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Compound containing a labile disulfide bond

a technology of labile disulfide and compound, which is applied in the field of compound containing labile disulfide bonds, can solve the problems of slow rate at which these bonds are broken under physiological conditions, and achieve the effect of lowering the pka of the constituent thiols

Inactive Publication Date: 2005-01-27
ROCHE MADISON
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

More particularly, a compound that contains an aliphatic disulfide bond with one or more electronegative (electron withdrawing groups) substituted alpha or beta to one or both of the sulfur atoms. These groups serve to lower the pKa of the constituent thiols.

Problems solved by technology

However, the rate at which these bonds are broken under physiological conditions is slow.

Method used

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  • Compound containing a labile disulfide bond
  • Compound containing a labile disulfide bond
  • Compound containing a labile disulfide bond

Examples

Experimental program
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Effect test

example 1

Synthesis of Cysteine-terminal Tat Peptide (Tat-Cys).

Peptide syntheses were performed using standard solid phase peptide techniques using FMOC chemistry. A cysteine was added to the amino terminus of Tat to allow for conjugation through the thiol group to make the peptide Tyr-Gly-Arg-Lys-Lys-Arg-Arg-Gln-Arg-Arg-Arg-Cys (Tat-Cys).

example 2

Synthesis of Noncleavably Linked (Irreversible Covalent) Tat-Cys and Fluorescein through a Thioether Bond.

To a solution of succinimidyl-4-(N-maleimidomethyl) cyclohexane-carboxylate (SMCC from Pierce) 1.0 mg in 0.1 mL dimethylformamide was added 1.2 mg (1 eq) of 4′-(aminomethyl)fluorescein. After two hours, this solution was added to a 1 mL aqueous solution of 8.4 mg Tat-Cys (1 eq). The solution was buffered to pH 8 by the addition of potassium carbonate. This solution was used for transport studies without further purification.

example 3

Synthesis of Unactivated (Non-labile) Disulfide Linked Lissamine Dimer (Dilissamine Cystamine)

To a solution of cystamine dihydrochloride (10 mg) in water (1 mL) was added diisopropylethylamine (15 μL, 2 eq). To this was added lissamine chloride (Rhodamine B sulfonyl chloride, Molecular Probes) 77 mg (3 eq) in 5 mL of methanol. The solution was stirred for 1 hour and then chromatographed by reverse-phase HPLC using an Aquasil C-18 column using a gradient from 100% 0.1% trifluoroacetic acid in water to 100% 0.1% triflouroacetic acid in acetonitrile. The fraction containing the product was determined by mass spectroscopy. The molecular weight of compound is 1234, which was detected in positive ion mode. The concentration of the product-containing fraction was determined by the absorbance of the solution at 588 nm (ε=88,000 M−1 cm−1).

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Abstract

A labile disulfide-containing compound under physiological conditions containing a labile disulfide bond and a transduction signal.

Description

BACKGROUND Bifunctional molecules, commonly referred to as crosslinkers, are used to connect two molecules together. Bifunctional molecules can contain homo or heterobifunctionality. The disulfide linkage (RSSR′) may be used within bifunctional molecules. The reversibility of disulfide bond formation makes them useful tools for the transient attachment of two molecules. Disulfides have been used to attach a bioactive compound and another compound (Thorpe, P. E. J. Natl. Cancer Inst. 1987, 79, 1101). The disulfide bond is reduced thereby releasing the bioactive compound. Disulfide bonds may also be used in the formation of polymers (Kishore, K., Ganesh, K. in Advances in Polymer Science, Vol. 21, Saegusa, T. Ed., 1993). There are many commercially available reagents for the linkage of two molecules by a disulfide bond. Additionally there are bifunctional reagents that have a disulfide bond present. Typically, these reagents are based on 3-mercaptopropionic acid, i.e. dithiobispropi...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K38/08A61K48/00C07C323/60C07C323/62C07D207/46
CPCA61K31/155A61K31/198A61K38/08C07D207/46C07C323/60C07C323/62A61K48/00C07H21/04
Inventor WOLFF, JON A.MONAHAN, SEAN D.BUDKER, VLADIMIR G.SLATTUM, PAUL M.ROZEMA, DAVID B.
Owner ROCHE MADISON
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