CN103788128A - Organic phosphonic quad-core copper complex as well as preparation method and application thereof - Google Patents

Abstract

The invention relates to an organic phosphonic quad-core copper complex which has the chemical formula of Na4 (Cu4 (HMMPA) 4).16H2O, wherein HMMPA is 2-hydroxy benzene methylamine methyl ethyl ester phosphate. The preparation method comprises the steps of dissolving the 2-hydroxy benzene methylamine methyl ethyl ester phosphate ligand and CuCl2.2H2O into methanol water solution, wherein the molar ratio between the 2-hydroxy benzene methylamine methyl ethyl ester phosphate ligand and the CuCl2.2H2O is 1: 1; carrying out heating reflux reaction for 1-3h, and then adjusting the pH value of the reaction liquid to 8-9 by 20% NaOH; continuously carrying out heating reflux reaction for 1-4h, and then stopping the reaction; cooling the reaction liquid, and standing still overnight; filtering to obtain bottle green filtrate; enabling the filtrate to slowly volatilize, and separating out green block crystal; carrying out suction filtration, washing and drying to obtain green crystal. The organic phosphonic quad-core copper complex is simple in preparation method, low in cost and high in product purity, and raw materials are easily available; the organic phosphonic quad-core copper complex is capable of effectively inhibiting the activity of protein-tyrosine-phosphatase, thus being used as an efficient protein-tyrosine-phosphatase inhibitor.

Description

A kind of organic phosphine four core copper complexes and its preparation method and application

Technical field:

The present invention relates to metal complexes, be specifically related to a kind of organic phosphine four core copper (II) title complexs and its preparation method and application.

Background technology:

Copper is one of essential trace element of organism, form many copper-containing metal enzymes and cupric biological activity protein, participate in some important cell processes, such as formation and the angiogenesis etc. of respiration, free radical defence, neural myelin, cupric ion also can participate in the signal conductive process of protein kinase and Phosphoric acid esterase, and Recent study shows that thereby copper complex can cause by proteasome enzyme inhibition the apoptosis of cancer cells, this viewpoint provides new thinking for the biological function that we study copper complex.Consider that copper complex can be treated the mechanism of disease and the phosphorylation level of albumen has very large relation, therefore copper complex is expected to by the active treatment various diseases of arrestin tyrosine phosphatase (PTPs).This is for we study metabolic process in vivo of copper and exploitation cupric drug provision theoretical foundation.

PTPs plays a significant role in cell signaling with in regulating cell processes, the growth of such as cell, division, propagation etc., the active disorder of PTPs can cause the abnormal of protein tyrosine phosphatase level, thereby cause the multiple human diseases including cancer, diabetes, obesity, immunologic derangement etc., in view of PTPs is at the outstanding role aspect disease control, using Protein-tyrosine-phosphatase as target spot, research and development efficiently, PTPs inhibitor optionally, the particularly inhibitor based on metal ion, significant as the medicine of disease.

Summary of the invention:

The object of the present invention is to provide a kind of organic phosphine four core copper (II) title complexs and preparation method thereof, and this title complex is as the application of Protein-tyrosine-phosphatase (PTP) inhibitor.

A kind of organic phosphine four core copper (II) title complexs provided by the invention, its chemical formula is: Na ₄[Cu ₄(HMMPA) ₄] 16H ₂o, wherein HMMPA=2-hydroxybenzene methylamine methyl phosphonous acid ethyl ester, its structural formula is:

The preparation method of a kind of organic phosphine four core copper complexes provided by the invention, comprises the steps:

(1) 2-hydroxybenzene methylamine methyl phosphonous acid ethyl ester part is synthetic

2:1 adds salicylic aldehyde and methylamine in round-bottomed flask in molar ratio, take dehydrated alcohol as solvent, after heating reflux reaction 2～6h, to slowly dripping the ethanol solution containing with the diethyl phosphite of salicylic aldehyde equimolar amount in reaction solution, finish, continuing heating reflux reaction to the solid producing no longer increases, cooling reaction solution is to room temperature, leave standstill, suction filtration, respectively washs and obtains yellow solid at least 3 times with ice dehydrated alcohol and anhydrous diethyl ether; Yellow solid obtains light yellow part through dehydrated alcohol/water mixed solvent recrystallization.

(2) take the CuCl of above-mentioned part and equimolar amount ₂2H ₂o is dissolved in methanol aqueous solution, it is between 8-9 that heating reflux reaction was adjusted the pH value of reaction solution with 20% NaOH after 1～3 hour, continue heating reflux reaction after 1～4 hour, stopped reaction, by cooling reaction solution hold over night, filter to obtain deep green filtrate, room temperature is slowly volatilized, and separates out green bulk crystals after two weeks; Suction filtration, anhydrous methanol, the each washing of water at least 3 times, vacuum-drying, obtains green crystal sample.

Four core copper complexes of the present invention can be used as efficient inhibitors of protein tyrosine phosphatase.

Organic phosphine four core copper complexes of the present invention obtain under normal temperature and pressure conventional chemical synthesis condition, and preparation method's technique is simple, and its raw material is easy to get, and cost is low, and product is separated out with crystalline form, and sample purity is high; Title complex of the present invention is arrestin tyrosine phosphatase enzymic activity effectively.

Accompanying drawing explanation

Fig. 1 title complex Na of the present invention ₄[Cu ₄(HMMPA) ₄] 16H ₂the crystalline structure figure of O

The X-ray powder diffraction pattern of Fig. 2 title complex of the present invention

The thermogravimetric analysis figure of Fig. 3 title complex of the present invention

Inhibition type and the inhibition constant measuring of Fig. 4 title complex of the present invention to PTP1B activity

Embodiment

Below in conjunction with accompanying drawing and example, the invention will be further described.

Embodiment 1

The preparation of title complex:

(1) synthetic 2-hydroxybenzene methylamine methyl phosphonous acid ethyl ester part: add 0.04mol (4.18mL) salicylic aldehyde and 0.02mol (0.94mL) methylamine in 100mL round-bottomed flask, add 30mL dehydrated alcohol as solvent, after heating reflux reaction 4h, in above-mentioned reaction solution, slowly drip the 20mL ethanol solution containing 0.04mol (5.14mL) diethyl phosphite, finish, the solid that continuation heating reflux reaction 35h extremely produces no longer increases, cooling reaction solution is to room temperature, leave standstill, suction filtration, obtain yellow solid three times with the each washing of ice dehydrated alcohol and anhydrous diethyl ether.Yellow solid obtains light yellow sterling through dehydrated alcohol/water (v/v=1:1) mixed solvent recrystallization.The heavy 2.93g of white products, productive rate is 54%.Results of elemental analyses is according to C ₁₀h ₁₆nO ₄p calculates (%), theoretical value: C48.98; H6.58; N5.71, experimental value: C49.08; H6.51; N5.65.Ir data (cm ^-1, s is strong; M, in strong): 3420m, ν (O-H, N-H); 2984m, ν (C-H); 1228, ν (P=O); 1064,1048s, ν (P-O-C); 957s, ν (P-C).

(2) synthetic Na ₄[Cu ₄(HMMPA) ₄] 16H ₂o title complex: take the above-mentioned part of 1.0mmol (0.245g) and 1.0mmol (0.170g) CuCl ₂2H ₂o is dissolved in 8mL H ₂in the mixed solvent of O and 16mL anhydrous methanol, heating reflux reaction is stopped reaction after 2 hours, is cooled to room temperature.It is between 8-9 that NaOH with 20% adjusts the pH value of reaction solution, continues heating reflux reaction after 2 hours, and stopped reaction, by cooling reaction solution hold over night, filters to obtain deep green filtrate, and room temperature is slowly volatilized, and separates out green bulk crystals after two weeks.Suction filtration, anhydrous methanol, water respectively wash three times, vacuum-drying, the heavy 0.112g of green crystal sample, productive rate is 26.9%.Results of elemental analyses is according to Na ₄c ₃₂h ₃₅cu ₄n ₄o ₁₆p ₄16H ₂o calculates (%), theoretical value: C25.74; H4.73; N3.75, experimental value: C25.67; H4.71; N3.49.Ir data (cm ^-1, s is strong; M, in strong): 3430m, ν (O-H, N-H); 2980m, ν (C-H); 1182s, ν (P=O); 1095,1012s, ν (P-O-C); 983s, ν (P-C).

Complex crystal structure determination:

The crystalline diffraction data of title complex of the present invention are collected (operating voltage of 2.2GeV adopts MARCCD-165 detector) under Beijing Synchrotron Radiation 1W2B line station 100K, HKL2000 programe reduction data, and SHELXTL resolves.Detailed axonometry data are in table 1, and structure is shown in Fig. 1.Crystal structure determination result shows that this complex crystal is tetragonal system, and spacer is P4, and unit cell parameters is a=b=30.9020 (2), c=12.4990 (10), α=β=γ=90.In this title complex agent structure, the phosphonic acids O of four organophosphorus ligands is with μ _1,3-O, O and μ ₂these two kinds of bridging modes of-O, form respectively Cu-O-P-O-Cu and Cu-O-Cu chain, connect four metal copper ions, form four core negatively charged ion cage structures.In this four core anion structure, four metal copper ions are pentacoordinate, and each cupric ion has identical coordination environment, take Cu1 as example, Cu1 ion except with an organophosphorus ligand molecule in the O3 Atomic coordinate of N1 atom, phenolic hydroxyl group O1 atom and phosphonic acids part, also with two other part in the respectively coordination of Sauerstoffatom O14, O6 of phosphonic acids part, form tetragonal pyramid configuration, at the bottom of wherein ligating atom N1, O1, O14 and O6 have formed the cone of tetragonal pyramid, O3 is on the axis of tetragonal pyramid.Axially the coordination bond lengths between Cu-O is 2.351 (11)-2.436 (10)

than the bond distance (1.900 (8)-1.995 (13) of tetragonal pyramid bottom Cu-O

long a lot, this has shown that central metal cupric ion is subject to the impact of ' Jahn-Teller ' effect.The bond distance of Cu-N at the bottom of tetragonal pyramid is respectively 1.994 (12)

2.067 (12)

The crystallographic data of table 1 title complex

The powdery diffractometry of title complex:

X-ray powder diffraction result shows, crystal article thing phase homogeneous, and experiment diffracting spectrum, with consistent according to the powder diffraction spectrum of crystalline structure simulation, is shown in Fig. 2.

The thermogravimetric analysis of title complex:

Thermogravimetric analysis result shows that this title complex is between 30 ℃-140 ℃ gradually weightless approximately 17.6%, illustrate and in title complex, have crystal water and coordinated water (theoretical value 18.3%), this result has further been proved the existence of water molecules in match crystal body structure; Also can find out from thermogravimetric analysis Fig. 3 in addition, its agent structure is decomposed more than 200 ℃, illustrates that title complex has higher thermostability.

Embodiment 2

Title complex of the present invention suppresses the mensuration of PTPs activity

Experimental result shows (table 2), and organic phosphine four core copper complexes can effectively suppress the activity of different types of PTPs (PTP1B, TCPTP, PTP-MEG2, SHP-1, SHP-2), and it is to PTP1B, TCPTP, and the inhibition ability of SHP-1 activity is close, IC ₅₀value is about 0.11-0.22 μ M, but the ability that this title complex suppresses three kinds of enzymes above to the inhibition energy force rate of SHP-2 activity is low 10 times, and this title complex there is no restraining effect to PTP-MEG2, its inhibition ability to different PTP activity of the structure influence of these presentation of results copper complexes.

Table 2 title complex is to the active IC of the inhibition of different PTPs ₅₀value (μ M)

Title complex suppresses type to PTP1B and suppresses the mensuration of constant K i: in reaction system, the concentration of solid PTP1B enzyme, chooses the inhibitor concentration (0 of a series of different concns, 50,100,200,300 μ M), under each inhibitor concentration, change the concentration (0.2 of substrate pNPP from low to high, 0.3,0.5,1.0,2.0,8.0mM), measure the increase along with concentration of substrate, the initial reaction rate changing value of enzymatic reaction.According to two 1/ ν-1/[S reciprocal] scheme to determine the inhibition type of inhibitor and suppress constant K i value.The inhibition type measurement result of title complex as shown in Figure 4, as can be seen from the figure, the L-B equation of different inhibitor concentration meets at y axle positive axis a bit, show that this title complex belongs to typical competitive inhibitor, according to suppressing type measurement result, the inhibition constant K i value that calculates title complex is 0.15 μ M.

Claims (3)

1. organic phosphine four core copper complexes, is characterized in that, structural formula is:

2. the preparation method of a kind of organic phosphine four core copper complexes as claimed in claim 1, is characterized in that, comprises the steps:

(1) 2:1 adds salicylic aldehyde and methylamine in round-bottomed flask in molar ratio, take dehydrated alcohol as solvent, after heating reflux reaction 2～6h, to slowly dripping the ethanol solution containing with the diethyl phosphite of salicylic aldehyde equimolar amount in reaction solution, finish, continuing heating reflux reaction to the solid producing no longer increases, cooling reaction solution is to room temperature, leave standstill, suction filtration, respectively washs and obtains yellow solid at least 3 times with ice dehydrated alcohol and anhydrous diethyl ether; Yellow solid obtains light yellow part through dehydrated alcohol/water mixed solvent recrystallization;

(2) take the CuCl of above-mentioned part and equimolar amount ₂2H ₂o is dissolved in methanol aqueous solution, it is between 8-9 that heating reflux reaction was adjusted the pH value of reaction solution with 20% NaOH after 1～3 hour, continue heating reflux reaction after 1～4 hour, stopped reaction, by cooling reaction solution hold over night, filter to obtain deep green filtrate, room temperature is slowly volatilized, and separates out green bulk crystals after two weeks; Suction filtration, anhydrous methanol, the each washing of water at least 3 times, vacuum-drying, obtains green crystal sample.

3. organic phosphine four core copper complexes as claimed in claim 1 are as inhibitors of protein tyrosine phosphatase.

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