CN114409721A - Pentacyclic triterpene derivatives containing electrophilic warheads, and preparation method and application thereof - Google Patents
Pentacyclic triterpene derivatives containing electrophilic warheads, and preparation method and application thereof Download PDFInfo
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Abstract
The invention relates to the field of medicines, in particular to a series of novel pentacyclic triterpene derivatives containing electrophilic warheads, and also discloses a preparation method, structural characteristics and medical application of the compounds, especially application in preventing and/or treating tumor diseases.
Description
Technical Field
The invention relates to the field of medicines, in particular to a series of novel pentacyclic triterpene derivatives containing electrophilic warheads, and also discloses a preparation method, structural characteristics and medical application of the compounds, especially application in preventing and/or treating tumor diseases.
Background
Chemical antitumor drugs have entered the molecular targeted drug age through the development of more than half a century. With the wide application of small-molecule kinase inhibitors in recent years, the inhibitors face the problem of drug resistance caused by residue mutation of binding sites, so that the development of novel kinase inhibitors capable of overcoming tumor resistance is a problem to be solved in the research of the current antitumor drugs. In recent decades, covalent kinase inhibitors containing electrophilic active groups have become a hotspot in the field of research of antitumor drugs due to better resistance to drugs.
In recent years, natural products have been receiving much attention as effective drugs for treating various diseases. The pentacyclic triterpenoid is one of natural products, is widely distributed, and has various unique biological activities. Therefore, researchers have generated a great deal of interest in pentacyclic triterpenoid compounds and derivatives thereof, and synthesized thousands of pentacyclic triterpenoid derivatives with different backbone modifications.
Oleanolic acid is the most widely studied pentacyclic triterpenoid, mainly found in many edible and medicinal plants. CDDO-Me (2-cyano-3, 12-dioxy oleanane-1, 9(11) -diene-28-carboxylic acid methyl ester) is an oleanolic acid derivative with potential anti-tumor activity, and the deep research finds that the derivative has good biological activity and enters the clinical research stage of a plurality of diseases such as leukemia, chronic nephropathy, solid tumors and the like.
Based on the above, if the covalent inhibitor design strategy is applied to the structural modification of natural products, the high activity of the covalent reaction group and the biocompatibility of the skeleton of the natural products are utilized, so that the method has important significance for finding the efficient and safe targeted covalent kinase inhibitor.
Disclosure of Invention
The invention aims to provide a series of novel synthesis of pentacyclic triterpene derivatives containing electrophilic warheads.
The invention also aims to provide a preparation method of the derivative of the pentacyclic triterpenoid natural product.
The invention also aims to provide the application of the derivative of the pentacyclic triterpenoid natural product in preparing an anti-tumor medicament.
The technical scheme of the invention is as follows:
a kind of pentacyclic triterpene natural product derivatives have structures shown in general formulas I-III:
wherein: r1Represents independently hydrogen, NHR8、OR8，R2Represents independently hydrogen, NHR8、OR8Or R is1And R2Together represent oxygen; wherein R is3Represents independently hydrogen, NHR8、OR8；R4Represents independently hydrogen, NHR8、OR8(ii) a And R is1、R2、R3And R4At least one of them is NHR8OR OR8(ii) a And R is1And R2Not simultaneously NHR8、OR8And R is1If it is NHR8、OR8Then R is2Is hydrogen, R2If it is NHR8、OR8Then R is1Is hydrogen; and R is3And R4Not simultaneously NHR8、OR8And R is3If it is NHR8、OR8Then R is4Is hydrogen, R4If it is NHR8、OR8Then R is3Is hydrogen;
R5represents hydrogen or methyl, R6Represents hydrogen or methyl, and R5When represents hydrogen, R6Represents only methyl, and R6When represents hydrogen, R5Represents only methyl;
R7represents CH2OR9、COOR9、CONHR9、COR10；
R8Represents COCH2X、COCHX2、COCX3、SO2CH2X、COCR11＝CH2、COCH＝CHR11；
X represents F, Cl, Br and I, and when the X is substituted by polyatomic atoms, the X is the same element or different elements;
R9represents an unsubstituted straight or branched chain alkane, alkene, alkyne, phenyl, benzyl, naphthyl of 1 to 10 carbon atoms;
or R9Represents a linear or branched alkane, alkene, alkyne, phenyl, benzyl, naphthyl substituted by Y with 1 to 10 carbon atoms; y represents H, X, CF3、SH、OH、CN、NO2、NH2、、COOH、OCH3、OC2H5COOCH3、COOC2H5Straight or branched alkanes of 1 to 10 carbon atoms, alkenes, alkynes, phenyl, benzyl, naphthyl;
R10represents piperazine, piperidine, pyrrole, methylpiperazine, morpholine, tert-butyloxycarbonyl piperazine;
R11represents H, X, CN, CF3Methyl, ethyl, phenyl, benzyl, CH2OH、CH2OMe、CH2NMe2、CH2NEt2、CH2R10。
The derivatives of the pentacyclic triterpenoid natural products are applied to form pharmaceutically acceptable salts, including sodium salts, potassium salts, ammonium salts, organic amine salts or basic amino acids of the compounds shown in the general formulas I-III; also included are acid addition salts of compounds of formulae I-III with the following acids: hydrochloric acid, hydrobromic acid, sulfuric acid, carbonic acid, citric acid, tartaric acid, phosphoric acid, lactic acid, pyruvic acid, acetic acid, maleic acid, methanesulfonic acid, benzenesulfonic acid, or p-toluenesulfonic acid.
The preparation method of the derivatives of pentacyclic triterpenoid natural products comprises the following steps:
(1)
(a) under the temperature condition of 0-70 ℃, the volume ratio of 1:1, using dichloromethane and acetone as solvents, and reacting oleanolic acid with the Jones reagent for 1-6 h to obtain a compound A1, wherein the molar ratio of the oleanolic acid to the Jones reagent is 1: 1.3-1: 5;
(b) under the condition of 0-90 ℃, tert-butyl alcohol is used as a solvent, and the compound A1 and isoamylnitrite react for 8-24 hours under the alkaline condition to obtain a compound A2; wherein the molar ratio of the compound A1 to isoamyl nitrite is 1: 1.1-1: 15; the base used was potassium tert-butoxide and the molar ratio of compound a1 to potassium tert-butoxide was 1: 3-1: 15;
(c) under the condition of the temperature of 0-90 ℃, methanol and concentrated hydrochloric acid in the volume ratio of 20:1-5:1 are used as solvents, and the compound A2 is subjected to catalytic hydrogenation reduction reaction for 8-24 hours through palladium carbon to obtain a compound A3; wherein the mass ratio of the palladium carbon to the compound A2 is 1: 10-1: 5;
(d) the method comprises the following steps: reacting the compound A3 with acyl chloride or acid anhydride for 4-12 h at the temperature of 0-90 ℃ under the alkaline condition to obtain a compound A4; wherein the solvent comprises one or more of dichloromethane, tetrahydrofuran and acetonitrile, the base comprises potassium carbonate, sodium bicarbonate, triethylamine and N, N-diisopropylethylamine, and the molar ratio of the compound A3 to the base is 1: 1-1: 5; the molar ratio of compound a3 to acid chloride or anhydride is 1: 1-1: 10;
the second method comprises the following steps: reacting the compound A3 with carboxylic acid or carboxylate for 6-24h through condensation reaction at the temperature of 0-90 ℃ to obtain a compound A4; wherein, the solvent used in the reaction system is one or the combination of more than two of dichloromethane, tetrahydrofuran, acetonitrile and N, N-dimethylformamide; the alkali comprises potassium carbonate, sodium bicarbonate, triethylamine and N, N-diisopropylethylamine, and the molar ratio of the compound A3 to the alkali is 1: 1-1: 5; the condensing agent used in the reaction system comprises one or the combination of more than two of EDCI, DCC, HoBt, HBTU and organophosphorus; the molar ratio of compound a3 to condensing agent was 1: 1-1: 5; the molar ratio of compound a3 to carboxylic acid or carboxylate is 1: 1.1-1: 4;
(2)
(a) under the temperature condition of 0-70 ℃, the volume ratio of 1:1, using dichloromethane and acetone as solvents, and reacting oleanolic acid with the Jones reagent for 1-6 h to obtain a compound B1, wherein the molar ratio of the oleanolic acid to the Jones reagent is 1: 1.3-1: 5;
(b) under the temperature condition of 0-90 ℃, the volume ratio of the components is 40: 1-15: 1, ethanol and water are used as solvents, and the compound B1 reacts with hydroxylamine hydrochloride and anhydrous sodium acetate for 6-24 hours to obtain a compound B2; wherein the molar ratio of the compound B2 to the hydroxylamine hydrochloride is 1: 1.1-1: 15; the molar ratio of compound B2 to anhydrous sodium acetate was 1: 4-1: 20;
(c) under the condition of the temperature of 0-90 ℃, taking methanol and dichloromethane in a volume ratio of 1:1 as solvents, and reacting the compound B2 with a sodium cyanoborohydride reducing agent for 8-24 h to obtain a compound B3; the molar ratio of compound B2 to sodium cyanoborohydride is 1: 1.1-1: 30, of a nitrogen-containing gas;
(d) the method comprises the following steps: reacting the compound B3 with acyl chloride or acid anhydride for 4-12 h at the temperature of 0-90 ℃ under the alkaline condition to obtain a compound B4; wherein, the solvent comprises one or the combination of more than two of dichloromethane, tetrahydrofuran and acetonitrile; the alkali comprises potassium carbonate, sodium hydroxide, triethylamine and N, N-diisopropylethylamine, and the molar ratio of the compound B3 to the alkali is 1: 1-1: 5; the molar ratio of the compound B3 to the acid chloride or acid anhydride is 1: 1-1: 10;
the second method comprises the following steps: reacting the compound B3 with carboxylic acid or carboxylate for 6-24h through condensation reaction at the temperature of 0-90 ℃ to obtain a compound B4; the solvent used in the reaction system comprises one or the combination of more than two of dichloromethane, tetrahydrofuran, acetonitrile and N, N-dimethylformamide; the alkali comprises potassium carbonate, sodium hydroxide, triethylamine and N, N-diisopropylethylamine, and the molar ratio of the compound B3 to the alkali is 1: 1-1: 5; the condensing agent used in the reaction system comprises one or a combination of more than two of EDCI, DCC, HoBt, HBTU and organophosphorus, and the molar ratio of the compound B3 to the condensing agent is 1: 1-1: 5; the molar ratio of compound B3 to carboxylic acid or carboxylate is 1: 1.1-1: 4.
use of a derivative of a pentacyclic triterpenoid natural product in preparation of a medicament for preventing and/or treating tumor diseases. The derivative of the pentacyclic triterpenoid natural product is prepared by the preparation method.
A pharmaceutical composition comprises a compound of formulae I-III and a pharmaceutically acceptable carrier.
The invention has the beneficial effects that: the invention provides a series of novel pentacyclic triterpene derivatives containing electrophilic warheads and application thereof. The analogues of a series of pentacyclic triterpenoid natural products provided by the invention have obvious antiproliferative activity on tumor cells and have potential for further research.
Detailed Description
The invention is further illustrated by the following experimental examples, without restricting the invention thereto. The structure of the compound prepared by the invention is verified by analysis means such as nuclear magnetism, mass spectrum and the like.
Example 1
Preparation of compound 3-hydroxy-oleanane-12-alkene-28-benzyl carboxylate
Oleanolic acid (4.567g, 10mmoL, 1.0eq.) was dissolved in 30mL of anhydrous DMF, and anhydrous K was added2CO3(2.764g, 20mmol, 2.0 eq.). Under the protection of nitrogen, slowly dropwise adding benzyl bromide (1.46mL, 12mmol, 1.2eq.) to react at room temperature, monitoring the reaction by TLC, and reacting completely for 6 h. Pouring the reaction liquid into ice water to separate out a large amount of white solid, fully precipitating the solid, filtering, washing the filter cake with a large amount of water, and drying in vacuum at 40 ℃. 5.198g of a white solid was obtained with a yield of 95%.
Example 2
Preparation of compound 3-oxo-oleanane-12-ene-28-carboxylic acid benzyl ester
Compound 01(1.15g, 2.1mmoL, 1.0eq.) was weighed into a 100mL reaction flask, and dissolved by adding 40mL of a mixed solvent of acetone and dichloromethane (Ace: DCM ═ 1: 1). Under the protection of nitrogen, ice-water bath, dropwise adding a freshly prepared Jones reagent (chromium trioxide 490mg, 4.9mmol, 2.3eq.), and raising the reaction temperature to room temperature for reactionThe reaction was monitored by TLC to completion. The solvent was removed by rotary evaporation, the solid was dissolved by adding dichloromethane and transferred to a separatory funnel. Extraction with dichloromethane, saturated NaHCO3Aqueous solution washing, saturated aqueous NaCl solution washing, NaSO4Drying, rotary steaming and concentrating. Column chromatography with PE/EA ═ 10:1 isolated 1.02g of white solid in 89% yield.
1H NMR(400MHz,CDCl3)δ7.38-7.28(m,5H),5.31(t,J＝3.6Hz,1H),5.10(d,J＝12.5Hz,1H),5.05(d,J＝12.5Hz,1H),2.91(dd,J＝13.8,4.1Hz,1H),2.62–2.46(m,1H),2.40–2.29(m,1H),1.13(s,3H),1.08(s,3H),1.03(s,3H),1.01(s,3H),0.92(s,3H),0.90(s,3H),0.65(s,3H).
Example 3
Preparation of compound 3-hydroxyimino-oleanane-12-ene-28-benzyl carboxylate
Compound 02(500mg, 0.91mmoL,1.0eq.), hydroxylamine hydrochloride (254mg, 3.68mmoL,4.0eq.), and anhydrous sodium acetate (302mg, 3.68mmoL,4.0eq.) were weighed into a 100mL reaction flask, and 20mL of ethanol and 1mL of water were added to dissolve most of the starting material. After 12 hours at room temperature, a large amount of white solid precipitated and the reaction was monitored by TLC for completion. The solvent was removed by rotary evaporation, the solid was dissolved with ethyl acetate and water, extracted with ethyl acetate, washed with saturated sodium chloride solution, dried and concentrated to give 473mg of white powder in 92% yield.
Example 4
Preparation of compound 3-amino-oleanane-12-alkene-28-benzyl carboxylate
Compound 03(200mg, 0.136mmoL, 1.0eq.) was weighed out and dissolved in a mixture of dichloromethane and methanol (1 mL: 1mL), and ammonium acetate (157mg, 2.72mmoL, 15.0eq.) was added under nitrogen protection in an ice-water bath. Sodium cyanoborohydride (171mg, 2.72mmoL, 20.0eq.) was weighed out quickly and dissolved thoroughlyIn methanol solution, then slowly added dropwise to the reaction flask. While maintaining the reaction temperature, a titanium trichloride solution (352. mu.L, 3.0eq.) was added dropwise to turn the reaction solution purple and then gray. After the completion of the dropwise addition, the reaction mixture was allowed to react at room temperature for 12 hours, whereby the reaction mixture became colorless and a large amount of white solid was precipitated, and the reaction was monitored by TLC to be completed. Adjusting pH to 10 with 2N sodium hydroxide solution, extracting with dichloromethane, and extracting with saturated NaHCO3Washing with water solution, washing with saturated NaCl water solution, drying, and concentrating. D/M is 10:1 isolated as a white solid 169.6mg, 87% yield.
MS m/z:546.52[M+H]+
Example 5
Preparation of compound 3-acrylamido-oleanane-12-ene-28-benzyl carboxylate
Compound 04(45mg, 0.083mmoL, 1.0eq.) was weighed out and dissolved in 2mL tetrahydrofuran solution under nitrogen protection, followed by dropwise addition of 1.27N aqueous sodium hydroxide (65 μ L, 0.083mmoL, 1.0eq.) and acryloyl chloride (7.5 μ L, 0.091mmoL, 1.1eq.) in an ice-water bath. The reaction was carried out for 5h and TLC monitored for completion. The solvent was removed by rotary evaporation, the solid was dissolved by adding dichloromethane and transferred to a separatory funnel. Extraction with dichloromethane, saturated NaHCO3Washing with water solution, washing with saturated NaCl water solution, drying, and concentrating. Column chromatography with PE/EA ═ 3:1 afforded 38.6mg of a white solid, 78% yield.
1H NMR(600MHz,CDCl3)δ7.36–7.26(m,5H),6.27(dd,J＝16.9,0.9Hz,1H),6.08(dd,J＝16.9,10.3Hz,1H),5.63(dd,J＝10.3,0.9Hz,1H),5.37(d,J＝9.8Hz,1H),5.29(t,1H),5.09(d,J＝12.6Hz,1H),5.05(d,J＝12.5Hz,1H),3.83–3.71(m,1H),2.90(d,J＝10.8Hz,1H),1.13(s,3H),0.92(s,3H),0.90(s,6H),0.88(s,3H),0.79(s,3H),0.61(s,3H).
Example 6
Preparation of compound 3-chloroacetamide-oleanane-12-ene-28-benzyl carboxylate
Compound 04(50mg, 0.092mmoL, 1.0eq.) was weighed out and dissolved in 1mL of tetrahydrofuran solution. Under nitrogen protection, ice-water bath, 1.27N aqueous sodium hydroxide solution (108. mu.L, 0.138mmoL, 1.5eq.) and chloroacetyl chloride (15. mu.L, 0.183mmoL, 2.0eq.) were added dropwise, the reaction was carried out at room temperature for 12 hours, and the reaction was monitored by TLC to be completed. The solvent was removed by rotary evaporation, the solid was dissolved by adding dichloromethane and transferred to a separatory funnel. Extraction with dichloromethane, saturated NaHCO3Washing with water solution, washing with saturated NaCl water solution, drying, and concentrating. Column chromatography with PE/EA ═ 5:1 afforded 52.4mg of white solid isolated in 92% yield.
MS m/z:622.42[M+H]+
1H NMR(600MHz,CDCl3)δ7.28–7.22(m,5H),6.40(d,J＝9.9Hz,1H),5.21(t,1H),5.01(d,J＝12.5Hz,1H),4.97(d,J＝12.6Hz,1H),3.99(s,2H),3.73(dd,J＝9.6,3.0Hz,1H),3.66–3.47(m,1H),2.83(dd,J＝13.7,4.4Hz,1H),1.05(s,3H),0.84(s,3H),0.82(s,3H),0.81(s,6H),0.74(s,3H),0.53(s,3H).
Example 7
Preparation of compound 3-bromoacetamido-oleanane-12-alkene-28-benzyl carboxylate
Compound 04(50mg, 0.092mmoL, 1.0eq.) was weighed out and dissolved in 1mL of tetrahydrofuran solution. Under nitrogen protection, ice-water bath, 1.27N aqueous sodium hydroxide solution (108. mu.L, 0.138mmoL, 1.5eq.) and bromoacetyl bromide (16. mu.L, 0.183mmoL, 2.0eq.) were added dropwise, the reaction was carried out at room temperature for 12 hours, and the reaction was monitored by TLC to be completed. The solvent was removed by rotary evaporation, the solid was dissolved by adding dichloromethane and transferred to a separatory funnel. Extraction with dichloromethane, saturated NaHCO3Washing with water solution, washing with saturated NaCl water solution, drying, and concentrating. Column chromatography with PE/EA ═ 10:1 afforded 43.4mg of white solid isolated in 71% yield.
MS m/z:666.42[M+H]+
1H NMR(400MHz,CDCl3)δ7.36–7.28(m,5H),6.38(d,J＝9.8Hz,1H),5.29(t,J＝3.6Hz,1H),5.09(d,J＝12.5Hz,1H),5.04(d,J＝12.6Hz,1H),3.91(s,2H),3.68–3.57(m,1H),2.90(dd,J＝13.7,3.9Hz,1H),1.12(s,3H),0.92(s,3H),0.90(s,3H),0.89(s,6H),0.82(s,3H),0.61(s,3H).
Example 8
Preparation of compound 3- (dichloroacetamido) -oleanane-12-alkene-28-benzyl carboxylate
Compound 04(50mg, 0.092mmoL, 1.0eq.) was weighed out and dissolved in 1mL of tetrahydrofuran solution. Under nitrogen protection, ice-water bath, 1.27N aqueous sodium hydroxide solution (108. mu.L, 0.138mmoL, 1.5eq.) and dichloroacetyl chloride (17. mu.L, 0.183mmoL, 2.0eq.) were added dropwise, the reaction was carried out at room temperature for 12 hours, and the reaction was monitored by TLC to be completed. The solvent was removed by rotary evaporation, the solid was dissolved by adding dichloromethane and transferred to a separatory funnel. Extraction with dichloromethane, saturated NaHCO3Washing with water solution, washing with saturated NaCl water solution, drying, and concentrating. Column chromatography with PE/EA ═ 10:1 afforded 51.8mg of a white solid, isolated in 86% yield.
MS m/z:656.37[M+H]+
1H NMR(600MHz,CDCl3)δ7.39–7.26(m,5H),6.32(d,J＝9.9Hz,1H),5.92(s,1H),5.29(t,J＝3.5Hz,1H),5.09(d,J＝12.5Hz,1H),5.05(d,J＝12.5Hz,1H),3.68–3.55(m,1H),2.91(dd,J＝13.6,4.5Hz,1H),1.13(s,3H),0.92(s,3H),0.91(s,3H),0.90(s,3H),0.89(s,3H),0.84(s,3H),0.61(s,3H).
Example 9
Preparation of compound 3- (difluorochloroacetamido) -oleanane-12-alkene-28-benzyl carboxylate
Compound 04(50mg, 0.09mmoL, 1.0eq.) was weighed out and dissolved in 2mL of dichloromethane. Under the protection of nitrogen, the nitrogen is used for protecting,EDCI (21mg, 0.25mmoL, 1.2eq.) and HOBt (15mg, 0.11mmoL, 1.2eq.) were added under an ice-water bath. After 1 hour of reaction, sodium difluorochloroacetate (17mg, 0.11mmoL, 1.2eq.) was added and the reaction was continued for 8 hours, followed by TLC monitoring. The solvent was removed by rotary evaporation, the solid was dissolved by adding dichloromethane and transferred to a separatory funnel. Extraction with dichloromethane, saturated NaHCO3Washing with water solution, washing with saturated NaCl water solution, drying, and concentrating. Column chromatography with PE/EA ═ 5:1 afforded 60.3mg of white solid isolated in 93% yield.
MS m/z:658.24[M+H]+
1H NMR(400MHz,CDCl3)δ7.41–7.29(m,5H),6.03(d,J＝9.8Hz,1H),5.29(t,1H),5.10(d,J＝12.6Hz,1H),5.04(d,J＝12.5Hz,1H),3.76–3.60(m,1H),2.91(dd,J＝13.7,3.7Hz,1H),1.13(s,3H),0.92(s,3H),0.91(s,3H),0.90(s,3H),0.89(s,3H),0.82(s,3H),0.61(s,3H).
Example 10
Preparation of compound 3- (trans-4-dimethylamino-but-2-ene-amide) -oleanane-12-ene-28-benzyl carboxylate
Compound 04(100mg, 0.183mmoL, 1.0eq.) was weighed out and dissolved in 2mL of DMF solution. Under nitrogen protection, EDCI (38mg, 0.2mmoL, 1.1eq.) and HOBt (27mg, 0.2mmoL, 1.1eq.) and trans-4-dimethylaminocrotonate (30mg, 0.183mmoL, 1.0eq.) were added in an ice-water bath, and the reaction was continued for 8 hours and monitored by TLC for completion of the reaction. The solvent was removed by rotary evaporation, the solid was dissolved by adding dichloromethane and transferred to a separatory funnel. Extraction with dichloromethane, saturated NaHCO3Washing with water solution, washing with saturated NaCl water solution, drying, and concentrating. PE/EA-5: 1 column chromatography was performed to give a white solid 99mg, 82% yield
MS m/z:657.63[M+H]+
1H NMR(400MHz,CDCl3)δ7.35–7.28(m,5H),6.87–6.69(m,J＝14.8,6.0Hz,1H),6.18(d,J＝15.3Hz,1H),5.97(d,J＝9.4Hz,1H),5.29(t,J＝2.5Hz,1H),5.09(d,J＝12.6Hz,1H),5.04(d,J＝12.6Hz,1H),3.99–3.85(m,J＝9.4Hz,1H),3.28(d,J＝5.6Hz,2H),2.91(d,J＝13.4Hz,1H),2.43(s,6H),1.18(s,3H),0.96(s,3H),0.92(s,6H),0.90(s,3H),0.85(s,3H),0.61(s,3H).
1H NMR(400MHz,CDCl3)δ7.35–7.28(m,5H),6.87–6.69(m,J＝14.8,6.0Hz,1H),6.18(d,J＝15.3Hz,1H),5.97(d,J＝9.4Hz,1H),5.29(t,J＝2.5Hz,1H),5.09(d,J＝12.6Hz,1H),5.04(d,J＝12.6Hz,1H),3.99–3.85(m,J＝9.4Hz,1H),3.28(d,J＝5.6Hz,2H),2.91(d,J＝13.4Hz,1H),2.43(s,6H),1.18(s,3H),0.96(s,3H),0.92(s,6H),0.90(s,3H),0.85(s,3H),0.61(s,3H).
Example 11
Preparation of compound benzyl 3- (E-4- (piperidin-1-yl) but-2-ene-amide) -oleanane-12-ene-28-carboxylate
Compound 04(100mg, 0.18mmoL, 1.0eq.) was weighed out and dissolved in 2mL of DMF solution. Under nitrogen protection, EDCI (38mg, 0.2mmoL, 1.1eq.) and HOBt (27mg, 0.2mmoL, 1.1eq.) and E-4- (piperidin-1-yl) but-2-enoic acid hydrochloride (32mg, 0.18mmoL, 1.0eq.) were added in an ice-water bath to continue the reaction for 8 hours, and the reaction was monitored by TLC to be completed. The solvent was removed by rotary evaporation, the solid was dissolved by adding dichloromethane and transferred to a separatory funnel. Extraction with dichloromethane, saturated NaHCO3Washing with water solution, washing with saturated NaCl water solution, drying, and concentrating. Column chromatography with PE/EA ═ 5:1 gave 91mg of white solid isolated in 72% yield.
MS m/z:697.25[M+H]+
1H NMR(400MHz,CDCl3) δ 7.37-7.28 (m,5H), 6.92-6.67 (m,1H),6.08(d, J ═ 15.4Hz,1H),5.50(d, J ═ 10.0Hz,1H),5.29(s,1H),5.09(d, J ═ 12.6Hz,1H),5.04(d, J ═ 12.6Hz,1H), 3.84-3.70 (m,1H),3.29(s,2H),2.90(dd, J ═ 13.7,3.6Hz,1H),2.63(s,4H),1.13(s,3H),0.92(s,3H),0.90(s,3H),0.89(s,3H),0.87(s,3H),0.78(s,3H), example 12 (s, 12H), example 1H), and (dd, J ═ 13, 3H)
Preparation of compound benzyl 3- (4-dimethylamino-butyramide) -oleanane-12-ene-28-carboxylate
Compound 04(100mg, 0.183mmoL, 1.0eq.) was weighed out and dissolved in 2mL of DMF solution. EDCI (38mg, 0.2mmoL, 1.1eq.) under nitrogen protection, HOBt (27mg, 0.2mmoL, 1.1eq.), 4- (dimethylamino) butyric acid hydrochloride (36mg, 0.183mmoL, 1.2eq.), DIPEA (64. mu.L, 0.37mmoL, 2.0eq.) were added under ice-water bath to continue the reaction for 8h, and TLC monitored for the end of the reaction. Extraction with dichloromethane, saturated NaHCO3Washing with water solution, washing with saturated NaCl water solution, drying, and concentrating.
DCM/MeOH 10:1 column chromatography afforded 87.1mg of white solid, 73% yield.
MS m/z:659.23[M+H]+
1H NMR(600MHz,CDCl3)δ7.36–7.27(m,5H),7.18(d,J＝8.2Hz,1H),5.26(t,1H),5.08(d,J＝12.6Hz,1H),5.03(d,J＝12.6Hz,1H),3.88–3.77(m,J＝8.5Hz,1H),3.00(d,J＝6.8Hz,2H),2.88(d,J＝10.9Hz,1H),2.75(s,6H),2.67–2.54(m,2H),1.23(s,3H),0.93(s,3H),0.90(s,6H),0.87(s,6H),0.60(s,3H).
1H NMR(600MHz,CDCl3)δ7.42–7.27(m,5H),6.43(d,J＝7.7Hz,1H),5.28(t,1H),5.08(d,J＝12.7Hz,1H),5.04(d,J＝12.7Hz,1H),3.65(s,1H),2.89(d,J＝12.0Hz,1H),2.81(s,2H),2.60(s,6H),2.45(s,2H),1.12(s,3H),0.91(s,3H),0.89(s,3H),0.86(s,6H),0.80(s,3H),0.60(s,3H).
Example 13
Preparation of 2-hydroxyimino-3-oxo-oleanane-12-ene-28-carboxylic acid methyl ester
Compound 13(50mg, 0.11mmoL, 1.0eq.) was dissolved in a 25mL reaction flask by the addition of 2mL of tert-butanol followed by the addition of potassium tert-butoxide (56mg, 0.5mmoL, 4.5 eq.). Reacting for half an hour under the protection of nitrogen, dropwise adding isoamyl nitrite (78 mu L, 4.5eq.) and continuing to reactThe reaction was monitored by TLC for 12 hours to completion. Removing reaction liquid by rotary evaporation, adding ethyl acetate and 1% potassium hydroxide solution for dissolving and transferring, extracting with ethyl acetate, washing with 1% potassium hydroxide solution, and saturating with NH4Washing with Cl solution, washing with saturated NaCl solution, drying and concentrating. D/M ═ 20:1 isolation gave 44.8mg of a yellowish solid in 87% yield.
MS m/z:484.30[M+H]+
Example 14
Preparation of 2-amino-3-oxo-oleanane-12-ene-28-carboxylic acid methyl ester
Compound 14(50mg, 0.1mmoL, 1.0eq.) was placed in a 25mL reaction flask, and 2.5mL of concentrated hydrochloric acid in methanol (conc. hcl: MeOH ═ 1:9) was added, and the nitrogen gas was replaced three times. Under the protection of nitrogen, 5mg of 10% Pd/C was added, and nitrogen and hydrogen were exchanged for three times. The reaction was carried out for 10 hours under a hydrogen atmosphere, and the completion of the reaction was monitored by TLC. Palladium on carbon was removed by filtration through Celite, and 42.7mg of a yellowish solid was concentrated in 89% yield.
MS m/z:470.47[M+H]+
Example 15
Preparation of 2-acrylamide-3-oxo-oleanane-12-ene-28-carboxylic acid methyl ester
Compound 15(120mg, 0.248mmoL, 1.0eq.) was weighed, dissolved in 2mL tetrahydrofuran solution under nitrogen protection, and 1.27N aqueous sodium hydroxide (167 μ L, 0.213mmoL, 1.0eq.) and acryloyl chloride (21 μ L, 0.26mmoL, 1.1eq.) were added dropwise in an ice water bath. The reaction was carried out for 5h and TLC monitored for completion. The solvent was removed by rotary evaporation, the solid was dissolved by adding dichloromethane and transferred to a separatory funnel. Extraction with dichloromethane, saturated NaHCO3Washing with water solution, washing with saturated NaCl water solution, drying, and concentrating. Performing PE/EA-3: 1 column chromatography, and separating to obtain white extract98.7mg of a colored solid, 74% yield.
MS m/z:538.43[M+H]+
1H NMR(600MHz,CDCl3)δ6.66(d,J＝5.8Hz,1H),6.28(d,J＝17.0Hz,1H),6.15(dd,J＝17.0,10.3Hz,1H),5.66(d,J＝10.3Hz,1H),5.27(s,1H),4.98–4.84(m,1H),3.61(s,3H),2.85(dd,J＝13.6,3.4Hz,1H),2.67(t,J＝12.4Hz,1H),1.17(s,3H),1.14(s,3H),1.11(s,3H),0.92(s,3H),0.91(s,3H),0.80(s,3H),0.72(s,3H).
Example 16
Preparation of 2- (trans-4-dimethylamino-but-2-ene-amide) -3-oxo-oleanane-12-ene-28-carboxylic acid methyl ester
Compound 15(100mg, 0.21mmoL, 1.0eq.) was weighed out and dissolved in 2mL of dichloromethane solution, and 2 drops of DMF were added dropwise. EDCI (48mg, 0.25mmoL, 1.2eq.) and HOBt (34mg, 0.25mmoL, 1.2eq.) were added under nitrogen protection in an ice-water bath. After 1h reaction, trans-4-dimethylaminocrotonate, DIPEA (80. mu.L, 0.46mmoL, 2.2eq.) was added and the reaction was continued for 8h, and the reaction was monitored by TLC to be complete. The solvent was removed by rotary evaporation, the solid was dissolved by adding dichloromethane and transferred to a separatory funnel. Extraction with dichloromethane, saturated NaHCO3Washing with water solution, washing with saturated NaCl water solution, drying, and concentrating. Column chromatography with DCM/eOH ═ 10:1 gave 100.8mg white solid isolated in 82% yield.
MS m/z:595.53[M+H]+
1H NMR(400MHz,CDCl3)δ6.95–6.76(m,1H),6.64(d,J＝5.3Hz,1H),6.06(d,J＝15.0Hz,1H),5.27(t,1H),5.03–4.82(m,1H),3.61(s,3H),3.17(d,J＝5.1Hz,2H),2.85(d,J＝12.3Hz,1H),2.34(s,6H),1.16(s,4H),1.13(s,3H),1.11(s,3H),0.92(s,7H),0.79(s,3H),0.72(s,3H).
Example 17
3 beta- (trans-4-dimethylamino-but-2-ene-amide) oleanane-12-oxo-9 (11) -ene-28-carboxylic acid benzyl ester
Compound 18(100mg, 0.183mmoL, 1.0eq.) was weighed out and dissolved in 2mL of DMF solution. EDCI (38mg, 0.2mmoL, 1.1eq.) under nitrogen protection, HOBt (27mg, 0.2mmoL, 1.1eq.), 4- (dimethylamino) butyric acid hydrochloride (36mg, 0.183mmoL, 1.2eq.), DIPEA (64. mu.L, 0.36mmoL, 2.0eq.) were added under ice-water bath to continue the reaction for 8h, and TLC monitored for the end of the reaction. Extraction with dichloromethane, saturated NaHCO3Washing with water solution, washing with saturated NaCl water solution, drying, and concentrating.
Column chromatography with DCM/MeOH 10:1 afforded 126.2mg of white solid, 91% yield.
1H NMR(600MHz,CDCl3)δ7.38–7.26(m,5H),6.83–6.72(m,1H),6.16(d,J＝15.1Hz,1H),5.79(d,J＝9.0Hz,1H),5.69(s,1H),5.14(d,J＝12.3Hz,1H),5.11(d,J＝12.4Hz,1H),3.78–3.69(m,J＝15.6,6.4Hz,1H),3.34(d,J＝3.6Hz,2H),3.05(d,J＝13.5Hz,1H),2.73(d,J＝4.3Hz,1H),2.47(s,6H),1.12(s,3H),0.99(s,3H),0.95(s,3H),0.90(s,6H),0.88(s,3H),0.80(s,3H).
The analogues of the pentacyclic triterpenoid natural products have the anti-proliferation effect on tumor cells
To evaluate the antitumor activity of the synthetic OA derivatives, we tested their inhibition of proliferation of MCF-7, HepG2, HeLa, MDA-MB-468, MDA-MB-231 and JIMT-1 by the MTT method.
The experimental principle is as follows: MTT is available under the trade name thiazole blue, yellow dye. Succinate dehydrogenase in mitochondria of living cells can reduce MTT, and blue-purple formazan is generated and precipitated in cells by cytochrome C, formazan can be dissolved in DMSO, and the amount of formazan can be detected by absorbance. Therefore, the number of living cells can be estimated from the absorbance value.
The method comprises the following operation steps: wiping a 96-hole plate, gloves, a centrifuge tube and the like used in the experiment with 75% alcohol, placing the wiped 96-hole plate, gloves, centrifuge tube and the like into a super clean bench, irradiating the wiped 96-hole plate, gloves, centrifuge tube and the like with an ultraviolet lamp for 30min, taking out the culture solution, PBS, medicines and the like from a refrigerator, and returning the temperature to 37 ℃. Taking cells in logarithmic growth phase, obtaining cell suspension by the method of passage, counting by using a cell counting plate, preparing cell suspension by using culture solution, adding 100 mu L of cell suspension into each hole of a 96-hole plate, placing in an incubator, and culturing for 24 h. All the drugs to be tested are provided with 6 concentration gradients and 4 auxiliary holes, the drug stock solution is diluted to the required concentration by using the culture solution, a 96-hole plate is taken out, and 100 mu L of the drugs are added into each hole. After 48 hours of incubation, 20 μ of LMTT (5mg/mL) solution was added to each well, after 4 hours of incubation, the culture solution was aspirated, 200 μ of LDMSO was added to each well to dissolve formazan, the plate was shaken for 5min after the microplate reader was warmed to 37 ℃, and then the absorbance at 570nm was measured.
Data was processed through IBM SPSS Statistics software.
The result of the anti-proliferation experiment of the analogues of the pentacyclic triterpenoid natural products on tumor cells is as follows:
wherein: a and b represent that the alpha and beta configurations of the ring of the compound A are different; c represents the measurement value of three times of experiments; d indicates that no activity test was performed
From the experimental data, the pentacyclic triterpene derivative with the electrophilic activity warhead provided by the invention has universal antitumor activity on various cancer cells, and partial compounds such as the compound 5, the compound 6 and the compound 13 have stronger antitumor activity. Therefore, the invention can be used for treating tumor diseases, especially breast cancer, cervical cancer, liver cancer and the like. In addition, the invention creatively introduces the electrophilic active warhead into the natural product structure of the pentacyclic triterpene, and provides a thought for developing the novel derivative of the pentacyclic triterpene containing the electrophilic warhead.
Claims (6)
1. The derivatives of the pentacyclic triterpenoid natural products are characterized by having structures shown in general formulas I-III:
wherein: r1Represents independently hydrogen, NHR8、OR8，R2Represents independently hydrogen, NHR8、OR8Or R is1And R2Together represent oxygen; wherein R is3Represents independently hydrogen, NHR8、OR8；R4Represents independently hydrogen, NHR8、OR8(ii) a And R is1、R2、R3And R4At least one of them is NHR8OR OR8(ii) a And R is1And R2Not simultaneously NHR8、OR8And R is1If it is NHR8、OR8Then R is2Is hydrogen, R2If it is NHR8、OR8Then R is1Is hydrogen; and R is3And R4Not simultaneously NHR8、OR8And R is3If it is NHR8、OR8Then R is4Is hydrogen, R4If it is NHR8、OR8Then R is3Is hydrogen;
R5represents hydrogen or methyl, R6Represents hydrogen or methyl, and R5When represents hydrogen, R6Represents only methyl, and R6When represents hydrogen, R5Represents only methyl;
R7represents CH2OR9、COOR9、CONHR9、COR10；
R8Represents COCH2X、COCHX2、COCX3、SO2CH2X、COCR11＝CH2、COCH＝CHR11；
X represents F, Cl, Br and I, and when the X is substituted by polyatomic atoms, the X is the same element or different elements;
R9represents an unsubstituted straight or branched chain alkane, alkene, alkyne, phenyl, benzyl, naphthyl of 1 to 10 carbon atoms;
or R9Represents a linear or branched alkane, alkene, alkyne, phenyl, benzyl, naphthyl substituted by Y with 1 to 10 carbon atoms;y represents H, X, CF3、SH、OH、CN、NO2、NH2、、COOH、OCH3、OC2H5COOCH3、COOC2H5Straight or branched alkanes of 1 to 10 carbon atoms, alkenes, alkynes, phenyl, benzyl, naphthyl;
R10represents piperazine, piperidine, pyrrole, methylpiperazine, morpholine, tert-butyloxycarbonyl piperazine;
R11represents H, X, CN, CF3Methyl, ethyl, phenyl, benzyl, CH2OH、CH2OMe、CH2NMe2、CH2NEt2、CH2R10。
2. The derivative of a pentacyclic triterpenoid natural product of claim 1, which is used for forming a pharmaceutically acceptable salt comprising a sodium salt, a potassium salt, an ammonium salt, an organic amine salt or a basic amino acid of a compound shown in general formulas I-III; also included are acid addition salts of compounds of formulae I-III with the following acids: hydrochloric acid, hydrobromic acid, sulfuric acid, carbonic acid, citric acid, tartaric acid, phosphoric acid, lactic acid, pyruvic acid, acetic acid, maleic acid, methanesulfonic acid, benzenesulfonic acid, or p-toluenesulfonic acid.
3. The method for preparing the derivative of the pentacyclic triterpenoid natural product, according to claim 1, comprises the following steps:
(1)
(a) under the temperature condition of 0-70 ℃, the volume ratio of 1:1, taking dichloromethane and acetone as solvents, and reacting oleanolic acid with the Jones reagent for 1-6 hours to obtain a compound A1, wherein the molar ratio of the oleanolic acid to the Jones reagent is 1: 1.3-1: 5;
(b) under the condition of 0-90 ℃, tert-butyl alcohol is used as a solvent, and the compound A1 and isoamylnitrite react for 8-24 hours under the alkaline condition to obtain a compound A2; wherein the molar ratio of the compound A1 to isoamyl nitrite is 1: 1.1-1: 15; the used alkali is potassium tert-butoxide, and the molar ratio of the compound A1 to the potassium tert-butoxide is 1: 3-1: 15;
(c) under the condition of the temperature of 0-90 ℃, methanol and concentrated hydrochloric acid in the volume ratio of 20:1-5:1 are used as solvents, and the compound A2 is subjected to catalytic hydrogenation reduction reaction for 8-24 hours through palladium carbon to obtain a compound A3; wherein the mass ratio of the palladium carbon to the compound A2 is 1: 10-1: 5;
(d) the method comprises the following steps: reacting the compound A3 with acyl chloride or acid anhydride for 4-12 h at the temperature of 0-90 ℃ under the alkaline condition to obtain a compound A4; wherein the solvent comprises one or more of dichloromethane, tetrahydrofuran and acetonitrile, the base comprises potassium carbonate, sodium bicarbonate, triethylamine and N, N-diisopropylethylamine, and the molar ratio of the compound A3 to the base is 1: 1-1: 5; the molar ratio of the compound A3 to acyl chloride or acid anhydride is 1: 1-1: 10;
the second method comprises the following steps: reacting the compound A3 with carboxylic acid or carboxylate for 6-24h through condensation reaction at the temperature of 0-90 ℃ to obtain a compound A4; wherein, the solvent used in the reaction system is one or the combination of more than two of dichloromethane, tetrahydrofuran, acetonitrile and N, N-dimethylformamide; the alkali comprises potassium carbonate, sodium bicarbonate, triethylamine and N, N-diisopropylethylamine, and the molar ratio of the compound A3 to the alkali is 1: 1-1: 5; the condensing agent used in the reaction system comprises one or the combination of more than two of EDCI, DCC, HoBt, HBTU and organophosphorus; the molar ratio of the compound A3 to the condensing agent is 1: 1-1: 5; the molar ratio of the compound A3 to the carboxylic acid or the carboxylate is 1: 1.1-1: 4;
(2)
(a) under the temperature condition of 0-70 ℃, the volume ratio of 1:1, taking dichloromethane and acetone as solvents, and reacting oleanolic acid with the Jones reagent for 1-6 hours to obtain a compound B1, wherein the molar ratio of the oleanolic acid to the Jones reagent is 1: 1.3-1: 5;
(b) under the condition of 0-90 ℃, ethanol and water with the volume ratio of 40: 1-15: 1 are used as solvents, and the compound B1 reacts with hydroxylamine hydrochloride and anhydrous sodium acetate for 6-24 hours to obtain a compound B2; wherein the molar ratio of the compound B2 to the hydroxylamine hydrochloride is 1: 1.1-1: 15; the molar ratio of the compound B2 to anhydrous sodium acetate is 1: 4-1: 20;
(c) under the condition of the temperature of 0-90 ℃, taking methanol and dichloromethane in a volume ratio of 1:1 as solvents, and reacting the compound B2 with a sodium cyanoborohydride reducing agent for 8-24 h to obtain a compound B3; the molar ratio of the compound B2 to the cyano sodium borohydride is 1: 1.1-1: 30;
(d) the method comprises the following steps: reacting the compound B3 with acyl chloride or acid anhydride for 4-12 h at the temperature of 0-90 ℃ under the alkaline condition to obtain a compound B4; wherein, the solvent comprises one or the combination of more than two of dichloromethane, tetrahydrofuran and acetonitrile; the alkali comprises potassium carbonate, sodium hydroxide, triethylamine and N, N-diisopropylethylamine, and the molar ratio of the compound B3 to the alkali is 1: 1-1: 5; the molar ratio of the compound B3 to acyl chloride or acid anhydride is 1: 1-1: 10;
the second method comprises the following steps: reacting the compound B3 with carboxylic acid or carboxylate for 6-24h through condensation reaction at the temperature of 0-90 ℃ to obtain a compound B4; the solvent used in the reaction system comprises one or the combination of more than two of dichloromethane, tetrahydrofuran, acetonitrile and N, N-dimethylformamide; the alkali comprises potassium carbonate, sodium hydroxide, triethylamine and N, N-diisopropylethylamine, and the molar ratio of the compound B3 to the alkali is 1: 1-1: 5; the condensing agent used in the reaction system comprises one or a combination of more than two of EDCI, DCC, HoBt, HBTU and organophosphorus, and the molar ratio of the compound B3 to the condensing agent is 1: 1-1: 5; the molar ratio of the compound B3 to the carboxylic acid or the carboxylate is 1: 1.1-1: 4.
4. Use of a derivative of a pentacyclic triterpenoid natural product in the preparation of a medicament for preventing and/or treating tumor diseases.
5. The use according to claim 4, wherein the derivative of the pentacyclic triterpenoid natural product is prepared by the preparation method of claim 3.
6. A pharmaceutical composition comprises a compound of formulae I-III and a pharmaceutically acceptable carrier.
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