Integrin ligand cyclic peptide analogues and cyclization method

A technology of analogs and integrins, applied in the field of cyclic peptide analogs and their cyclization, can solve the problems of reduced cyclization yield, etc., and achieve the effects of mild conditions, increased biological activity, and simple cyclization method

Inactive Publication Date: 2009-07-29
ZHEJIANG UNIV
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  • Abstract
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  • Claims
  • Application Information

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Problems solved by technology

Since the cyclization is an ordinary amide bond condensation reaction, the cycliz

Method used

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  • Integrin ligand cyclic peptide analogues and cyclization method
  • Integrin ligand cyclic peptide analogues and cyclization method
  • Integrin ligand cyclic peptide analogues and cyclization method

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preparation example Construction

[0040] 1.1 Preparation of trifluoromethanesulfonyl azide:

[0041] Dissolve sodium azide (6 g) in a 150 ml round bottom flask, add 24 ml of DCM, cool to 0° C. in an ice bath, and stir for 20 minutes. The reaction mixture was extracted with DCM (2×12ml). The organic phases were combined and washed with saturated sodium carbonate to obtain trifluoromethanesulfonyl azide dissolved in DCM, which was directly used in the next reaction without further purification.

[0042] 1.2 Preparation of azidoglycine:

[0043] Glycine (0.675g), K 2 CO 3 (1.783g), CuSO 4 (0.0226g) was added to a round bottom flask, then water (30ml), methanol (60ml) and DCM (48ml) containing trifluoromethanesulfonyl azide were added, stirred at room temperature, and reacted overnight. Subsequently, the organic solvent was removed by rotary evaporation under reduced pressure, and the remaining part was diluted with water (150ml). Then the pH value was adjusted to 6 with hydrochloric acid, diluted with phospha...

Embodiment 1

[0053] 1. Synthesis of Cyclo[-Arg-Gly-Asp-ψ(triazole)-Gly-Gly-](7a):

[0054] 1. Synthesis of Azido-glycine (according to the principle of diazonium transfer):

[0055] 1.1 Preparation of trifluoromethanesulfonyl azide:

[0056] Dissolve sodium azide (6 g) in a 150 ml round bottom flask, add 24 ml of DCM, cool to 0° C. in an ice bath, and stir for 20 minutes. The reaction mixture was extracted with DCM (2×12ml). The organic phases were combined and washed with saturated sodium carbonate to obtain trifluoromethanesulfonyl azide dissolved in dichloromethane, which was directly added to the next reaction without further purification.

[0057] 1.2 Preparation of azidoglycine:

[0058] Glycine (0.675g), K 2 CO 3 (1.783g), CuSO 4 (0.0226g) was added to a round bottom flask, then water (30ml), methanol (60ml) and dichloromethane (48ml) containing trifluoromethanesulfonyl azide were added, stirred at room temperature, and reacted overnight. Subsequently, the organic solvent was ...

Embodiment 2

[0069] Synthesis of Cyclo[-Arg-Gly-Asp-ψ(triazole)-Gly-Ala-](7b):

[0070] The steps in this embodiment are the same as in Embodiment 1, wherein:

[0071] In the third step, Fmoc-Arg(Pbf)-OH, fluorenylmethoxycarbonyl-alanine (Fmoc-Ala-OH) and Azido-glycine are sequentially condensed to generate linear tetrapeptide analogs.

[0072] The physicochemical analysis data of gained final product are as follows:

[0073] Cyclo[-Arg-Gly-Asp-ψ(triazole)-Gly-Ala-](7b).White solids, mp: 164-165℃; [ α ] D 25 = + 56.3 (c=1.0in CHCl 3 ); 1 H NMR (500MHz, DMSO-d 6 ): δ1.23 (1H, J = 6.3Hz, d), 1.28 (2H, J = 7.0Hz, d), 1.38-1.45 (2H, m), 1.87-1.93 (2H, m), 2.67-2.75 ( 2H, m), 2.89(2H, s), 4.12-4.19(3H, m), 4.21(1H, J=5.0Hz, d), 4.28(1H, J=6.3Hz, d), 4.39(1H, J =14.3, 7.2Hz, dd), 4.40(1H, J=7.1Hz, d), 5.07(1H, J=6.3Hz, d), 5.27(1H, J=16.6Hz, d), 6.92(2H, s ...

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Abstract

The invention relates to a cyclopeptide analog and a cyclization method thereof, which aims at providing an integrin ligand cyclopeptide analog and a cyclization method thereof. The cyclization method comprises the following steps: Azido-glycine is firstly generated by glycin with the effects of trifluoromethanesulfonic anhydride and Sodium azide; Fmoc-Asp-Propargyl is then generated by condensation with propargylamine in solution; after side-chain carboxyl of propargyl acyl aspartic acid is then hung on 2-CTC resin, linear tetrapeptide analogs are condensed in turn, and the linear tetrapeptide analogs are then cut down from the resin; and the cyclopeptide analog is synthesized in the condition of liquid phase (DCM is used as a solvent and CuBr/DBU is used as catalyst) after 4 to 6 hours of reaction at room temperature. The cyclopeptide analog and cyclization method has the following advantages: (1) the integrin ligand cyclopeptide analog in the invention is introduced with heterocyclic rings (triazole rings), thereby being capable of increasing biological activity; and (2) the cyclization method in the invention is more simple, convenient and high-efficient, and the condition is moderate.

Description

technical field [0001] The present invention relates to a cyclic peptide analog and a cyclization method thereof, and more specifically relates to an integrin ligand cyclic peptide analog and a cyclization method thereof. Background technique [0002] An obvious feature of tumor growth is to stimulate the secretion of various growth factors by vascular endothelial cells to further promote the rapid growth of tumor blood vessels, so that the cells have sufficient blood supply and grow malignantly. Tumor growth and metastasis are a process dependent on blood vessels. Usually, when the tumor diameter is less than 2-3mm, the required nutrients can be obtained through the diffusion of blood vessels around the tumor. Tumor enlargement requires the formation of new blood vessels to supply nutrients. As early as 1971, American scientists Folkman and others proposed that tumor growth could be inhibited and tumor metastasis prevented by blocking tumor angiogenesis. According to this...

Claims

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Application Information

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IPC IPC(8): C07K5/11C07K7/06
Inventor 刘雅琴徐宇虹
Owner ZHEJIANG UNIV
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