KR100586618B1 - Supramolecular complexes between cyclopeptides and fullerenes and preparation thereof - Google Patents

Abstract

The present invention relates to a cyclopeptide-fullerene macromolecular complex and a method for preparing the same, wherein the complex according to the present invention has a weight loss of 60% or more at 550 ° C. in thermogravimetric analysis and an additional weight loss of 20% at heating to 800 ° C. It is characterized by more than%, can be prepared by a simple method of liquid or solid phase.

Description

Macromolecular Complexes of Cyclopeptides and Fullerenes and Methods for Manufacturing the Same {SUPRAMOLECULAR COMPLEXES BETWEEN CYCLOPEPTIDES AND FULLERENES AND PREPARATION THEREOF}

1 is a space filling model of a cyclopeptide- [60] fullerene complex according to the present invention,

2 is a thermal analysis (TGA) of the cyclopeptide- [60] fullerene complex and cyclopeptide (insert) prepared in Example 1,

3 is an X-ray diffraction pattern of the cyclopeptide- [60] fullerene complex (a), cyclopeptide (b) and [60] fullerene (c) prepared in Example 3,

4 is an FT-IR spectrum of the cyclopeptide- [60] fullerene complex prepared in Example 3. FIG.

The present invention relates to a macromolecular complex between a cyclopeptide and fullerene and a method for preparing the same.

Macromolecular chemistry is one of the promising methods for designing and constructing new structures with unique properties. Much research has been done to apply macromolecular assemblies to applications such as photosynthetic systems, nonlinear optical materials, molecular wires or sensors.

One method for making self-assembled structures is to use macrocycle molecules that have a rigid cavity that is large enough to accommodate small guest molecules.

Rigid cyclic molecules, such as crown ethers, cyclopanes, calissarens, or cyclodextrins, are known to be useful building blocks in macromolecular chemistry because they interact with ions and are readily available through non-covalent bonds such as ion-dipole interactions and hydrogen bonds. It can be polarized to combine with organic compounds, ions or polar compounds.

Cyclopeptides possess various biological activities and can be used as hormones, antibodies or toxins. Recently, as a cyclic depsipeptide derived from tunicates, Didemnin B4, which has strong immunosuppressive and antiviral activity and suppresses the increase of tumor cells, has attracted attention. However, cyclopeptides are relatively flexible and difficult to use as artificial receptors because they rarely react with substrates in well defined cavities.

In addition, fullerenes are expected to biomedical use due to their high reactivity to free radicals and their ability to cleave DNA in the presence of light.

 Accordingly, the present inventors seek to provide a method for preparing macromolecular complexes by reacting fullerenes with cyclopeptides, which have properties useful in the biomedical field.

The present invention provides a cyclopeptide-fullerene complex having a weight loss of 60% or more at 550 ° C. and a further weight loss of 20% or more when heated to 800 ° C. in order to solve the above technical problem.

The cyclopeptide-fullerene complex according to the present invention may bind in a 1: 2 to 2: 1 molar ratio of the cyclopeptide and fullerene, and more preferably in a 2: 1 molar ratio as shown in FIG. 1.

Complexes according to the invention can be prepared in a solid or liquid phase reaction.

First, in the case of liquid phase reaction, the cyclopeptide solution and the fullerene solution having various pore sizes are mixed and stirred, and then the complex is separated.

Dimethyl formamide (DMF), dimethyl sulfoxide (DMSO), chloroform (CHCl ₃ ), etc. are preferable as the solvent of the cyclopeptide, and toluene is preferable as the solvent of fullerene.

According to a preferred embodiment of the present invention, the concentration of the cyclopeptide solution is 0.1-0.85 mmol / L, most preferably 0.7-0.85 mmol / L, and the concentration of the fullerene solution is 0.1-0.7 mmol / L, most preferably 0.5-0.7 mmol / L.

The reaction molar ratio of cyclopeptide / fullerene is preferably 1 / 0.5-2.0, more preferably 1 / 0.7-0.85. It is preferable to perform a liquid phase reaction at normal temperature of 20-30 degreeC for 5 to 12 days.

The solid phase reaction is carried out by milling the reaction molar ratio of cyclopeptide / fullerene to 1 / 0.4-2.0, most preferably 1 / 0.4-0.6, and the solid phase reaction for about 2 to 6 hours. In the case of a solid phase reaction, since the purification process is not necessary, the reaction molar ratio for the cyclopeptide and fullerene to form a 2: 1 complex can be almost 2: 1.

Cyclopeptides suitable for use in the method according to the present invention are those having reduced flexibility, wherein the flexibility of the cyclopeptides consists of sequences in which the (L)-and (D) -amino acids are alternately located or a rigid bottom such as an aromatic ring. It can be reduced by including the unit.

In particular, it is preferable that the natural amino acid and 3-aminobenzoic acid is composed of a sequence located alternately, specifically, for example, as shown in the formula (1) and (2).

Such cyclic peptides are described in S. et al. Kubik, J. Am. Chem. Soc. 1999, 121, 5846]. Specifically, the butoxycarbonyl (BOC) -protected L-glutamic acid derivative is combined with the benzyl ester of 3-aminobenzoic acid to give a linear peptide after several steps of binding reaction, and the cycling is finally carried out in a very dilute solution. Is carried out. This yields cyclopeptides of various sizes that resemble common host molecules, such as calissaren, cyclodextrin, cyclopan, or cucurbituril.

<Example 1>

A violet solution of [60] fullerene in toluene (0.5 mmol / L) and a colorless solution of cyclopeptide in DMF (0.7 mmol / L) were mixed and reacted at 25 ° C. The purple solution turned brown within two days, indicating that the complex was formed. After stirring for 8 days, the complex was separated. After removing the organic solvent, distilled water was added to give a yellow aqueous solution. Purification via membrane filtration of fractional molar mass 2 kg / mol followed by freeze drying yielded the product (yield 23%).

<Example 2>

Fullerene-cyclopeptide macromolecular complexes were obtained in the same manner as in Example 1, except that the concentration of the fullerene solution was 0.7 mmol / L and the concentration of the cyclopeptide solution was 0.84 mmol / L.

<Example 3>

The solid cyclopeptide and [60] fullerene were mixed at a 2: 1 molar ratio, and then pulverized with a mixer mill for 4 hours (20 cycles / sec) to obtain a fullerene-cyclopeptide macromolecular complex.

(1) thermal analysis

FIG. 2 is a thermal analysis of the cyclopeptide- [60] fullerene complex and cyclopeptide (insert) prepared in Example 1. FIG. The fullerene complex prepared in Example 1 was decomposed at 550 ℃ to 800 ℃. The mass loss at 550 ° C. was 67.7% and is thought to be due to degradation of the cyclopeptide. Slow increase to 800 ° C. resulted in additional losses of 26.7%. Theoretically calculated fullerene content is 29.8, 45.3 and 62.3% when the molar ratio of cyclopeptide to fullerene in the complex is 2: 1, 1: 1 and 1: 2, respectively. Therefore, the above results show that the 2: 1 complex of the cyclopeptide and fullerene as shown in FIG. 1 was formed.

(2) X-ray diffraction analysis

Figure 3 is an X-ray diffraction pattern for the product prepared in Example 3, showing the results for the cyclopeptide- [60] fullerene complex (a), cyclopeptide (b) and [60] fullerene (c), respectively. In the pattern (a) for the complex, it can be seen that the pattern of the cyclopeptide (b) or the fullerene (c) has disappeared.

(3) IR analysis

4 is an FT-IR spectrum of a general cyclopeptide and the complex prepared in Example 3. FIG. Bands representing the intermolecular hydrogen-bonded NH of the cyclopeptide (inset graph of FIG. 4) appear at 3270 cm ⁻¹ and weak shoulders showing free NH ₅ at 3398 cm ⁻¹ . In complex formation with fullerene, the band strength of the free NH group increased while the strength of the hydrogen-bonded NH band decreased. This means that the intermolecular hydrogen bonds of the cyclopeptides were broken due to their interaction with [60] fullerenes.

 The present invention reacts full peptides and cyclopeptides possessing biomedical useful properties to form macromolecular complexes in an easy manner, allowing them to be actively utilized in pharmaceutical applications as well as other potential applications, such as drug delivery media. .

Claims (8)

A cyclopeptide-fullerene complex wherein cyclopeptide and fullerene are bonded in a 1: 2 to 2: 1 molar ratio. delete A solution of cyclopeptide prepared by dissolving cyclopeptide in dimethylformamide, dimethyl sulfoxide, chloroform or a mixture thereof and a solution of fullerene prepared by dissolving fullerene in toluene were mixed at a reaction molar ratio of 1: 0.5-2.0. Method for producing a cyclopeptide-fullerene complex of claim 1, characterized in that for 12 to 12 days at room temperature to react. delete The method of claim 3, wherein the concentration of the cyclopeptide solution is 0.1-0.85 mmol / L and the concentration of the fullerene solution is 0.1-0.7 mmol / L. delete Method for producing a cyclopeptide-fullerene complex of claim 1, characterized in that the cyclopeptide and fullerene are mixed at a reaction molar ratio of 1: 0.4-2.0 and milled together for 2 to 6 hours. delete

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