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Cyclic depsipeptide as well as preparation method and application thereof

A cyclic lipopeptide and reaction technology, applied in the field of medicinal chemistry, can solve problems such as difficult chemical preparation, instability, and limited application

Inactive Publication Date: 2017-11-14
FUDAN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, this natural product contains an unstable and difficult to prepare chemically thiazoline ring, which limits its application

Method used

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  • Cyclic depsipeptide as well as preparation method and application thereof
  • Cyclic depsipeptide as well as preparation method and application thereof
  • Cyclic depsipeptide as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0020] Embodiment 1 prepares cyclic lipopeptide, specifically comprises the following steps:

[0021] 1. Preparation of linear tetrapeptide (taking R=allyl as an example)

[0022]

[0023] Take compound I (prepared according to literature method, see: Doi, T.; Numajiri, Y.; Munakata, A.; Takahashi, T.Org.Lett.2006,8,531-534.) 492mg (1.1mmol) was dissolved in 10mL dry In dichloromethane, compound II (301.2 mg, 1.1 mmol) and HATU (627.4 mg, 1.65 mmol) were added, and DIPEA (576.0 μL, 3.3 mmol) was added dropwise in ice bath. Stir at room temperature under nitrogen protection for 12 h, LC-MS showed that the reaction was complete. Quenched with saturated ammonium chloride, diluted with dichloromethane, washed several times with 5% aqueous potassium bisulfate solution until the aqueous phase was nearly colorless, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was subjected to silica gel col...

Embodiment 2

[0033] Example 2 In Vitro Antitumor Activity Screening Experiment

[0034] In this example, the in vitro anti-tumor activity screening experiment of cyclic ester peptide Oxoapratoxin E was carried out. Staurosporine was used as a positive control, tetrazolium salt reduction method and sulforhodamine B protein staining method were used as screening methods; four tumor cell lines were used A549, HCT 116, Hela, MCF-7 (the tumor cell line is commercially available) have carried out activity test, the result shows (as shown in table 1), cyclic lipopeptide Oxoapratoxin E of the present invention has stronger antitumor activity , has potential application value in the field of medicine, especially in the research and development of antitumor drugs.

[0035] Table 1 compound Oxoapratoxin E antitumor activity (IC 50 / μM)

[0036]

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Abstract

The invention belongs to the field of medical chemistry and relates to cyclic depsipeptide Oxoapratoxin E with a structure shown as a formula (I) as well as a preparation method and application thereof. When the cyclic depsipeptide is prepared, a cyclized precursor is synthesized first; after N-end and C-end protective groups are removed, a large ring is closed; then a dehydration reagent is utilized to form the cyclic depsipeptide of the invention. The cyclic depsipeptide provided by the invention is subjected to in-vitro anti-tumor activity screening experiments and a result shows that the cyclic depsipeptide has relatively strong anti-tumor activity and has potential application value in the field of medicines, especially research and development of anti-tumor medicines. (The formula (I) is shown in the description.).

Description

technical field [0001] The invention belongs to the field of medicinal chemistry. It relates to a cyclic lipopeptide and its preparation method and application. Background technique [0002] The prior art discloses that Apratoxin is one of the marine natural products with the strongest anti-tumor activity discovered in recent years, and its half inhibitory concentration to tumor cells is at nanomolar and picomolar levels ((a) Zhang Wei et al. , 34, 475; (b) Tarsis, E.M. et al. Tetrahedron 2015, 71, 5029; (c) Doi, T. Chem. Pharm. Bull. 2014, 62, 735; (d) Luesch, H. et al. J. Am. Chem. Soc. 2001, 123, 5418). Studies have shown that apratoxin E (Matthew, S. et al. J. Nat. Prod. 2008, 71, 1113), one of the members of this family, has a strong killing effect on cancer cells such as colon cancer, cervical cancer and bone cancer It is expected to be developed as an antitumor drug. However, this natural product contains an unstable and difficult to prepare thiazoline ring, which...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K7/06C07K1/02A61K38/08A61P35/00
CPCA61K38/00C07K7/06Y02P20/55
Inventor 张伟吴平胥森瀚
Owner FUDAN UNIV
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