Gnrh analogue-cytotoxic molecule conjugate, preparation method and use thereof

A compound and small molecule technology, applied in the fields of medicine and chemistry, can solve problems such as toxic side effects and low stability

Inactive Publication Date: 2019-06-21
INST OF PHARMACOLOGY & TOXICOLOGY ACAD OF MILITARY MEDICAL SCI P L A
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] At present, the research on this type of compounds has made great progress, and individual compounds have entered the clinical research stage, but there are still disadvantages of low stability, and it is easy to release cytotoxic molecules prematurely, resulting in toxic side effects

Method used

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  • Gnrh analogue-cytotoxic molecule conjugate, preparation method and use thereof
  • Gnrh analogue-cytotoxic molecule conjugate, preparation method and use thereof
  • Gnrh analogue-cytotoxic molecule conjugate, preparation method and use thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0156] Example 1: Synthesis of Peptide Sequences

[0157] Using 0.5g MBHA resin (0.54mmol) as the solid phase carrier and DIC / HOBt as the condensing agent, according to the amino acid sequence of the compound, all amino acids and modification units were sequentially connected according to the Boc and Fmoc cross-protection strategies, and the above peptide resin was placed in HF Add 1.0mL of anisole and 0.5mL of ethanedithiol to the reactor of the cutting instrument. After installation, vacuum the system of the HF cutting instrument, cool the reactor with liquid nitrogen, transfer about 10mL of liquid HF, and ℃ reaction 1h. Use an oil pump to pump out HF, remove the reactor, add frozen anhydrous ether to precipitate a solid, and then transfer the suspension to a funnel with a sand core. Wash three times with a small amount of cooled anhydrous ether, and then rinse with 10% acetic acid aqueous solution until the resins no longer adhere to each other, collect the washing liquid,...

Embodiment 2

[0160] Example 2: Synthesis of GnRH analogue-paclitaxel conjugates linked by thioether bonds

[0161] Weighing equimolar amounts of the peptide sequence and paclitaxel derivative A in 50% acetonitrile / water solution, reacting with stirring at room temperature, after the reaction was complete, purified by medium-pressure preparative chromatography to obtain a pure product.

[0162] Conjugates were synthesized in this way: 1, 9, 10, 11, 17, 18, 19.

Embodiment 3

[0163] Example 3: Synthesis of Disulfide-Linked GnRH Analogue-Paclitaxel Conjugates

[0164] Weigh the equimolar amount of peptide sequence and paclitaxel derivative B in DMSO, react with stirring at room temperature, after the reaction is complete, purify by medium pressure preparative chromatography to obtain pure product.

[0165] Conjugates were synthesized in this way: 4, 12, 16, 20, 24, 29.

[0166] The mass spectrum characterization data of Example 2 and Example 3 are shown in Table 2.

[0167] Table 2 GnRH analogs - Maldi-Tof-MS Characterization of Paclitaxel Conjugates

[0168]

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Abstract

Provided are a GnRH analog-cytotoxic molecule conjugate as shown by the following formula (I), and a preparation method and a use thereof in the preparation of drugs for treating tumours. The cytotoxic molecule is a taxol derivative or a docetaxel derivative. The conjugate can maintain the binding activity with GnRH receptors, and has a relatively good plasma stability and the growth inhibition activity on tumour cells. (X)Aaa1Aaa2-Aaa3-Ser-Aaa5-Aaa6(Y)-Leu-Aaa8-Pro-Aaa10-NH2

Description

technical field [0001] The invention belongs to the fields of medicine and chemistry, and in particular relates to a GnRH analogue-cytotoxic molecule conjugate, a preparation method thereof and an application in preparation of drugs for preventing and / or treating tumors. Background technique [0002] Gonadotropin-releasing hormone (GnRH), also known as luteinizing hormone-releasing hormone (LHRH), is a decapeptide hormone secreted by the hypothalamus in pulses (Glp–His–Trp–Ser–Tyr–Gly–Leu–Arg–Pro–Gly ·NH 2 ), is a key molecule regulating the reproductive system. Produced by neurons of the hypothalamus, it reaches the pituitary gland via the portal vein. In the pituitary gland, GnRH activates its receptor GPCR, a seven-fold transmembrane G-protein coupled receptor, thereby promoting the synthesis and secretion of LH (luteinizing hormone) and FSH (follicle stimulating hormone). Recent studies have shown that GnRH also has a role in the hypothalamus and other organs outside ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07K7/23A61K31/337A61K47/64A61P35/00A61P35/02C07K1/107C07K1/06C07K1/04
CPCC07K7/23A61K47/50C07K1/04C07K1/06C07K1/107
Inventor 刘克良周宁马永涛王晨宏冯思良
Owner INST OF PHARMACOLOGY & TOXICOLOGY ACAD OF MILITARY MEDICAL SCI P L A
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