Linkable Lewis X Analogs

a sialyl lewis and analog technology, applied in the field of linkable sialyl lewis x, can solve the problems of unsuitable for many applications, including targeting, tissue damage instead of repair, etc., and achieve the effects of enhancing the ability of sialyl lewis to inhibit, increasing the usefulness of targeting applications, and increasing binding strength

Inactive Publication Date: 2008-12-04
BRACCO SUISSE SA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0005]The dramatic increase in binding strength exhibited by multivalent Sialyl Lex compositions as compared to monomeric analogs indicates that oligosaccharide multivalency enhances the ability of these compositions to inhibit selectin-mediated cellular adhesion. This amplified level of binding strength makes these multivalent compositions more effective as therapeutic agents and increases their usefulness in targeting applications.

Problems solved by technology

In certain situations, adhesion of leukocytes to the endothelium may be abnormal or excessive, resulting in tissue damage instead of repair.
The binding of monomeric SLex analogs to E-selectin and L-selectin is generally weak (i.e. only in the range of 1-2 mm), often making them unsuitable for many applications, including targeting.

Method used

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  • Linkable Lewis X Analogs
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Examples

Experimental program
Comparison scheme
Effect test

example 1

Synthesis of p-Nitrophenyl 2-acetamido-4,6-benzylidine 2-deoxy-β-D-glucopyranoside (Compound 5)

[0109]The preparation of this compound was conducted as described in J. Roger, et al., Carbohydrate Res., 6:184-196 (1968), and is given below.

[0110]A mixture of p-nitrophenyl-2-acetamido-2-deoxy-β-D-glucopyranoside (compound 4) (10.0 g, 30 mmol), benzaldehyde dimethylacetal (10.0 g) and PTS.H2O (0.18 g) in DMF (50 mL) was stirred at 50° C. for about 3 h. TLC of the reaction mixture indicated complete conversion of the starting material to the benzylidine derivative. The mixture was cooled to RT and slowly added to a stirred ice-water (700 mL). The white solid formed was collected by filtration, washed with water and dried in vacuo to give p-nitrophenyl 2-acetamido-4,6-benzylidine 2-deoxy-β-D-glucopyranoside (compound 5) (12.2 g, yield 97%). TLC analysis (silica gel, 5% MeOH in CH2Cl2) showed a single spot (Rf 0.5, compared to 0.25 for the starting material) thus indicating that the produc...

example 2

Synthesis of 2,3,4-Tri-O-benzyl-1-O-p-nitrobenzoyl-α-L-fucopyranose (Compound 8)

[0111]The preparation of this compound was conducted as described in M. Dejter-Juszynski and H. M. Flowers, Carbohydrate Res., 18:219-216 (1971), and is given below.

[0112]To a cooled solution (5° C.) of 2,3,4-tri-O-benzyl-L-fucopyranose (compound 6) (6.0 g, 13.45 mmol) in dry CH2Cl2 (100 mL) was added pyridine (7.5 mL) followed by a slow addition of p-nitrobenzoyl chloride (compound 7) (3.15 g, 17 mmol) in portions over a 5 min period. After the addition, the mixture was stirred at 5° C. for 5-10 min then at RT for 18 h. The mixture was diluted with CH2Cl2 (100 mL) and the solution was washed successively with cold 1N HCl, water, cold aqueous NaHCO3, water, dried and concentrated to give a gummy product (9.0 g). TLC analysis (silica gel, hexane-EtOAc 3:1) indicated the presence of a major (Rf 0.6) and a minor (Rf 0.48) product, but no starting material. This could be due to a mixture of α and β isomers, ...

example 3

Synthesis of 2,3,4-tri-O-benzyl-α-L-fucopyranosyl bromide (Compound 9)

[0116]The preparation of this compound was conducted as described in M. Dejter-Juszynski and H. M. Flowers, Carbohydrate Res., 18:219-216 (1971), and is given below.

[0117]A saturated solution of HBr in CH2Cl2 (20.0 mL) was prepared by passing anhydrous HBr in CH2Cl2 at 0° C. for 30 min. This solution was added to a cold solution of the α-isomer of the 2,3,4-tri-O-benzylfucopyranose-p-nitrobenzoate (compound 8) (6.5 g, 11 mmol) in CH2Cl2 (150 mL) at 0-5° C., and the mixture was stirred at 5° C. for 30-40 min. The precipitated p-nitrobenzoic acid was filtered off, and the filtrate was successively washed with cold sat. NaHCO3 and water until neutral. The extract was dried (MgSO4) and the solvent removed at RT in vacuo to afford exclusively the α-fucopyranosyl bromide as a highly viscous liquid (5.3 g, yield 95%).

[0118]Similarly, treatment of the β-isomer of the fucopyranosyl-p-nitrobenzoate (compound 8) (583 mg, 1 m...

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Abstract

Disclosed herein is a class of linkable tetrasaccharide compounds that includes the amino phenyl glycoside of sialyl Lewis X (SLeX) and related analogs. These compounds have conjugatable nucleophilic groups, making them useful in preparing multimeric SLeX compositions. In particular, the disclosed SLeX compounds can be used to prepare selectin binding ligand conjugates by linking them to a reporter moiety, such as a contrast agent, a radiodiagnostic agent, or a cytotoxic or chemotherapeutic agent. The SLeX compounds and conjugates of the invention exhibit binding to selectin that is similar to native Sialyl LeX, and are, therefore, useful for diagnosing and treating selectin-mediated disorders and related conditions.

Description

FIELD OF THE INVENTION[0001]The invention relates to linkable sialyl Lewis X (sialyl Lex or SLex) analogs and methods of using these compounds to treat inflammation and related disorders.BACKGROUND OF THE INVENTION[0002]The phenomenon of cellular adhesion plays an important role in the complex processes of inflammation and cancer metastasis. In response to injury and infection, damaged tissues release activating factors known as cytokines. The released cytokines signal vascular endothelial cells to change their shape and express cell adhesion proteins called selectins on their surfaces. The selectins promote the adhesion of leukocytes to the endothelium by binding to carbohydrate antigens, such as sialyl Lex, that are present on the surface of leukocytes in the blood stream. The leukocytes then move past the endothelial cells, through the blood vessel wall, and into the areas of injury and infection, thereby establishing a foci of inflammation.[0003]In certain situations, adhesion o...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/715C07H15/22C07H15/00A61K31/192A61K31/337A61K31/546A61K31/555A61K31/7028A61K31/7036A61K38/17A61K45/00A61K47/44A61K47/48A61K49/00A61K51/00A61P3/04A61P3/10A61P9/10A61P29/00A61P31/00A61P35/00C07D257/02C07H7/02C07H15/04C07H15/18C07K5/083C07K7/02
CPCA61K49/0002C07H7/02C07H15/00C07H15/04A61P3/04A61P3/10A61P7/02A61P9/10A61P17/00A61P17/06A61P19/00A61P19/02A61P29/00A61P31/00A61P35/00A61P43/00
Inventor RANGANATHAN, RAMACHANDRANRAMALINGAM, KONDAREDDIARPILLAI, RADHAKRISHNAMARINELLI, EDMUND R.SWENSON, ROLF E.
Owner BRACCO SUISSE SA
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