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Chiral isoindrone fused cyclic hexapeptide derivative and preparation method and application of derivative

A technology of isoindolinone and cyclic hexapeptide, which is applied in the field of synthetic medicinal chemistry and anti-tumor, can solve the problems of difficult extraction and separation of Phakellistatin6 cyclic peptide, and difficulty in meeting actual needs, and achieve simple reaction conditions, convenient operation, and good anti-tumor active effect

Active Publication Date: 2019-09-17
HARBIN NORMAL UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0004] The purpose of the present invention is to provide chiral isoindolinoxocyclic hexapeptide derivatives, their preparation methods and uses, and solve the existing difficulties in the extraction and separation of Phakellistatin 6-cyclic peptides , it is difficult to meet the actual needs of the problem

Method used

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  • Chiral isoindrone fused cyclic hexapeptide derivative and preparation method and application of derivative
  • Chiral isoindrone fused cyclic hexapeptide derivative and preparation method and application of derivative
  • Chiral isoindrone fused cyclic hexapeptide derivative and preparation method and application of derivative

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specific Embodiment approach 1

[0016] Specific embodiment 1: The chemical name of the chiral isoindolinocyclic hexapeptide derivative in this embodiment is 3-hydroxyl-isoindolinocyclic (glycyl-prolyl-L-leucyl-pro aminoacyl-L-isoleucyl-prolylbenzylamine), wherein the proline configuration is pure L-type or D-type, and its C-3 position is pure R-configuration or S-configuration, and the structural formula is :

[0017]

[0018] Wherein R&S means that the chirality of the carbon atom is R or S type.

[0019] The C-3 position described in this embodiment is a chiral carbon atom.

specific Embodiment approach 2

[0020] Specific embodiment two: the preparation method of the chiral isoindolinone cyclohexapeptide derivative in this embodiment is carried out according to the following steps:

[0021]1. ①Dissolve Boc-proline in solvent Ⅰ, condense with N-trimethylsilylbenzylamine under the catalysis of condensing agent Ⅰ, and then use trifluoroacetic acid to remove the Boc protection of the amino terminal to obtain intermediate product Ⅰ ; ② Dissolve Boc-L-isoleucine in solvent Ⅱ, condense with intermediate product Ⅰ under the catalysis of condensation agent Ⅱ, and then use trifluoroacetic acid to remove the Boc protection of the amino terminal to obtain intermediate product Ⅱ; ③ Boc-L- Dissolve proline in solvent III, condense with intermediate product II under the catalysis of condensation agent III, and then use trifluoroacetic acid to remove the Boc protection at the amino terminal to obtain intermediate product III; ④ Dissolve Boc-L-leucine in solvent In IV, condense with intermediate...

specific Embodiment approach 3

[0029] Embodiment 3: This embodiment is different from Embodiment 2 in that: the reaction temperature of the condensation described in step 1 ① to ⑤ is all 10-50° C. Others are the same as in the second embodiment.

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Abstract

The invention discloses a chiral isoindrone fused cyclic hexapeptide derivative and a preparation method and application of the derivative, belongs to the technical field of synthetic medical chemistry, in particular relates to a novel preparation method of isoindrone fused cyclic hexapeptide analogue containing chiral proline structure, and also concerns the application of the derivative in the field of anti-tumor. The invention aims to solve the problems that the extraction and separation of prior phakellistatin 6 cyclic peptide are difficult and the actual needs are hard to meet. The chemical name of the chiral isoindrone fused cyclic hexapeptide derivative is 3-hydroxy-isoindrone-fused-cyclo-(glycyl-prolyl-L-leucyl-prolyl-L-isoleusyl-prolyl benzylamine). The structure formula is represented in the description. The method is as follows: preserving the fragment in a precursor, transforming the easily oxidized tryptonpan in the precursor into a more stable and rigid isoindrone fragment, changing the configuration of the proline in the precursor structure at the same time, and obtaining the chiral cyclic peptide analogue by photoinduced cyclic peptide reaction and column chromatography purification. The invention is applied in the field of tumor treatment.

Description

technical field [0001] The invention belongs to the technical field of synthetic medicinal chemistry, in particular to a preparation method of a novel isoindolinone cyclohexapeptide analog containing a chiral proline structure, and also relates to the use of the derivative in the field of antitumor. Background technique [0002] Peptide compounds widely exist in nature and exhibit a variety of pharmacological effects, especially in the fields of antibacterial and antitumor. Peptide-based drug research has become an important direction for the development of new drugs. [0003] The natural cyclic heptapeptide Phakellistatin 6 is a kind of cyclic peptide compound rich in proline residues isolated from the sponge of the genus Phakella, and its chemical name is ring-(Pro-Phe-Pro-Trp-Leu-Pro-Ile) seven Peptide, cell test studies show that it has a strong growth inhibitory effect on p388 leukemia cells (IC 50 =0.18μg / mL), therefore Phakellistatin6 is expected to become the lead ...

Claims

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Application Information

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IPC IPC(8): C07K7/06C07K1/16C07K1/06C07K1/02A61P35/00
CPCC07K7/06A61P35/00Y02P20/55
Inventor 王志强赵立双金英学吴静婉
Owner HARBIN NORMAL UNIVERSITY