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A mitomycin derivative released by targeting activation and its use

A technology of mitomycin and derivatives is applied in the field of mitomycin derivatives released by targeted activation and the preparation of anti-tumor drugs, which can solve problems such as toxic side effects and adverse reactions, and achieve reduced toxicity and improved efficacy. , the effect of good application prospects

Active Publication Date: 2017-10-31
YAFEI (SHANGHAI) BIOLOG MEDICINE SCI & TECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the clinical application of this compound is limited because of its severe toxic and side effects and adverse reactions.

Method used

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  • A mitomycin derivative released by targeting activation and its use
  • A mitomycin derivative released by targeting activation and its use
  • A mitomycin derivative released by targeting activation and its use

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0052] Example 1: Synthesis of mitomycin targeting tumor microenvironment.

[0053] The synthesis process includes the following steps:

[0054] 1) Synthesis of Fmoc-L-Ala-L-Ala-OMe (fluorenylmethoxycarbonyl-L-alanine-L-alanine methyl ester) (I).

[0055] Dissolve Fmoc-L-Ala-OH (fluorenylmethoxycarbonyl-L-alanine) (33 g, 0.1 mol) in N, N-dimethylformamide (1 L), and add 1-hydroxybenzo Triazole (20.2g, 0.15mol), 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (34g, 0.15mol) and L-alanine methyl ester (13.9 g, 0.1mol) and N,N-diisopropylethylamine (25.8g, 0.2mol) in N,N-dimethylformamide (500mL) solution, stirred at room temperature for 10 hours, and evaporated the solvent under reduced pressure , the crude product was dissolved in dichloromethane (2L), washed successively with saturated ammonium chloride solution, water and saturated sodium chloride solution, the organic phase was dried over anhydrous sodium sulfate, and the crude product was recrystallized after d...

Embodiment 2

[0077] Example 2: Obtaining injections S1, S2, S3 and S4.

[0078] The synthesized S1, S2, S3 and S4 are vacuum-dried, sterilized by gas, and subpackaged in a sterile room. Before the animal experiment, S1 was dissolved in water for injection containing 50% alcohol in a sterile room, and then diluted to the desired concentration with water for injection. S2, S3 and S4 can be directly diluted to the desired concentration with water for injection.

Embodiment 3

[0079] Embodiment 3: the method and content range of content determination of S1, S2, S3 and S4 in the obtained product.

[0080] Use analytical HPLC (Agilent 1220 (Agilent1220series), C8 column 5 μm, 4.6mm ID * 250mm, mobile phase is 0~95% acetonitrile (ACN), record S1, S2, the purity of S3 and S4 are all in the purity of 95 %-99% range.

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Abstract

The invention discloses a targeted activated-released mitomycin derivative and an application thereof. The structural formula of the targeted activated-released mitomycin derivative is shown in the specification, wherein R1 is any amino acid selected from Ala, Thr, Val or Ile; R2 is any amino acid selected from Ala, Thr, Val or Asn; and n is any integer selected from 1 to 300. The targeted activated-released mitomycin derivative has the application in preparing anti-tumor medicaments. The targeted activated-released mitomycin derivative disclosed by the invention has tumor specific targeting performance and more efficient and safer anti-tumor effects, can be used for greatly reducing the toxicity, and can be used for preparing the anti-tumor medicaments.

Description

technical field [0001] The invention relates to an antitumor drug compound, in particular to a mitomycin derivative targeted for activation and release and its use in preparing antitumor drugs. Background technique [0002] Mitomycin (structural formula is: ) is an effective anti-tumor agent widely used at present, and is mainly used for various solid tumors such as gastric cancer, colon cancer, liver cancer, pancreatic cancer, non-small cell lung cancer, breast cancer, and cancerous chest and ascites. However, the clinical application of this compound is limited to its dosage because of serious toxic side effects and adverse reactions. Mitomycin can be bone marrow toxic, causing leukopenia and thrombocytopenia. Can cause phlebitis, overflow blood vessels can cause tissue necrosis, hair loss, fatigue and liver and kidney damage. Therefore, it is necessary to provide a targeted drug that can reduce the toxicity of mitomycin and has high efficacy as an antitumor agent. C...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07K5/083A61K38/06A61P35/00A61P27/02A61P27/06A61P31/12A61P31/18A61P1/16
Inventor 刘辰刘源
Owner YAFEI (SHANGHAI) BIOLOG MEDICINE SCI & TECH CO LTD