CN106188089B

CN106188089B - Mangostin derivative A, preparation method and its anti-tumor application

Info

Publication number: CN106188089B
Application number: CN201610576117.3A
Authority: CN
Inventors: 孔令义; 王小兵; 吴佳佳
Original assignee: China Pharmaceutical University
Current assignee: China Pharmaceutical University
Priority date: 2016-07-20
Filing date: 2016-07-20
Publication date: 2018-07-31
Anticipated expiration: 2036-07-20
Also published as: CN106188089A

Abstract

The present invention relates to medicinal chemistry arts, more particularly to a kind of compound mangostin derivative A (I)), the pH that the present invention passes through regulation and control buffer solution, using α mangostins as substrate, it is selectively converted to mangostin derivative A, pharmacodynamics test shows that the compound of the present invention has excellent antitumor activity.

Description

Mangostin derivative A, preparation method and its anti-tumor application

Technical field

The present invention relates to medicinal chemistry arts, and in particular to a kind of compound mangostin derivative A, preparation method and Its anti-tumor application.

Background technology

The chemical reaction that carries out under the catalysis of the biocatalysts such as cell or enzyme, have environmentally protective, specificity is stronger, The advantages such as catalytic activity higher, condition be more easy to control.In complicated natural products, it is huge that bioconversion has more highlighted it Potential synthesis capability.Wherein, peroxidase is a kind of caused by microorganism or plant as a kind of biocatalyst Oxidoreducing enzyme, it is usually converted using hydrogen peroxide as electron acceptor to be catalyzed substrate, and there are commonly laccase, horseradish peroxides Compound enzyme, soybean peroxidase etc..Wherein horseradish peroxidase is most widely used.But with horseradish peroxidase Still it is faced with two people's problem in science urgently to be resolved hurrily for the bioconversion of catalyst：Practical application and selectivity.

Invention content

The present invention has selectively been converted to mangostin by regulating and controlling the pH of buffer solution using α-mangostin as substrate Derivative A (referred to as DIA), pharmacodynamics test show that the compound of the present invention has antitumor activity.

The structure of the compounds of this invention DIA is as follows：

The invention also discloses the preparation methods of compound DIA, including：

α-mangostin is dissolved in acetone/phosphate buffer (PBS), is stirred at 37 DEG C, while horseradish peroxidating is added Object enzyme (HRP) and hydrogen peroxide, stirring 2h obtain buff reaction solution.Reaction solution decompression boils off acetone, uses acetic acid second after cooling Fat extracts 3 times, through anhydrous Na after organic layer merging₂SO₄It is dry, it is spin-dried for, obtains buff powder.Sample is dissolved with 78% methanol, is led to It crosses high performance liquid chromatography (HPLC) and prepares column, the elution of 78% methanol obtains compound DIA.

Here is partial pharmacologic experiment and the data of the compounds of this invention：

According to the MTT methods of improvement, human liver cancer cell HepG2, breast cancer cell in exponential phase are taken respectively MCF-7, osteosarcoma cell U2-OS and colon cancer cell HT29, PBS flushing, the digestion of 0.25% pancreatin are added fresh culture and blow Break into maxicell suspension.Blood counting chamber is counted, and 96 orifice plates (5 × 10 are inoculated in³A cells/well), per 190 μ L cultures of hole The untested compound of various concentration is added after 37 DEG C are cultivated 12h in base, and per 10 μ L of hole, the working solution of sample is diluted to culture medium Final concentration is respectively 0.3125,0.625,1.25,2.5,5,10,20 μM, and each concentration sets 3 parallel holes.After being incubated 48h, often 20 μ L (5mg/mL) of MTT are added in hole, continue to be incubated 4h, discard culture medium later, 150 μ L of dimethyl sulfoxide (DMSO) are added per hole, will tie After brilliant fully shaking shakes up, measured using microplate reader

Absorbance under 570nm, reference wavelength 630nm calculate cell proliferation inhibition rate.Cell proliferation inhibition rate=(empty White control OD values-administration group OD values)/blank control group OD value × 100%.Experiment is averaged in triplicate, the results are shown in Table 1.

The antitumor activity result of 1 compound of table

IC₅₀(μM)	HepG2	MCF-7	U2-OS	HT29
					DIA	1.737±0.067	13.977±1.249	5.997±0.353	9.286±0.098
α-mangostin	22.800±0.709	22.763±0.743	9.343±0.725	13.718±0.317
					Cis-platinum	6.843±2.326	9.521±1.405	6.707±0.916	13.024±2.841

As it can be seen from table 1 the compounds of this invention DIA (I) to each tumor cell line be significantly better than positive drug cis-platinum and The activity of α-mangostin.

Specific implementation mode

Embodiment 1

50mg α-mangostin is taken to be dissolved in the two-phase organic solvent system of acetone/PBS buffer solution (100mM, pH 8.0) (3:4v/v, 7mL), it stirs at 37 DEG C, while horseradish peroxidase (75 μ L, 1mg/mL) is added, is added dropwise after 30 minutes 0.3% hydrogen peroxide of 60 μ L stirs 2 hours to solution in deep yellow turbid.Reaction solution decompression boils off acetone, uses after cooling Ethyl acetate extracts 3 times, through anhydrous Na after organic layer merging₂SO₄It is dry, it is spin-dried for, obtains buff powder.

Sample is dissolved with 78% methanol, prepares column by HPLC, the elution of 78% methanol obtains structure of the invention compound of formula I.

Compound I (DIA)

Faint yellow unformed powder, HRESIMS：440, molecular formula：C₂₄H₂₅O₈。

¹H-NMR(in CDCl₃,500MHz)δ:6.28(1H,s,H-4),6.82(1H,s,H-5),4.06(2H,d,5.9, H-1’),5.23(1H,br t,5.6,H-2’),1.82(3H,s,H-4’),1.69(3H,s,H-5’),6.10(1H,d,6.2,H- 1”),5.28(1H,d,6.2 H-2”),1.41(3H,s,H-4”),1.43(3H,s,H-5”),13.93(1H,s,1-OH),3.80 (3H,s,7-OMe)。

¹³C-NMR(in CDCl₃,125MHz)δ:161.0(C-1),105.8(C-2),167.2(C-3),88.3(C-4), 159.1(C-4a),101.8(C-5),155.9(C-6),143.0(C-7),137.3(C-8),12.2(C-8a),182.3(C- 9),104.6(C-9a),154.9(C-10a),26.7(C-1’),123.1(C-2’),132.5(C-3’),18.4(C-4’), 26.0(C-5’),82.4(C-1”),98.7(C-2”),85.7(C-3”),18.33(C-4”),23.93(C-5”),62.2(7- OMe)。

Claims

1. the compound or its pharmaceutically acceptable salt of a kind of structural formula I：

2. the preparation method of the compound of claim 1, including：

α-mangostin is dissolved in the phosphate buffer of acetone/pH8.0, is stirred at 37 DEG C, while horseradish peroxidase is added Enzyme and hydrogen peroxide, stirring 2h obtain buff reaction solution；Reaction solution decompression boils off acetone, and 3 are extracted with ethyl acetate after cooling It is secondary, through anhydrous Na after organic layer merging₂SO₄It is dry, it is spin-dried for, obtains buff powder；Sample is dissolved with 78% methanol, by efficient Liquid chromatography preparation post, 78% methanol elution, obtains the compound of claim 1.

3. a kind of pharmaceutical composition, wherein compound or its pharmaceutically acceptable salt comprising claim 1 and pharmaceutically may be used The carrier of receiving.

4. the compound of claim 1 or its pharmaceutically acceptable salt are used to prepare treatment liver cancer, human osteosarcoma or colon cancer Drug purposes.