Maytansine polypeptide conjugate as well as preparation method and application thereof

A technology of polypeptide coupling and maytansine, which is applied in the preparation methods of peptides, chemical instruments and methods, and peptides, etc., can solve the problems of insufficient ability to penetrate the membrane, poor water solubility, and poor selectivity of targeted peptides, so as to increase the anti-tumor effect. Efficacy, improvement of targeting, and reduction of toxic and side effects

Pending Publication Date: 2020-05-08
烟台药物研究所
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] Aiming at the disadvantages of existing maytansinoid drugs such as poor selectivity, poor water solubility, and insufficient membrane-penetra

Method used

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  • Maytansine polypeptide conjugate as well as preparation method and application thereof
  • Maytansine polypeptide conjugate as well as preparation method and application thereof
  • Maytansine polypeptide conjugate as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0028] A maytansine polypeptide conjugate has the following structural formula:

[0029]

[0030] Using the solid-phase peptide synthesis method of the Fmoc strategy, the peptide synthesizer produced by CSBio Company was used to synthesize the targeted polypeptide of the present invention.

[0031] Selection of reagents used for synthesis:

[0032] (1) Carrier resin: Fmoc-Arg(Pbf)Wang, degree of substitution: 0.67

[0033] (2) Selected protected amino acids: Fmoc-Leu-OH, Fmoc-Thr(tBu)-OH, Fmoc-Val-OH, Fmoc-Ser(tBu)-OH, Fmoc-Pro-OH, Fmoc-Trp(Boc )-OH, Fmoc-Tyr(tBu)-OH, Fmoc-Arg(pbf)-OH, Fmoc-Gly-OH, Fmoc-Asp(OtBu)-OH, N-maleimidocaproic acid, reacting A 3-fold excess of protected amino acids was used.

[0034] (3) The deprotection reagent used in the present invention is: piperidine / N,N-dimethylformamide, the ratio is 20:80.

[0035] (4) The coupling reagent used in the present invention is: DIEA / HBTU.

[0036] (5) The cleavage reagent used in the present invention is: ...

Embodiment 2

[0046] A maytansine polypeptide conjugate has the following structural formula:

[0047]

[0048] The preparation method of the above polypeptide drug conjugate precursor is as follows:

[0049] 1) Synthesis of MCC-LTVSPWYRGDR:

[0050] Using the solid-phase peptide synthesis method of the Fmoc strategy, the amino acid sequence was synthesized sequentially, and 4-(N-maleimidomethyl)cyclohexylcarboxylic acid was also directly connected to the peptide fragment through solid-phase synthesis to obtain MCC-LTVSPWYRGDR. The reaction was initiated with 0.2 g of Fmoc-Arg(Pbf) Wang resin, 120 mg of the crude polypeptide was obtained after cleavage, and 44 mg was obtained by purification in the preparative liquid phase, with a total yield of 21%.

[0051] 2) Synthesis of DM4-MCC-LTVSPWYRGDR:

[0052]Dissolve DM4 (50mg, 0.06mmol, 3eq), MCC-LTVSPWYRGDR (31mg, 0.02mmol) in 1mL THF, then add 1mL of PBS buffer to adjust the pH value of the system to 6-8, then stir the reaction at room t...

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Abstract

The invention relates to a maytansine polypeptide conjugate as well as a preparation method and application thereof. The conjugate has a molecular structure of a formula I shown in the description; inthe formula, Aaa1 is L or D-type Lys or Arg; Aaa2 is any L or D-type natural amino acid; Aaa3 is any L or D-type natural amino acid; Aaa4 is L or D-type Lys or Arg; R1 is cyclohexyl or -(CH2)n-; n is1-10; and R2-SH is maytansine DM1 or DM4. The maytansine polypeptide conjugate provided by the invention is capable of achieving targeted drug administration, meanwhile, a (Cend R)-R/KXXR/K (R: arginine, K: lysine, and X: any amino acid) sequence which meets rules of a C end is introduced to the C end to improve the transmembrane capability of the medicine to tumor cells, then the medicine can rapidly enter cells, the treatment effect of the medicine can be improved, and toxic and side effects on normal cells can be alleviated.

Description

technical field [0001] The present invention relates to a maytansine polypeptide conjugate and its preparation method and application, in particular to a maytansine polypeptide conjugate applicable to tumor targeting therapy and its preparation method and application. Background technique [0002] Maytansine (Maytansine) is a class of highly cytotoxic drugs, first isolated from the East African shrub Maytansine by Kupchan et al. According to related research reports, Maytansine is more toxic than traditional anti-tumor drugs. Drugs such as methotrexate, paclitaxel, camptothecin and other drugs are 100 to 1000 times more cytotoxic, but mainly due to their strong toxic side effects on the central nervous system and gastrointestinal symptoms, leading to the clinical application of maytansinoids restricted. [0003] The small molecule targeting peptide can selectively target the drug to the tumor site through receptor interaction, so that the therapeutic drug can be concentrate...

Claims

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Application Information

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IPC IPC(8): A61K47/64A61K31/537A61P35/00C07K7/06C07K1/107
CPCA61K47/64A61K31/537A61P35/00C07K7/06C07K19/00
Inventor 任春光李亚平孔德旭李艺张丽
Owner 烟台药物研究所
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