CN1887898A - Amino acid as chemical modifier for ursolic acid - Google Patents

Abstract

The amino acid chemically modified ursolic acid is one semi-synthesized product, and is prepared through the following steps: 1. reaction between ursolic acid and acetic anhydride to produce acetoxy ursolic acid; 2. reaction between acetoxy ursolic acid and oxalyl chloride and further reaction with corresponding amino acid to produce intermediate products; and 3. hydrolyzing the intermediate products to obtain amino acid chemically modified ursolic acids as the target compounds. The present invention obtains serial ursolic acid analogs, which are proved through pharmacological tests to have HELA human body cervical carcinoma cell inhibiting activity higher than that of ursolic acid.

Description

Amino acid as chemical modifier for ursolic acid

Technical field

The present invention relates to a kind of natural product and its semisynthetic, particularly relate to a kind of amino acid as chemical modifier for ursolic acid with anti-tumor activity.

Background technology

(ursolic acid, UA) (Compound I) has another name called urson, ursonic acid to ursolic acid, belongs to pentacyclic triterpenoid.It is widely distributed at occurring in nature, and has the various biological effect, and neural system is had obviously stable and cooling effect; External to G ⁺And G ^-Bacterium and yeast all have anti-microbial activity; Have reducing blood-fat, study of anti-atherogenic effect; Protect the liver in addition, antihepatitic activity.

The chemical structural formula of ursolic acid:

Studies show that ursolic acid not only has resistant function to multiple carcinogenic, short cancer thing, and multiple malignant tumour such as P-388 and L-1210 leukemia cell, A-549 human lung adenocarcinoma cell are had the growth of inhibition effect; Can induce the F9 teratocarcinoma cell to become the endoderm cell; T cell lymphoma Jurkat cell strain had the restraining effect of killing and wounding; In addition, also has the effect that antineoplastic vascular generates.

Summary of the invention

The object of the present invention is to provide a kind ofly to have multiple bioactive ursolic acid, design a kind of amino acid as chemical modifier for ursolic acid with anti-tumor activity as lead compound.

The objective of the invention is to be achieved through the following technical solutions:

Amino acid as chemical modifier for ursolic acid, its structural formula is as follows:

Wherein: R ₁Be hydroxyl or ethanoyl, R ₂Be substituted amino acid or hydroxyl.

Aforesaid amino acid as chemical modifier for ursolic acid is prepared by following steps:

(1) ursolic acid compound (I) and the acetic anhydride 3-acetoxyl group ursolic acid (II) that is;

(2) 3-acetoxyl group ursolic acid and oxalyl chloride reaction is again with the compound (III-VIII) of corresponding amino acid reaction;

(3) compound (III-VIII) gets compound (IX-XIV) through hydrolysis.

Aforesaid amino acid as chemical modifier for ursolic acid, they have anti-tumor activity, can be used for treating tumor disease.

Embodiment

Below the present invention is described in detail.

The present invention finishes through the following steps:

1. the extraction using alcohol medicinal extract of Loquat Leaf is with sherwood oil, 1% sodium hydroxide with to be washed to elutant colourless, the dehydrated alcohol heating for dissolving, and activated carbon decolorizing, filtrate placement is separated out white crystals, gets Compound I with recrystallization from hot methanol.

2. Compound I and acetic anhydride get Compound I I

3. Compound I I and oxalyl chloride at room temperature react, and the further following and amino acid methyl ester reaction in alkaline condition gets compound III-VIII

R wherein ₂Be the substituted amino acid methyl esters

4. compound III-VIII gets Compound I X-XIV through hydrolysis

R wherein ₂Be substituted amino acid

Such pentacyclic triterpenoid carries out antineoplastic pharmacological testing proves that it has the obvious suppression effect to the HELA human body cervical carcinoma cell, and the structural modification thing of ursolic acid suppresses the HELA activity and all is better than the parent compound ursolic acid.The human cancer cell tests the employing mtt assay.The in vitro tests result is by shown in the table 1.

Table 1 ursolic acid and structural modification thing thereof are to the restraining effect (inhibiting rate %) of HELA human body cervical carcinoma cell strain

Compound concentration	10 -5mol/l	10 -6mol/l	10 -7mol/l	10 -8mol/l
					I II III IV	12.36 37.83 61.69 59.90	2.24 6.22 8.45 22.63	0.26 2.76 1.63 20.0	0.16 2.07 0 13.16

V VI VII VIII IX X XI XII XIII XIV

51.53 32.86 55.92 10.58 16.84 23.58 27.47 21.95

33.31 13.53 28.03 5.01 3.31 20.99 24.71 16.14

9.79 3.78 3.93 1.83 0.29 18.04 22.66 12.17

6.35 0.89 2.15 0.04 0 15.45 19.32 3.19

Further specify enforcement of the present invention with example below

Embodiment 1

The preparation of Compound I I: in 50ml exsiccant eggplant type bottle, add 200mg ursolic acid (0.44mmol) and dissolve with THF, add the 1ml pyridine, a little DMAP stirred 4.5 hours under the room temperature, steaming desolventizes, resistates adds an amount of water, transfers pH 3～4, suction filtration with the hydrochloric acid of 2N, the washing filter cake is to neutral, column chromatography purification gets Compound I I (182mg, 82.9%).

1HNMR(300MHz，CDCl3)δ：5.23(1H，t，H-12)，4.47～4.52(1H，t，H-3)，

2.04(3H，s，CH3CO)，1.07(3H，s)，0.95(6H，s)，0.86(3H，s)，0.84(6H，s)，0.76(3H，s)(7×CH3)。

Embodiment 2

The preparation of compound III: 100mg (0.20mmol) the Compound I I dissolving that adds methylene chloride, add the 0.09ml oxalyl chloride, room temperature reaction 24 hours, after reaction mixture removes the gas of methylene dichloride and reaction generation under reduced pressure, add methylene dichloride dissolving resistates again, add triethylamine and transfer pH 8 to 9, add serine methylester 21mg, reaction finishes, and adds 4ml water in the reaction solution, transfer pH 3 to 4 with 2N hydrochloric acid, remove methylene dichloride under reduced pressure, the residuum filtration under diminished pressure is washed to neutrality, column chromatography purification gets compound III (59mg, 51.6%).

1HNMR(300MHz，DMSO-d6)，δ：6.52(1H，t，NH)，5.40(1H，t，H-12)，4.46～4.52(1H，t，H-3)，4.06～4.14(1H，dd，NHCH2CO)，3.79～3.87(1H，dd，NHCH2CO)，3.76(3H，s，OCH3)，2.04(3H，s，CH3CO)，1.09(3H，s)，0.96，0.93，0.90，0.86，0.85，(15H，s)，0.70(3H，s)(7×CH3).

Embodiment 3

The preparation of Compound I X: compound III 47mg hydrolysis in the alkaline solution of methyl alcohol/tetrahydrofuran (THF), react completely, in mixture, add an amount of water, transfer pH 3～4 with 2N hydrochloric acid, remove methyl alcohol/tetrahydrofuran (THF) under reduced pressure, the residuum filtration under diminished pressure is washed to neutrality, get Compound I X (21mg, 44.7%).

¹HNMR(300MHz，DMSO-d ₆)，δ：7.26(1H，t，NH)，5.21(1H，t，H-12)，3.43(1H，t，H-3)，3.00(2H，d，CH ₂COOH)，1.03(3H，s)0.91，0.89，0.84(12H，s)，0.66(6H，s)(7×CH ₃)。

Claims (3)

1. amino acid as chemical modifier for ursolic acid is characterized in that structural formula is as follows:

Wherein: R ₁Be hydroxyl or ethanoyl, R ₂Be substituted amino acid or hydroxyl.

2. amino acid as chemical modifier for ursolic acid according to claim 1 is characterized in that being prepared by following steps:

(1) ursolic acid compound (I) and the acetic anhydride 3-acetoxyl group ursolic acid (II) that is;

(2) 3-acetoxyl group ursolic acid and oxalyl chloride reaction is again with the compound (III-VIII) of corresponding amino acid reaction;

(3) compound (III-VIII) gets compound (IX-XIV) through hydrolysis.

3. amino acid as chemical modifier for ursolic acid according to claim 1 is characterized in that they have anti-tumor activity, can be used for treating tumor disease.