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A kind of method for preparing kahalalide F

A technology of resin and fragments, which is applied in the field of preparing Kahalalide F, can solve the problems of difficult purification of intermediate reactants, low yield, and difficult removal of impurities, and achieve the effects of mild reaction conditions, single product configuration, and easy post-treatment

Inactive Publication Date: 2017-03-22
HYBIO PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0008] However, in the solid-phase one-by-one coupling process, it is necessary to repeatedly remove the protective group in the gradually extended reaction chain, so it is easy to produce impurities that are difficult to remove, and then it is difficult to purify the intermediate reactants well, resulting in The final purification is extremely complicated and tedious, resulting in a low yield; moreover, the cyclization step of threonine side chain hydroxyl coupling in the route easily leads to racemization of the final product, and the configuration of the product cannot be satisfactorily controlled

Method used

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  • A kind of method for preparing kahalalide F
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  • A kind of method for preparing kahalalide F

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preparation example Construction

[0035] 2) Using the solid-phase peptide synthesis method to sequentially couple the corresponding amino acids to obtain the peptide resin R A and R B , the solid-phase polypeptide synthesis method comprises: i) removing Fmoc, and then washing the resin with a solvent until the complete removal of Fmoc is detected by a detection method; ii) adding an appropriate amount of amino acid to be coupled and a coupling agent in a solvent After dissolving and activating in the medium, add them together into the solid reaction column until the reaction is detected to be terminated by the detection method; iii) repeat i) and ii).

[0036] The reagent for removing Fmoc can be any reagent known in the art that can achieve this purpose, preferably 20% piperidine / DMF solution (DBLK), i.e. piperidine: DMF (volume ratio) is a mixed solution of 1:4 .

[0037] Wherein solid-phase polypeptide synthesis needs to use activator, the activator used in the present invention is the composition of DIPC...

Embodiment 1

[0069] Embodiment 1: Preparation of Fmoc-D-Pro-CTC resin

[0070] Weigh 221g of dry 2-CTC resin (the degree of substitution is 0.736mmol / g) and add it to the solid-phase reaction column. First, wash the resin with DMF for 2 times, and then use 2-3 times the volume of the resin bed to swell the resin for 1 hour. , and then washed 3 times with DMF and 2 times with DCM in turn, and kept for use.

[0071] Under the condition of cooling in an ice bath, dissolve 109.8g Fmoc-D-Pro-OH and 42.1g DIPEA in a mixed solvent of DMF and DCM. After the amino acid is dissolved, slowly dissolve the activated Fmoc-D-Pro-OH Add to the reaction column to react for 2 hours, after the reaction, add a blocking solution composed of 100mL methanol and 21.0g DIPEA to the reaction column to react for 30 minutes. After washing with DMF for 3 times, the Fmoc-D-Pro-CTC resin was obtained.

Embodiment 2

[0072] Embodiment 2: the preparation of Fmoc-L-Orn (Boc)-CTC resin

[0073] Weigh 288g of dry 2-CTC resin (the degree of substitution is 0.534mmol / g) and add it to the solid-phase reaction column. First, wash the resin with DMF twice, and then use 2-3 times the volume of the resin bed to swell the resin for 1 hour. , and then washed 3 times with DMF and 2 times with DCM in turn, and kept for use.

[0074] Under the condition of cooling in an ice bath, dissolve 139.8g Fmoc-L-Orn(Boc)-OH and 39.8g DIPEA in a mixed solvent of DMF and DCM. After the amino acid is dissolved, slowly dissolve the activated Fmoc-L-Orn (Boc)-OH was added to the reaction column to react for 2 hours. After the reaction, a blocking solution consisting of 95 mL methanol and 20.0 g DIPEA was added to the reaction column to react for 30 minutes. After washing with DMF for 3 times, the Fmoc-L-Orn(Boc)-CTC resin was obtained.

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Abstract

The invention relates to a preparation method for Kahalalide F. The method comprises steps: 2-CTC resin is employed as a carrier, polypeptide segments A and B are synthesized through a solid phase polypeptide synthesis method; the polypeptide segment B is subjected to a molecule esterification reaction and a segment Bi is synthesized; the the polypeptide segments A and Bi are subjected to liquid phase condensation; protecting groups are removed and Kahalalide F is obtained. The method has high yield and convenient post-treatment, and provides a new ideal for industrial scale production of Kahalalide F.

Description

technical field [0001] The invention relates to a method for preparing a polypeptide, in particular to a method for preparing Kahalalide F. Background technique [0002] Kahalalide F is a bioactive cyclic depsipetide isolated from the sarcoglossan mollusk Elysia rufescens and its food - Bryopsis pennata. Its structure is shown below: [0003] [0004] The structure is complex, comprising six amino acids as part of the loop, with an acyl-terminated chain of seven amino acids outside the loop. Kahalalide F is an extremely rare and effective antineoplastic drug derived from marine sources. It has a good therapeutic effect on prostate cancer and colon cancer cells, and also has certain biological activities in antiviral and fungal aspects. [0005] The biological and pharmacological activity of kahalalide F has been well documented, for example in Hamann, M.T.; Scheuer, P.J.J.Am.Chem.Soc. Bioactive depsipeptides isolated from ., Vol. 115, pp. 5825-5826; Hamann, M.T. et al.,...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07K7/08C07K1/04C07K1/02
CPCY02P20/55
Inventor 陈新亮刘建马亚平袁建成
Owner HYBIO PHARMA
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