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Conjugates of therapeutic or cytotoxic agents and biologically active peptides

a technology of biological active peptides and cytotoxic agents, which is applied in the field of conjugates of therapeutic or cytotoxic agents and biologically active peptides, can solve the problems of limiting the amount of active agent that can be administered to a patient, poor choice of commonly used ester derivatives, and inability to optimally linker strategies for peptide conjugates, etc., to achieve the effect of reducing the release and being easy to internaliz

Inactive Publication Date: 2009-12-31
THE ADMINISTRATORS OF THE TULANE EDUCATIONAL FUND
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The conjugates achieve targeted delivery of therapeutic or cytotoxic agents to specific cells or tissues with reduced toxicity, maintaining the biological activity of the peptides and controlling the release rate of the attached compound.

Problems solved by technology

Commonly used ester derivatives are a particularly poor choice of linker because peripherally circulating compound is rapidly attacked by ubiquitous esterases.
However, this linker strategy is not optimal for peptide conjugates because most of the work-up and purification of synthetic peptides is done in acidic media.
The toxic side effects of many of these therapies, as well as standard treatments of neoplastic disease, effectively limit the amount of active agent that may be administered to a patient.
Additionally, many active agents cause organ-specific toxicities, further limiting the dose that may be delivered to the target tissue.
For instance, the cardiotoxicity of many anthracycline family members reduces the maximum therapeutic dose available for this group of chemotherapeutic agents.
The physical and chemical properties of many cytotoxic agents make drug conjugation to biologically active peptides, such as somatostatin and bombesin, problematic.
For example, the drug may reduce the specificity of binding or the biological activity of the peptide analog, limiting its effectiveness as a targeting agent.

Method used

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  • Conjugates of therapeutic or cytotoxic agents and biologically active peptides
  • Conjugates of therapeutic or cytotoxic agents and biologically active peptides
  • Conjugates of therapeutic or cytotoxic agents and biologically active peptides

Examples

Experimental program
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Effect test

example 1

Preparation of the Chloroformate of Camptothecin

[0119]Camptothecin (250 mg) and 4-dimethylaminopyridine (DMAP; 50 mg) were suspended in 3 mL anhydrous pyridine and 50 mL anhydrous methylene chloride. Phosgene (750 μL of a 20% solution in toluene) was added to the slurry and mixed 2 h at ambient temperature. Excess phosgene and methylene chloride were evaporated in a chemical fume hood and the chlorformate of camptothecin dissolved in DCM.

example 2

Preparation of Camptothecin-carbonyl-N-aminoethyl-glycine-D-tert-butyl-Ser-Nle-D-tert-butyl-Tyr-D-tert-butyl-Ser-S- trityl-Cys-Phe-D-Trp -epsilon-tert-butyloxycarbonyl-Lys-tert-butyl-Thr-S-trityl-Cys-tert-butyl-Thr-Rink-amide-resin (SEQ ID NO: 16)

[0120]Rink amide [4-(2′,4′-dimethoxyphenyl-Fmoc-(aminomethyl)phenoxyacetamido-norleucyl-methylbenzhydrylamine resin (0.063 mmole), 100-200 mesh (Novabiochem, San Diego, Calif.) was added to the reaction vessel of a CS136 automatic peptide synthesizer (CS Bio, Inc., San Carlos, Calif.) and swollen in dimethylformamide (DMF) for approximately 1 hour. The resin was filtered and an excess of 20% piperidine in DMF was added and mixed (2 min). The resin was filtered and again an excess amount of 20% piperidine added and mixed (20 min) to ensure complete removal of the resin Fmoc group. After deprotection, the resin was washed 4 times with DMF and then the first protected amino acid, Fmoc-Thr(tBut) (0.188 mmol), diisopropylcarbodiimide (DIC) (0.1...

example 3

Preparation of camptothecin-carbonyl- N-(2-aminoethyl)-glycine-D-Ser-Nle-D-Tyr-D-Ser-cyclo[Cys-Phe-D-Trp-Lys-Thr-Cys]-Thr-amide (SEQ ID NO: 17)

[0122]The camptothecin-peptide resin prepared in EXAMPLE 2 (0.063 mmol) was placed in a round bottomed flask to which was added 15 mL of a solution of trifluoroacetic acid (TFA) containing water (2.5%), 1,2-ethanedithiol (2.5%), and triisopropylsilane (1%). The suspension was agitated (2 h) and filtered and washed several times with TFA. The TFA was evaporated in vacuo and ether added to the resulting oil to give a yellow powder that was then dissolved in 60% acetic acid (250 mL). A concentrated solution of iodine in methanol was added dropwise with vigorous stirring until a permanent brown coloration was formed whereupon excess iodine was removed by addition of a small quantity of ascorbic acid.

[0123]The solution was reduced to a volume of around 10 mL in vacuo and the crude camptothecin peptide purified by preparative reverse phase high pr...

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Abstract

The invention features conjugates of therapeutic or cytotoxic agents and biologically active peptides and methods of use thereof.

Description

FIELD OF THE INVENTION[0001]The invention relates to conjugates of therapeutic or cytotoxic agents and biologically active peptides and uses thereof.BACKGROUND OF THE INVENTION[0002]The use of carbamate compounds as prodrugs is well known. Carbamate compounds are well suited for prodrug design because they can be used to regenerate the parent drug whether the point of connection to a vector molecule is a hydroxyl group or an amine. Carbamate prodrugs based on intramolecular cyclizations have been reported since the late 1980s. For example, U.S. Pat. No. 4,812,590 (which corresponds to EP 0 296 811) discloses derivatives of 4-hydroxyanisole carbamate as prodrugs for the delivery and concentration of 4-hydroxyanisole in melanomas. Vigroux et al. (J. Med. Chem. 38, 3983-3994, 1995) disclose prodrugs of acetaminophen which incorporate N-(substituted 2-hydroxyphenyl)- and N-(substituted 2-hydroxypropyl)carbamates.[0003]An optimal prodrug design is one in which the drug is conjugated to a...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K39/395A61K38/12A61K31/4745C07K7/64C07K16/00C07D491/147A61K47/48C07K7/06C07K16/46
CPCA61K47/48338A61K47/48269A61K47/65A61K47/642A61P1/00A61P19/02A61P19/04A61P27/02A61P29/00A61P31/06A61P35/00A61P43/00A61P9/00A61P9/10C07K7/06A61K39/395
Inventor FUSELIER, JOSEPH A.COY, DAVID H.
Owner THE ADMINISTRATORS OF THE TULANE EDUCATIONAL FUND
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