamides and maleimides for the modification of free sulfhydryl groups, are described.

Small-molecule selectin inhibitor protects against liver inflammatory response after ischemia and reperfusion

BACKGROUND The selectin family of adhesion molecules plays a key role in the neutrophil-mediated injury observed after ischemia and reperfusion. In our study, we investigated the effects of TBC-1269, a novel small-molecule, nonoligosaccharide inhibitor of P-, E-, and L-selectin binding, in the liver inflammatory response after 90 minutes of warm ischemia. STUDY DESIGN Total liver ischemia was produced in Sprague-Dawley rats for 90 minutes using an extracorporeal portosystemic shunt. The animals were divided into five groups including: the sham (group 1), ischemic control (group 2) receiving only the vehicle, and the treated groups receiving TBC-1269 at a dose of 25 mg/kg at different times of administration: 15 minutes before reperfusion (group 3), at reperfusion (group 4), and 15 minutes after reperfusion (group 5). The following indices were analyzed: 7-day survival, liver injury tests, liver tissue myeloperoxidase as an index of neutrophil infiltration, and liver histology. RESULTS TBC-1269 treated groups experienced a significant increase in survival compared with controls. Best overall survival, 70%, was observed when TBC-1269 (Texas Biotechnology Corporation, Houston, TX) was administered 15 minutes before reperfusion (p < 0.05). This group also showed a marked decrease (p < 0.05) in liver enzyme levels at 6 hours after reperfusion. Neutrophil migration was also significantly ameliorated (81%), as reflected by decreased myeloperoxidase levels. We observed improved histologic damage scores in the treated group compared with controls (p < 0.05). CONCLUSIONS A small-molecule selectin inhibitor (TBC-1269) had a protective effect in livers subjected to 90 minutes of warm hepatic ischemia and 6 hours of reperfusion by decreasing neutrophil infiltration, migration and subsequent tissue damage. The best protective effect was achieved when the compound was administered 15 minutes before reperfusion. These findings offer a new therapeutic alternative for protection against ischemia and reperfusion injury.

A Regio- and stereocontrolled total synthesis of (-)-indolactam-V

Abstract (-)-Indolactam-V (IL-V) ( 1 ) -was prepared in 10 steps from L-tryptophan methyl ester in 17.1% overall yield. The key steps involve regiospecific thallation of the acylindole intermediate ( 4 ), followed by azide displacement and reduction to introduce the 13-amino group. Control of the C-ll stereocenter was achieved by S N 2 displacement of the chiral inflate ( 10 ), derived from D-valine. The thallium mediated closure of dipeptide ( 17 ) did not provide an alternative route to IL-V.

Glycomimetic selectin inhibitors: (α-D-mannopyranosyloxy)methylbiphenyls

Abstract A novel class of biphenyl-based compounds were investigated for their ability to inhibit sialyl Lewis X (sLex) dependent binding of HL-60 cells to E- and P-selectin fusion proteins. Compounds ( 2b ) and ( 2h ) demonstrated improved binding as compared to both the natural ligand sLex and a previously reported inhibitor TBC-265 ( 1 , R = 3-CH2CO2H).

Novel inhibitors of α4β1 integrin receptor interactions through library synthesis and screening

Abstract A library of 2302 small molecule β-turn mimetics was screened for inhibition of the α4β1 integrin-CS1 splice variant binding interaction. Preliminary data revealed several active ligands, and validation with purified material culminated in the identification of some of the first small molecule ligands (1, IC50 = 5 μM, and 2, IC50 = 8 μM) to be reported for this class of integrins.

A 3D Structure Model of Integrin α4β1 Complex: I. Construction of a Homology Model of β1 and Ligand Binding Analysis

It is well established that integrin alpha 4 beta 1 binds to the vascular cell adhesion molecule (VCAM) and fibronectin and plays an important role in signal transduction. Blocking the binding of VCAM to alpha 4 beta 1 is thought to be a way of controlling a number of disease processes. To better understand how various inhibitors might block the interaction of VCAM and fibronectin with alpha 4 beta 1, we began constructing a structure model for the integrin alpha 4 beta 1 complex. As the first step, we have built a homology model of the beta 1 subunit based on the I domain of the integrin CD11B subunit. The model, including a bound Mg(2+) ion, was optimized through a specially designed relaxation scheme involving restrained minimization and dynamics steps. The native ligand VCAM and two highly active small molecules (TBC772 and TBC3486) shown to inhibit binding of CS-1 and VCAM to alpha 4 beta 1 were docked into the active site of the refined model. Results from the binding analysis fit well with a pharmacophore model that was independently derived from active analog studies. A critical examination of residues in the binding site and analysis of docked ligands that are both potent and selective led to the proposal of a mechanism for beta 1/beta 7 ligand binding selectivity.

Solution-phase combinatorial synthesis of ureas using nitrophenylcarbamates.

Nitrophenylcarbamates were reacted with various amines to yield ureas. A high throughput purification of these crude products was achieved by using polymer bound scavengers.

The synthesis of chiral 3-oxo-6-[(phenylmethoxy)-carbonyl]-2-piperazineacetic acid esters designed for the presentation of an aspartic acid side chain. A subsequent novel Friedel Crafts reaction

Abstract The syntheses of (2 S , 6 R )-, and (2 S , 6 S )-3-oxo-6-[(phenylmethoxy)carbonyl]-2,-piperazineacetic acid methyl esters from L - or D -serine and dimethyl- D -malate are described. Acylation of the (2 S , 6 S ) isomer with 3-methoxyphenylacetyl chloride, hydrogenolysis of the benzyl ester, followed by treatment with oxalyl chloride then aluminum chloride led to an unexpected tricyclic product into which a C 2 O 2 unit had been incorporated.

Stereospecific α-d-mannosylation

Abstract The stereospecific formation of α- d -mannosyl glycosidic linkages has been achieved in high yield using tetra- O -pivaloyl-α- d -mannopyranosyl fluoride and boron trifluoride diethyl etherate in dichloromethane. Examples of the α- d -mannosylation of primary, secondary, benzylic and phenolic hydroxyl groups are described.

A Highly Practical Route to 7-Hydroxy-1,3-dihydro-2H-1,4-benzodiazepin-2-one from p-Anisidine

Abstract The title compound was accessed via a Friedel-Crafts reaction on anisidine, followed by cyclization, N-methylation and O-demethylation. NO column chromatography was required in the process.