CN106946972B - A kind of ursolic acid derivative with anti-tumor activity and preparation method thereof - Google Patents
A kind of ursolic acid derivative with anti-tumor activity and preparation method thereof Download PDFInfo
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- CN106946972B CN106946972B CN201710341785.2A CN201710341785A CN106946972B CN 106946972 B CN106946972 B CN 106946972B CN 201710341785 A CN201710341785 A CN 201710341785A CN 106946972 B CN106946972 B CN 106946972B
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- ursolic acid
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- 150000003675 ursolic acids Chemical class 0.000 title claims abstract description 20
- 230000000259 anti-tumor effect Effects 0.000 title claims abstract description 12
- 238000002360 preparation method Methods 0.000 title claims abstract description 8
- 210000004881 tumor cell Anatomy 0.000 claims abstract description 10
- 150000001875 compounds Chemical class 0.000 claims description 71
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims description 32
- 229940096998 ursolic acid Drugs 0.000 claims description 25
- PLSAJKYPRJGMHO-UHFFFAOYSA-N ursolic acid Natural products CC1CCC2(CCC3(C)C(C=CC4C5(C)CCC(O)C(C)(C)C5CCC34C)C2C1C)C(=O)O PLSAJKYPRJGMHO-UHFFFAOYSA-N 0.000 claims description 25
- WCGUUGGRBIKTOS-GPOJBZKASA-N (3beta)-3-hydroxyurs-12-en-28-oic acid Chemical compound C1C[C@H](O)C(C)(C)[C@@H]2CC[C@@]3(C)[C@]4(C)CC[C@@]5(C(O)=O)CC[C@@H](C)[C@H](C)[C@H]5C4=CC[C@@H]3[C@]21C WCGUUGGRBIKTOS-GPOJBZKASA-N 0.000 claims description 24
- 238000006243 chemical reaction Methods 0.000 claims description 24
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 23
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 22
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 19
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 15
- -1 acetoxyl group Chemical group 0.000 claims description 15
- LRHPLDYGYMQRHN-UHFFFAOYSA-N Butanol Natural products CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 12
- 239000012153 distilled water Substances 0.000 claims description 11
- FQUYSHZXSKYCSY-UHFFFAOYSA-N 1,4-diazepane Chemical class C1CNCCNC1 FQUYSHZXSKYCSY-UHFFFAOYSA-N 0.000 claims description 10
- 239000012065 filter cake Substances 0.000 claims description 10
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims description 9
- LNUFLCYMSVYYNW-ZPJMAFJPSA-N [(2r,3r,4s,5r,6r)-2-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[[(3s,5s,8r,9s,10s,13r,14s,17r)-10,13-dimethyl-17-[(2r)-6-methylheptan-2-yl]-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-3-yl]oxy]-4,5-disulfo Chemical compound O([C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1C[C@@H]2CC[C@H]3[C@@H]4CC[C@@H]([C@]4(CC[C@@H]3[C@@]2(C)CC1)C)[C@H](C)CCCC(C)C)[C@H]1O[C@H](COS(O)(=O)=O)[C@@H](OS(O)(=O)=O)[C@H](OS(O)(=O)=O)[C@H]1OS(O)(=O)=O LNUFLCYMSVYYNW-ZPJMAFJPSA-N 0.000 claims description 7
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- MUCRYNWJQNHDJH-UHFFFAOYSA-N Ursonic acid Natural products C1CC(=O)C(C)(C)C2CCC3(C)C4(C)CCC5(C(O)=O)CCC(C)C(C)C5C4=CCC3C21C MUCRYNWJQNHDJH-UHFFFAOYSA-N 0.000 claims description 5
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- WWTBZEKOSBFBEM-SPWPXUSOSA-N (2s)-2-[[2-benzyl-3-[hydroxy-[(1r)-2-phenyl-1-(phenylmethoxycarbonylamino)ethyl]phosphoryl]propanoyl]amino]-3-(1h-indol-3-yl)propanoic acid Chemical compound N([C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)O)C(=O)C(CP(O)(=O)[C@H](CC=1C=CC=CC=1)NC(=O)OCC=1C=CC=CC=1)CC1=CC=CC=C1 WWTBZEKOSBFBEM-SPWPXUSOSA-N 0.000 claims description 4
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- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 4
- AOSZTAHDEDLTLQ-AZKQZHLXSA-N (1S,2S,4R,8S,9S,11S,12R,13S,19S)-6-[(3-chlorophenyl)methyl]-12,19-difluoro-11-hydroxy-8-(2-hydroxyacetyl)-9,13-dimethyl-6-azapentacyclo[10.8.0.02,9.04,8.013,18]icosa-14,17-dien-16-one Chemical compound C([C@@H]1C[C@H]2[C@H]3[C@]([C@]4(C=CC(=O)C=C4[C@@H](F)C3)C)(F)[C@@H](O)C[C@@]2([C@@]1(C1)C(=O)CO)C)N1CC1=CC=CC(Cl)=C1 AOSZTAHDEDLTLQ-AZKQZHLXSA-N 0.000 claims description 3
- IWZSHWBGHQBIML-ZGGLMWTQSA-N (3S,8S,10R,13S,14S,17S)-17-isoquinolin-7-yl-N,N,10,13-tetramethyl-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3-amine Chemical compound CN(C)[C@H]1CC[C@]2(C)C3CC[C@@]4(C)[C@@H](CC[C@@H]4c4ccc5ccncc5c4)[C@@H]3CC=C2C1 IWZSHWBGHQBIML-ZGGLMWTQSA-N 0.000 claims description 3
- ONBQEOIKXPHGMB-VBSBHUPXSA-N 1-[2-[(2s,3r,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]oxy-4,6-dihydroxyphenyl]-3-(4-hydroxyphenyl)propan-1-one Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1OC1=CC(O)=CC(O)=C1C(=O)CCC1=CC=C(O)C=C1 ONBQEOIKXPHGMB-VBSBHUPXSA-N 0.000 claims description 3
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- SUKJFIGYRHOWBL-UHFFFAOYSA-N sodium hypochlorite Chemical compound [Na+].Cl[O-] SUKJFIGYRHOWBL-UHFFFAOYSA-N 0.000 claims description 2
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 claims 2
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- 230000006698 induction Effects 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 230000009545 invasion Effects 0.000 description 1
- 150000002611 lead compounds Chemical class 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 238000003199 nucleic acid amplification method Methods 0.000 description 1
- 150000002966 pentacyclic triterpenoids Chemical class 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Substances [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 229960002668 sodium chloride Drugs 0.000 description 1
- 235000002639 sodium chloride Nutrition 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 235000010265 sodium sulphite Nutrition 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 238000010025 steaming Methods 0.000 description 1
- 239000004575 stone Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 238000012549 training Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J63/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton has been modified by expansion of only one ring by one or two atoms
- C07J63/008—Expansion of ring D by one atom, e.g. D homo steroids
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J71/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton is condensed with a heterocyclic ring
- C07J71/0036—Nitrogen-containing hetero ring
- C07J71/0057—Nitrogen and oxygen
- C07J71/0063—Nitrogen and oxygen at position 2(3)
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a kind of ursolic acid derivatives with anti-tumor activity and its preparation method and application.The present invention has synthesized a series of ursolic acid derivatives with anti-tumor activity.In-vitro pharmacological experiments show that the ursolic acid derivative synthesized in this patent has significant antiproliferative activity to Hela and MNK45 tumour cell, and tool has been widely used in the preparation of antitumor drugs.
Description
Technical field
The present invention relates to ursolic acid derivative, the preparation method of ursolic acid derivative and its purposes in antitumor field.
Background technique
Ursolic acid (Ursolic acid, UA) also known as malol, ursolic acid belong to pentacyclic triterpenoid, chemical name 3
(β) -3-Hydroxyurs-12-en-28-oic acid, relative molecular weight 456.68, molecular formula C30H48O3, it is a kind of
The reactive compound being distributed widely in plant resources.Pharmaceutical research shows that UA has antiviral, antibacterial, antitumor, anti-bone
Matter is loose, anti-oxidant, anti-inflammatory, the treatment multiple efficacies such as diabetes and liver protection.UA poorly water-soluble lacks target specificity, limitation
Its clinical application.
The chemical structure of ursolic acid:
UA has the anticancer activity of wide spectrum, studies have shown that the mechanism that UA plays antitumor action includes: induction tumour cell
Apoptosis and differentiation inhibit invasion, amplification and angiogenesis, promote chemotherapy once quick effect, inducing cell cycle arrest and autophagy etc..
Document: (102558279 B of CN), (Meng Yanqiu etc., the synthesis of oleanolic acid derivate and the research of anti-tumor activity, pharmacy
Report 2011,46 (10): 1215-1220) and (Ming-Chuan Liu et al, Synthesis and cytotoxicity
ofnovel ursolic acid derivatives containing an acyl piperazine moiety,Eur j
Med chem, 2012, (58), 128-135) report ursolic acid or oleanolic acid and glycol dibromide or 1,3- dibromopropane
Reaction generates bromoethanol ester or propyl alcohol ester derivant, then with primary amine or swollen amine through SN2 reactions obtain a series of derivatives.1,2-
Bromofume or 1 lacks selectivity, can generate a large amount of by-products, obtained bromine when 3- dibromopropane is reacted with the 28-COOH of UA
When reacting for ethyl alcohol ester or bromo propyl alcohol ester derivant with primary amine or secondary amine, yield is lower.In the document of the reports such as Meng Yanqiu, together
Pier tartaric acid bromoethanol ester derivant and secondary amine reaction yield are below 10%.
Summary of the invention
Present invention aims at using ursolic acid as lead compound, design synthesizes a series of with more preferable antitumor work
The novel ursolic acid derivative of property.
The noval chemical compound that the present invention is obtained with ursolic acid, shown in general structure I, II:
Wherein R1、R2And R3As shown in table 1, table 2:
Chemical compounds I -1~I -22 representated by 1 general formula I of table
Compound ii -1~II -8 representated by 2 general formula II of table
Another object of the present invention is to provide the preparation methods for the ursolic acid derivative that general formula is I, II.Of the invention
Reaction process is completed through the following steps, wherein Arabic numerals 2~24 represent the compound of reaction, and such as 2 be chemical combination
Object 2 represents 3- acetoxyl group ursolic acid, and 9 represent 3- oxo ursolic acid, and 17 represent 2,3- dioxime ursolic acid, and compound 2~24 exists
Hereinafter repeat no more explanation.
(1) ursolic acid and acetic anhydride obtain 3- acetoxyl group ursolic acid (2), compound 2 respectively with ethylene chlorhydrin, 3-
The chloro- n-butyl alcohol of trimethylewne chlorohydrin 3-, 4- reacts to obtain corresponding compound 3~5；Compound 3~5 is reacted with methylsufonyl chloride respectively
Obtain corresponding sulfonate derivatives 6~8；Compound 6~8 reacts to obtain respective compound I -1~I -3 respectively with piperazine；Chemical combination
Object 6~8 reacts to obtain respective compound I -4~I -6 respectively with homopiperazine；
(2) chemical compounds I -1 reacts to obtain chemical compounds I -7 and I -8 with bromobenzyl, 4- fluorine bromobenzyl respectively；
(3) ursolic acid reacts to obtain with pyridinium chloro-chromate (PCC) 3- oxo ursolic acid (9), compound 9 respectively with 2- chlorine
The chloro- n-butyl alcohol of ethyl alcohol, trimethylene chlorohydrin, 4- reacts to obtain respective compound 10~12；Compound 10~12 respectively with methyl sulphur
Acyl chloride reaction obtains corresponding sulfonate derivatives 13~15；Compound 13~15 reacts to obtain respective compound I-respectively with piperazine
9~I -11；Compound 13~15 reacts to obtain respective compound I -12~I -14 respectively with homopiperazine；
(4) chemical compounds I -9 reacts to obtain chemical compounds I -15 and I -16 with bromobenzyl and 4- fluorine bromobenzyl respectively；
(5) chemical compounds I -3, I -4, I -5, I -6, I -7, I -8 obtain respective compound I -17, I-after alkaline condition hydrolyzes
18,Ⅰ-19,Ⅰ-20,Ⅰ-21,Ⅰ-22；
(6) crude product of chemical compounds I -9~I -14, I -17~I -20 is dissolved in dehydrated alcohol respectively, with concentrated hydrochloric acid tune
Section pH≤3 are prepared into the hydrochloride of corresponding product, filter, and filter cake is after distilled water washing filtering, then with ethyl alcohol or ethyl acetate
Ultrasonic immersing is washed 1~3 time, is filtered the hydrochloride sterling that corresponding product can be obtained, the hydrochloride of product is dispersed in anhydrous
In ethyl alcohol, alkali is added to be adjusted to pH >=7, be concentrated under reduced pressure, is extracted, dries I -9~I -14, I -17~I -20 sterling can be obtained；
(7) 3- oxo ursolic acid (9) reacts to obtain 2- oxime -3- oxo ursolic acid (16), compound with isoamyl nitrite
16 react generation 2,3- dioxime ursolic acid (17) with hydroxylamine hydrochloride, and compound 17 is anti-with sodium hydroxide and sodium hypochlorite in ethanol
It should obtain compound 18；Compound 18 reacts to obtain corresponding chemical combination to ethylene chlorhydrin, trimethylene chlorohydrin, the chloro- n-butyl alcohol of 4- respectively
Object 19~21；Compound 19~21 reacts to obtain corresponding sulfonate derivatives 22~24 respectively to methylsufonyl chloride；Compound 22
~24 react to obtain respective compound II -1~II -3 respectively with piperazine；Compound 22~24 reacts to obtain phase respectively with homopiperazine
Answer compound ii -4~II -6；Compound ii -1 reacts to obtain compound ii -7 and II -8 with bromobenzyl and 4- fluorine bromobenzyl respectively.
Wherein compound 3~15 is the intermediate product for synthesizing I list of target compound process of general formula, as follows,
Wherein, their related group R1、R2It is as shown in table 3:
The intermediate 3~15 that 3 general formula I of table represents
Wherein compound 16,17 is the intermediate product in II series compound synthesis process of general formula, and structure is as follows:
Wherein compound 18~24 is the intermediate product during II list of target compound synthesis of general formula, as follows:Their related group R3It is as shown in table 4:
The intermediate 18~24 that 4 general formula II of table represents
It is a further object of the present invention to provide the purposes for the ursolic acid derivative that general formula is I, II.General formula is I, II
Ursolic acid derivative is used to prepare the purposes of anti-tumor drug；Further preferably, the ursolic acid derivative of general formula I, II is used for
The inhibition purposes of Hela and MNK45 tumour cell.
The advantage of the invention is that general formula I, II a series of ursolic acid new derivatives, pharmacological experiment shows compared to existing
Technology, they have more significant anti-proliferative capacity to Hela cell and MNK45 cell, while having higher yield, especially
It is important that ursolic acid new derivative good water solubility of the invention, is suitable for clinical application.
Specific embodiment
Accordingly, under the premise of not departing from above-mentioned basic fundamental thought of the invention, according to the common of this field
Technological know-how and customary means, to its content can also there are many modification, replacement or the changes of form.Below by specific implementation
Example, is further described in detail implementation content of the invention, but they are not limitation of the invention.It is all to be based on the present invention
The technology that above content is realized all belongs to the scope of the present invention.
The present invention is further illustrated combined with specific embodiments below.
Embodiment 1
The synthesis of chemical compounds I -1:
UA (2.0g, 4.38mmol) is added in 50mL eggplant-shape bottle, is dissolved in 15mL pyridine, 0 DEG C~10 DEG C of temperature control, delays
It is slow that acetic anhydride (1.0mL, 10.58mmol) is added dropwise, rear room temperature is added dropwise and is stirred to react 14h, TLC (cyclohexane/acetone=3:1)
Detection display fully reacting.Reaction solution is poured into 60mL ice water, there is solid precipitation, is filtered, filter cake is molten with 100mL ethyl acetate
Solution, and washed according to this with 1mol/L hydrochloric acid, distilled water, saturated sodium-chloride water solution, anhydrous sodium sulfate is dried overnight, and is depressurized dense
Contracting, is dried in vacuo to obtain 3- acetoxyl group-UA (2) 2.02g, yield 92.5%.
Compound 2 (1.16g, 2.33mmol) is added in 50mL eggplant-shape bottle, with 15mL DMF dissolution, ethylene chlorhydrin is added
(0.58g, 7.20mmol), potassium carbonate (0.49g, 3.55mmol) are stirred to react 1h, TLC (cyclohexane/acetone in 60 DEG C of oil baths
=3:1) detection display raw material completely disappear, stop reaction.Reaction solution is poured into 50mL ice water, there are a large amount of white solids to analyse
Out, it filters, filter cake is washed (twice) with distilled water, saturated sodium-chloride water solution according to this with the dissolution of 100mL ethyl acetate, anhydrous
Sodium sulphate is dried overnight, and is concentrated under reduced pressure, is dried in vacuo to obtain 1.20g product (3), yield 94.8%.
Compound 3 (1.2g, 2.21mmol) is added in 50mL eggplant-shape bottle, with 10mL pyridinium dissolution, 0~10 DEG C of temperature control,
Methylsufonyl chloride (0.52mL, 6.72mmol) is slowly added dropwise, reaction 100min, TLC (cyclohexane/acetone=3:1) is stirred at room temperature
Detection display fully reacting.Reaction solution is poured into 50mL ice water, is filtered, filter cake is successively used with the dissolution of 80mL ethyl acetate
1mol/L hydrochloric acid, distilled water, saturated sodium-chloride water solution washing, anhydrous sodium sulfate are dried overnight, are concentrated under reduced pressure, are dried in vacuo
1.28g product (6), yield 98.3%.
Compound 6 (0.5g, 0.806mmol) is added in 50mL eggplant-shape bottle, is dissolved with 8mLDMF, Piperazine anhydrous is added
(0.6g, 6.97mmol) reacts 30min, TLC (cyclohexane/acetone in 80 DEG C of oil baths of Anhydrous potassium carbonate (0.16g, 1.16mmol)
=3:1 or methylene chloride/methanol=10:1) detection display fully reacting.Reaction solution is poured into 40mL ice water, there is white solid
It being precipitated, filters, filter cake 100mL ethyl acetate dissolves, and successively washs (twice) with distilled water, saturated sodium-chloride water solution,
Anhydrous sodium sulfate is dry, silica gel column chromatography purifying, and it is white powder, yield that chloroform elution, which obtains chemical compounds I -1 0.41g,
83.3%.mp:80.1-82.9℃.
1H NMR(400MHz,CDCl3)δ5.21(1H,s,H-12),4.52–4.44(1H,m,H-3),4.16–4.04(2H,
m,CH2), 3.10 (4H, s, H in piperazine), 2.72 (4H, s, H in piperazine), 2.63 (2H, t, J=
5.6Hz,CH2), 2.18 (1H, d, J=12.5Hz, H-18), 2.04 (3H, s, CH3),1.06(3H,s,CH3),0.93(6H,d,J
=5.8Hz, 2 × CH3), 0.85 (9H, d, J=4.9Hz, 3 × CH3),),0.72(3H,s,CH3)。
HR-MS:calcd for C38H63N2O4[M+H]+611.47823；found 611.47836.
Embodiment 2
The synthesis of chemical compounds I -4:
Referring to the synthetic method of chemical compounds I -1 in embodiment 1, but Piperazine anhydrous is substituted with homopiperazine, obtains yellowish-white toner
End, total recovery 70.2%.mp:76.5-78.0℃.
1H NMR(400MHz,CDCl3)δ5.22(1H,s,H-12),4.53–4.44(1H,m,H-3),4.16(2H,s,
CH2),3.38(4H,s,H in homopiperazine),3.20(2H,s,CH2), 2.97 (4H, d, J=24.4Hz, H in
homopiperazine),2.04(3H,s,CH3),1.06(3H,s,CH3), 0.94 (6H, d, J=3.8Hz, 2 × CH3),0.85
(9H, d, J=4.6Hz, 3 × CH3),0.72(3H,s,CH3)。
HR-MS:calcd for C39H65N2O4[M+H]+625.49388；found 625.49126.
Embodiment 3
The synthesis of chemical compounds I -8:
Chemical compounds I -1 (60mg, 0.098mmol) is added in 10mL chicken heart bottle, is dissolved with 2mLDMF, potassium carbonate is added
(17mg, 0.123mmol), 4- fluorine bromobenzyl (0.02mL, 0.161mmol) react 30min in 60 DEG C of oil baths, TLC (methylene chloride/
Methanol=20:1) detection display fully reacting.It is extracted after natural cooling with 50mL ethyl acetate, 30mL water, organic phase saturation
Sodium-chloride water solution washs twice, and anhydrous sodium sulfate is dry, prepares lamellae purifying (methylene chloride/methanol=20:1), must produce
Object 29.8mg (I -8), be yellow-white powder, yield 42.3%, mp:140.0-141.8 DEG C.
1H NMR(400MHz,CDCl3) δ 7.76-7.58 (2H, m, ArH), 7.12 (2H, t, J=8.2Hz, ArH), 5.16
(1H,s,H-12),4.51–4.43(1H,m,H-3),4.08(2H,s,CH2),2.73–3.90(10H,m,CH2and 4×CH2in
), piperazine 2.09 (1H, d, J=11.3Hz, H-18), 2.04 (3H, s, CH3), 1.04 (3H, d, J=7.4Hz, CH3),
0.92 (6H, d, J=10.4Hz, 2 × CH3),0.88–0.81(9H,m,3×CH3), 0.65 (3H, d, J=13.5Hz, CH3)。
HR-MS:calcd for C45H68FN2O4[M+H]+719.51576；found 719.51562.
Embodiment 4
The synthesis of chemical compounds I -9:
UA (10.0g, 21.9mmol) is added in 500mL eggplant-shape bottle, with the dissolution of 300mL dioxane, PCC is added
(11.8g, 54.7mmol) is stirred at room temperature, and TLC (petroleum ether: ethyl acetate=1:2V/V) shows that raw material disappears after reacting 5h, stops
Only react.The aqueous solution 35mL for containing sodium sulfite (4.2g, 33.3mmol) is added, stirring 1h reaction system becomes blackish green, will
It is poured into 500mL ice water, there is solid precipitation, is filtered, and filter cake is dissolved with ethyl acetate, and successively with distilled water, saturation chlorination
Sodium water solution washs organic phase, and organic phase is dried overnight with anhydrous sodium sulfate, filters, and is concentrated under reduced pressure, and silica gel column chromatography purifies (stone
Oily ether (60-90 DEG C): ethyl acetate=3:1), obtain white powder 3- oxo ursolic acid (compound 9) 8.06g, yield 81.0%.
It is raw material with compound 9, it is white powder that the synthetic method of reference compound I -1, which obtains chemical compounds I -9, total recovery 56.0%,
mp:144.4-146.8℃。
1H NMR(400MHz,CDCl3): δ 5.24 (1H, s, H-12), 4.18-4.04 (2H, m, CH2),3.19(4H,s,H
In piperazine), 2.81 (4H, s, H in piperazine), 2.65 (2H, t, J=5.4Hz, CH2),2.59–2.47
(1H, m, H-2), 2.37 (1H, d, J=18.9Hz, H-2), 2.23-2.14 (1H, m, H-18), 1.08 (6H, s, 2 × CH3),
1.03(6H,s,2×CH3), 0.94 (3H, d, J=5.5Hz, CH3), 0.85 (3H, d, J=6.3Hz, CH3),0.77(3H,s,
CH3)。
13C NMR(101MHz,CDCl3)δ218.04,177.42,138.33,125.48,61.20,56.39,55.33,
53.06,49.91,48.20,47.52,46.82,43.72,42.27,39.60,39.38,39.15,38.95,36.83,
36.77,34.29,32.65,30.70,28.06,26.67,24.30,23.56,21.62,21.24,19.69,17.23,
17.13,15.36。
HR-MS:calcd for C36H59N2O3[M+H]+567.45202；found 567.44977.
Embodiment 5
The synthesis of chemical compounds I -17:
In 100mL eggplant-shape bottle, -3 crude product 1.5g of chemical compounds I is added, is dissolved in 42mL methanol/water (v/v=5:1),
It is added sodium hydroxide (0.39g, 9.75mmol), 30 DEG C are stirred to react 8h, TLC (methylene chloride/methanol=10:1) detection display
Raw material completely disappears.It is concentrated under reduced pressure, the dissolution of 150ml dehydrated alcohol is added, concentrated hydrochloric acid is added dropwise and stirs to PH≤3, have a large amount of white
Color solid is precipitated, and filters, and with 200mL distilled water flushing, obtains white filter cake.Filter cake is washed with 100mL dehydrated alcohol ultrasonic immersing
(3 times) are filtered after washing, white powder (the hydrochloride sterling of chemical compounds I -17) can be obtained, place it in 250mL eggplant-shape bottle, add
Entering 150mL ethyl alcohol, ultrasonic disperse is added dropwise saturation sodium hydroxide solution, and stirs, until reaction system becomes clear by muddiness,
It is concentrated under reduced pressure, 150mL ethyl acetate is added, and successively washed with distilled water (twice), saturated sodium-chloride water solution, anhydrous slufuric acid
Sodium is dried overnight, and is concentrated under reduced pressure, is dried in vacuo to obtain white powder (I -17) 1.0g, total recovery about 56%, mp:100.0-102.5
℃。
1H NMR(400MHz,CDCl3)δ5.21(1H,s,H-12),4.06–3.91(2H,m,CH2),3.21(5H,m,H-
3and 4H in piperazine), 2.70 (4H, s, H in piperazine), 2.41 (2H, t, J=7.0Hz, CH2),
2.20 (1H, d, J=11.2Hz, H-18), 1.07 (3H, s, CH3),0.98(3H,s CH3), 0.93 (3H, d, J=5.8Hz,
CH3),0.90(3H,s,CH3), 0.84 (3H, d, J=6.4Hz, CH3),0.77(3H,s,CH3),0.73(3H,s,CH3)。
13C NMR(101MHz,CDCl3)δ177.08,137.70,125.01,78.49,63.27,56.99,54.68,
52.38,49.31,47.56,47.00,43.16,41.55,39.02,38.55,38.37,38.24,38.10,36.45,
36.26,32.55,30.15,27.65,27.47,26.70,25.81,23.72,23.04,22.79,22.66,20.69,
17.80,16.63,16.54,15.17,14.99。
HR-MS:calcd for C38H65N2O3[M+H]+597.49897；found 597.49693.
Embodiment 6
The synthesis of chemical compounds I -18:
The synthetic method of reference compound I -17 obtains yellow-white powder with I -4 substitution I -3, total recovery 58.7%, mp:
189.2-192.0℃。
1H NMR(400MHz,CDCl3)δ5.22(1H,s,H-12),4.14–4.02(2H,m,CH2),3.27–2.78(9H,
H-3and 4×CH2In homopiperazine), 2.18 (1H, d, J=12.5Hz, H-18), 1.07 (3H, s, CH3),0.98
(3H,s,CH3), 0.93 (3H, d, J=5.7Hz, CH3),0.91(3H,s,CH3), 0.84 (3H, d, J=6.4Hz, CH3),0.77
(3H,s),0.73(3H,s)。
HR-MS:calcd for C37H63N2O3[M+H]+583.48332；found 583.48116.
Embodiment 7
The synthesis of compound ii -1:
Compound 9 (1.0g, 2.2mmol) is added in 50mL eggplant-shape bottle, with the dissolution of the 20mL tert-butyl alcohol, potassium tert-butoxide is added
(1.23g, 10.98mmol), isoamyl nitrite (1.24g, 10.58mmol), is stirred at room temperature 2.5h, TLC (cyclohexane/acetone
=3:1) detection, show that raw material completely disappears.It is concentrated under reduced pressure, the dissolution of 100mL ethyl acetate, organic phase saturated sodium-chloride is added
Aqueous solution washs twice, and anhydrous sodium sulfate is dried overnight, and filters, and is concentrated under reduced pressure, and silica gel column chromatography purifies (petroleum ether (60-90
DEG C): ethyl acetate=5:1), obtain 2- oxime -3- oxo ursolic acid (16) 970mg, yield 75.0%.
Compound 16 (550mg, 1.14mmol) is added in 25mL eggplant-shape bottle, with 6mL pyridinium dissolution, hydroxylamine hydrochloride is added
(237mg, 3.4mmol), 110 DEG C of reaction 2h.Reaction solution is poured into 50mL ice water, there is light pink solid precipitation, is filtered, filter
Cake 100mL ethyl acetate dissolves, and successively washs organic phase with 1mol/L hydrochloric acid, distilled water, saturated sodium-chloride water solution, has
Machine is mutually dried overnight with anhydrous sodium sulfate, and filtering is concentrated under reduced pressure, is dried in vacuo to obtain 2,3- dioxime ursolic acid (17) 550mg, is light
Pink powder, yield 96.8%.Compound 17 (550mg, 1.14mmol) is added in 100mL eggplant-shape bottle, it is anhydrous with 40mL
Ethyl alcohol dissolution, is added sodium hydroxide (120mg, 3mmol), and liquor natrii hypochloritis 2mL is added dropwise, 2min, TLC (hexamethylene is stirred at room temperature
Alkane/acetone=2.5:1) detection display fully reacting.It is concentrated under reduced pressure, residue is dissolved with appropriate ethyl acetate, and successively with steaming
Distilled water, saturated sodium-chloride water solution washing (twice), anhydrous sodium sulfate is dried overnight, filtering, is concentrated under reduced pressure, is passed through at 45 DEG C of filtrate
It is dried in vacuo to obtain white powder 502mg (compound 18), yield 88.7% is raw material with compound 18, reference compound I -1
Synthetic method obtains II -1, and silica gel column chromatography purifies (methylene chloride/methanol=15:1) and obtains white powder, total recovery 49.2%.
mp:134.1-136.8℃。
1H NMR(400MHz,CDCl3) δ 5.29 (1H, s, H-12), 4.12 (2H, t, J=5.7Hz, CH2),3.07(4H,
D, J=23.0Hz, H in piperazine), 2.64 (4H, d, J=4.1Hz, H in piperazine), 2.62 (2H, d, J
=5.8Hz, CH2), 2.24 (1H, d, J=11.1Hz, H-18), 1.41 (3H, s, CH3),1.33(3H,s,CH3),1.09(3H,
s,CH3), 0.94 (3H, d, J=5.7Hz, CH3),0.91(3H,s,CH3), 0.86 (3H, d, J=6.3Hz, CH3),0.79(3H,
s,CH3)。
HR-MS:calcd for C36H57O4N4[M+H+]609.43743；found 609.43526.
Embodiment 8
The anti-tumor activity of the ursolic acid new derivative of synthesis
37 DEG C, 5%CO2Under the conditions of routine culture Hela and MNK45 tumour cell, with 0.25% pancreatin digestion after, prepare
At certain density single cell suspension.According to the difference of vitro growth rates, 96 orifice plates are inoculated in by 4000/hole, every hole adds
Enter 100 μ L of cell suspension.After for 24 hours, the complete training of compound and cisplatin that concentration is 10 μM and coordinative solvent control is added
Support base.Every hole adds 100 μ L (DMSO final concentration < 0.1%), and every group sets 3 parallel holes, after 37 DEG C are continued to cultivate 72h, in abandoning
Clearly.The complete medium of 100 μ L MTT containing 0.5mg/mL is added in every hole, continues to cultivate 4h, and after abandoning supernatant, 150 μ L are added in every hole
DMSO dissolves MTT first a ceremonial jade-ladle, used in libation precipitating, and after microoscillator oscillation mixes, microplate reader is in reference wavelength 450nm, Detection wavelength 570nm
Under the conditions of measure OD value (OD), using solvent control handle tumour cell as control group, calculate every kind of change with following formula
Close the inhibiting rate of different tumour cells under object effect.
The tumour cell of logarithmic growth phase is configured to certain density single cell suspension after the digestion of 0.25% pancreatin.
According to the difference of vitro growth rates, 96 orifice plates are inoculated in by 4000/hole, 100 μ L of cell suspension is added in every hole.After for 24 hours, add
Entering the complete medium of compound containing various concentration and coordinative solvent control, every hole adds 100 μ L (DMSO final concentration < 0.1%),
Every kind of test-compound sets 8 dosage groups, and every group sets 3 parallel holes, after 37 DEG C are continued to cultivate 72h, abandons supernatant.Every hole is added
100 complete mediums of the μ L containing 0.5mg/mLMTT continue to cultivate 4h, and after abandoning supernatant, every hole is added 150 μ LDMSO and dissolves MTT first
A ceremonial jade-ladle, used in libation precipitating, after microoscillator oscillation mixes, it is close that microplate reader measures light under the conditions of reference wavelength 450nm, Detection wavelength 570nm
Angle value (OD).The tumour cell handled using solvent control is control group, after calculating inhibiting rate corresponding to various concentration, utilizes
Statistical analysis software Graphpadprism6 draws inhibitory rate of cell growth curve, obtains function by curve matching and calculates inhibition
Rate corresponding compound concentration at 50% is its half-inhibitory concentration (IC to the tumour cell50).It is surveyed under the same terms
Compound is determined to the IC of different cells50Value, each cell strain are averaged in triplicate.Anti-tumor activity the results are shown in Table 5
The inhibitory activity of 5 ursolic acid of table and its structural modification object to Hela and MNK45 tumour cell
In table 5, a: the inhibiting rate that compound concentration measures when being 10 μM；B: the medium effective concentration of compound；C: chemical combination
The medium effective concentration of object is greater than 10 μM；D: cis-platinum is positive control drug.
Claims (4)
1. ursolic acid derivative with anti-tumor activity, it is characterised in that structural formula is such as shown in (I) and (II):
Wherein, R1When for acetoxyl group or carbonyl, R2Selected from group
R1When for hydroxyl, R2Selected from group
Wherein, R3Selected from group
2. the purposes of ursolic acid derivative described in claim 1, it is characterised in that the ursolic acid derivative is used for antineoplastic
The application of object preparation.
3. the purposes of ursolic acid derivative according to claim 2, it is characterised in that the ursolic acid derivative is used for Hela
With the purposes of the inhibition of MNK45 tumour cell.
4. the preparation method of ursolic acid derivative described in claim 1, Arabic numerals 2~24 represent the compound of reaction,
It is characterized in that processing step is as follows:
Ursolic acid and acetic anhydride obtain 3- acetoxyl group ursolic acid (2), compound 2 respectively with ethylene chlorhydrin, the chloro- 1- third of 3-
The chloro- n-butyl alcohol reaction of alcohol, 4-, respectively obtains respective compound 3~5；Compound 3~5 is respectively with methylsufonyl chloride in pyridine
Reaction obtains corresponding sulfonate derivatives 6~8；Compound 6~8 reacts to obtain respective compound I -1~I -3 respectively with piperazine；
Compound 6~8 reacts to obtain respective compound I -4~I -6 respectively with homopiperazine；Chemical compounds I -1 respectively with bromobenzyl and 4- fluorine bromine
Benzyl reaction, obtains chemical compounds I -7 and I -8；The structural formula of compound 2~8, I -1~I -8 is as follows:
Wherein, R1ForWhen；
2:R2=-H；
3:
4:
5:
6:
7:
8:
I -1:
I -2:
I -3:
I -4:
I -5:
I -6:
I -7:
I -8:
In addition,
Ursolic acid and pyridine chlorochromate reactant salt obtain 3- oxo ursolic acid (9), compound 9 respectively with ethylene chlorhydrin, the chloro- 1- of 3-
The chloro- n-butyl alcohol reaction of propyl alcohol, 4-, obtains respective compound 10~12；Compound 10~12 is respectively with methylsufonyl chloride in pyridine
Middle reaction obtains corresponding sulfonate derivatives 13~15；Compound 13~15 reacts to obtain respective compound I -9 respectively with piperazine
~I -11；Compound 13~15 reacts to obtain respective compound I -12~I -14 respectively with homopiperazine；Chemical compounds I -9 respectively with bromine
Benzyl, the reaction of 4- fluorine bromobenzyl, obtain chemical compounds I -15 and I -16；
The structural formula of compound 9~15, I -9~I -16 is as follows:
Wherein, R1When for=O；
9:R2=-H；
10:
11:
12:
13:
14:
15:
I -9:
I -10:
I -11:
I -12:
I -13:
I -14:
I -15:
I -16:
In addition,
Chemical compounds I -3, I -4, I -5, I -6, I -7, I -8 hydrolyze under alkaline condition, take off acetyl group and obtain chemical compounds I -17, I -
18,Ⅰ-19,Ⅰ-20,Ⅰ-21,Ⅰ-22；
The structural formula of chemical compounds I -17~I -22 is as follows:
Wherein, R1When for-OH；
I -17:
I -18:
I -19:
I -20:
I -21:
I -22:
In addition,
Compound 9 is reacted with isoamyl nitrite generates 2- oxime -3- oxo ursolic acid (16), and compound 16 is reacted with hydroxylamine hydrochloride
It generates 2,3- dioxime ursolic acid (17), compound 17 and sodium hydroxide and sodium hypochlorite reaction obtain compound 18；Compound 18
It is reacted respectively with ethylene chlorhydrin, trimethylene chlorohydrin, the chloro- n-butyl alcohol of 4-, obtains respective compound 19~21；Compound 19~21
It reacts to obtain corresponding sulfonate derivatives 22~24 to methylsufonyl chloride respectively；Compound 22~24 reacts to obtain with piperazine respectively
Respective compound II -1~II -3；Compound 22~24 reacts to obtain respective compound II -4~II -6 respectively with homopiperazine；Change
It closes object II -1 to react with bromobenzyl, 4- fluorine bromobenzyl respectively, obtains compound ii -7 and II -8；
The structural formula of compound 16~24, II -1~II -8 is as follows:
19:
20:
21:
22:
23:
24:
II -1:
II -2:
II -3:
II -4:
II -5:
II -6:
II -7:
II -8:
In addition,
Chemical compounds I -9~I -14, I -17~I -20 crude product are dissolved in dehydrated alcohol respectively, concentrated hydrochloric acid is added dropwise to pH≤3, system
The standby hydrochloride at respective compound, filters, and filter cake is washed with distilled water 1~3 time, then washs 1~3 with EtOH Sonicate dipping
Time, the hydrochloride sterling that corresponding product can be obtained is filtered, then be respectively adjusted to the hydrochloride of compound in dehydrated alcohol
PH >=7, evaporating solvent under reduced pressure are extracted, dry I -9~I -14, I -17~I -20 sterling can be obtained.
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