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Bone targeting salmon calcitonin and preparation method thereof

A salmon calcitonin and bone-targeting technology, which is applied in the field of biomedicine, can solve the problems of reduced biological efficacy, achieve the effects of less difficult operation, easy production and application, and improved bioavailability

Active Publication Date: 2018-09-28
SICHUAN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Modification of Lys-11 and Lys-18 of salmon calcitonin (sCT) by acetylation leads to a significant reduction in biopotency, so derivatization of sCT by amino groups is not possible (see S.M.Ryan, etc., Journal of Controlled Release 149( 2) (2011) 126-132; G. Andreotti, etc., Journal of Biological Chemistry 281 (34) (2006) 24193-203.)
Studies have demonstrated that Gln-14 can derivatize transglutaminase without loss of activity, however this method is not a general method

Method used

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  • Bone targeting salmon calcitonin and preparation method thereof
  • Bone targeting salmon calcitonin and preparation method thereof
  • Bone targeting salmon calcitonin and preparation method thereof

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0037] In this embodiment, a method for preparing bone-targeted salmon calcitonin is provided, and the steps are as follows:

[0038] (1) Preparation of bone targeting coupling molecules

[0039] ① Synthesis of the first intermediate

[0040] Dissolve dithiophenylmaleimide and N-methylmorpholine in ethyl acetate at a molar ratio of 1:1 to make the concentration of dithiophenylmaleimide 3mg / mL, and add in the dark Methyl chloroformate in an equimolar amount with dithiophenyl maleimide was stirred at room temperature for 1 hour. After the reaction, the crude product was separated by rotary evaporation. The crude product was dissolved in dichloromethane and washed with deionized water. Three times, then remove the water phase, keep the organic phase, add desiccant anhydrous MgSO to the organic phase 4 Remove the water in the organic phase, then filter to remove MgSO 4 Rotate to remove dichloromethane to obtain the first intermediate 3,4-dithiophenyl-2,5-dioxo-pyrrole-1-carboxylic acid ...

Embodiment 2

[0055] In this embodiment, a method for preparing bone-targeted salmon calcitonin is provided, and the steps are as follows:

[0056] (1) Preparation of bone targeting coupling molecules

[0057] ① Synthesis of the first intermediate

[0058] Dissolve dibromomaleimide and N-methylmorpholine in ethyl acetate at a molar ratio of 1:1.2 to make the concentration of dibromomaleimide 4mg / mL, and add methyl chloroformate in the dark , The amount of methyl chloroformate added is 1.2 times the equivalent molar amount of dibromomaleimide, and the reaction is stirred at room temperature for 2 hours. After the reaction is completed, the crude product is separated by rotary evaporation, and the crude product is dissolved in dichloromethane. Wash with deionized water three times, then remove the water phase, keep the organic phase, and add desiccant anhydrous MgSO to the organic phase 4 Remove the water in the organic phase, then filter to remove MgSO 4 Rotate to remove the dichloromethane to obt...

Embodiment 3

[0069] In this embodiment, a method for preparing bone-targeted salmon calcitonin is provided, and the steps are as follows:

[0070] (1) Preparation of bone targeting coupling molecules

[0071] ① Synthesis of the first intermediate

[0072] Dissolve dithiophenylmaleimide and N-methylmorpholine in ethyl acetate at a molar ratio of 1:1 so that the concentration of dithiophenylmaleimide is 2mg / mL. Add it in the dark Methyl chloroformate in an equimolar amount with dithiophenyl maleimide was stirred at room temperature for 1 hour. After the reaction, the crude product was separated by rotary evaporation. The crude product was dissolved in dichloromethane and washed with deionized water. Three times, then remove the water phase, keep the organic phase, add desiccant anhydrous MgSO to the organic phase 4 Remove the water in the organic phase, then filter to remove MgSO 4 Rotate to remove the dichloromethane to obtain the first intermediate 3,4-dithiophenyl-2,5-dioxo-pyrrole-1-carboxylic...

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Abstract

The invention provides bone targeting salmon calcitonin. Disulfide bonds in salmon calcitonin molecules are opened and covalently coupled with bone targeting coupling molecules to form the bone targeting salmon calcitonin. A preparation method includes the steps: (1) preparing the bone targeting coupling molecules; (2) dissolving the salmon calcitonin in water-soluble solvents with the pH (potential of hydrogen) value of 5-7, adding reducing agents for reducing the disulfide bonds in the salmon calcitonin to form free sulfydryl, adding the bone targeting coupling molecules, performing stirringreaction for 0.5-12 hours at the temperature of 0-40 DEG C, separating crude products and preparative liquid chromatography purification to obtain the bone targeting salmon calcitonin. The bone targeting salmon calcitonin is free from cytotoxicity and immunogenicity, the bone tissue enrichment capacity of the calcitonin can be improved, bone tissues can be effectively repaired, and the bone targeting salmon calcitonin has a wide application prospect.

Description

Technical field [0001] The invention belongs to the field of biomedicine, and relates to a bone-targeting salmon calcitonin and a preparation method thereof. Background technique [0002] Salmon calcitonin (sCT) is a single-chain polypeptide hormone containing 32 amino acids, which can regulate the concentration of calcium ions in the blood, reduce bone resorption, and has a clear analgesic effect. With the increase of age, the human organs gradually age, and the ability to secrete calcitonin and other related hormones will be greatly reduced, leading to bone loss, bone structure disorder, and decreased ability to inhibit bone resorption, and gradually develop osteoporosis . At present, most of the drugs used to treat osteoporosis in postmenopausal women are calcitonin protein and peptide drugs, and long-term medication is required. [0003] During the treatment of exogenous administration of calcitonin, calcitonin has a very short half-life and will be quickly cleared from the b...

Claims

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Application Information

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IPC IPC(8): C07K14/585C07K1/06
CPCC07K14/585
Inventor 李建树刘衍朋俞鹏谢婧李安琦
Owner SICHUAN UNIV
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