CN116284033A - tubulin/AKT 1 double-targeting podophyllotoxin derivative and application thereof - Google Patents

tubulin/AKT 1 double-targeting podophyllotoxin derivative and application thereof Download PDF

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CN116284033A
CN116284033A CN202310319389.5A CN202310319389A CN116284033A CN 116284033 A CN116284033 A CN 116284033A CN 202310319389 A CN202310319389 A CN 202310319389A CN 116284033 A CN116284033 A CN 116284033A
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podophyllotoxin
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tubulin
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林红燕
艾东炫
王利群
卿青
朱劼
陶昱恒
阮玲玉
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Changzhou University
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Abstract

The invention discloses a microtubulin/AKT 1 double-targeting podophyllotoxin derivative and application thereof, belongs to the technical field of chemical pharmacy, and particularly relates to a podophyllotoxin ester derivative molecule and application thereof in preparing an anti-tumor medicament. The podophyllotoxin and phenoxyacetic acid aniline carboxylic acid groups are connected together through ester bonds, and the podophyllotoxin ester derivative molecules are obtained through semisynthesis, and in-vitro anti-tumor activity research shows that the molecules have strong inhibition activity on tumor cell lines and can target tubulin and AKT1 protein at the same time.

Description

tubulin/AKT 1 double-targeting podophyllotoxin derivative and application thereof
Technical Field
The invention belongs to the technical field of chemical pharmacy, and particularly relates to preparation of a microtubulin/AKT 1 double-targeting podophyllotoxin derivative.
Background
Podophyllotoxin (PPT), a natural cyclic xylan, is the main component of Podophyllotoxin, shows strong cytotoxic activity against various cancer cell lines, but has not been used in human clinical trials due to unacceptable toxic side effects. To overcome these limitations, researchers have focused on structural modification at the 4-position of cycloalkanes (C-rings) to produce derivatives with excellent pharmacological properties. Etoposide (Etoposide) and Teniposide (Teniposide) are two semisynthetic epothilone derivatives that have been successfully used clinically as antitumor agents by inhibiting DNA-topoisomerase II. The new series of podophyllotoxin derivatives discovered in recent years can show anti-tumor activity by inhibiting cancer cell microtubule assembly. However, their antitumor activity is still not strong (micromolar scale) and targeting tubulin still presents major toxic side effects. Thus, the present study was aimed at designing dual-targeting podophyllotoxin derivatives that target both tubulin and AKT1 based on podophyllotoxin scaffolds to find some more potent anti-tumor drug molecules.
Figure BDA0004151126830000011
Disclosure of Invention
The invention aims to provide a novel podophyllotoxin ester derivative, and a synthetic method and application thereof.
The technical scheme adopted by the invention is as follows:
the podophyllotoxin ester derivative has the following general formula:
Figure BDA0004151126830000012
wherein the substituents are selected from the following ranges: r is R 1 、R 2 、R 3 、R 4 、R 5 Each independently selected from H, cl, F, CH (CH) 3 ) 2 ,C(CH 3 ) 3 ,CH 3 Br or OCH 3 ；R 6 =h or CH 3 。
A method for preparing the podophyllotoxin ester derivative, which comprises the following steps:
step 1, taking different substituted phenoxyacetic acid (A) and HATU (2- (7-azabenzotriazol) -N, N, N ', N' -tetramethyl urea hexafluorophosphate) in a round bottom flask, adding DMF solution, stirring at room temperature for dissolution, adding methyl p-aminophenylacetate (or m-aminophenylacetate) and DIPEA (N, N-diisopropylethylamine), stirring at room temperature for reaction for 6 hours, and detecting the reaction progress by TCL. After the reaction, the reaction solution was diluted with water, extracted with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and the organic solvent was removed by rotary evaporation to obtain a crude product of B1 (or B2), which was then added with a dichloromethane solution and silica gel powder, dried to prepare a sample, and separated by column chromatography to obtain an intermediate (B1 or B2).
Figure BDA0004151126830000021
Wherein, the molar ratio of the phenoxyacetic acid (A), the HATU and the methyl para-aminophenylacetate (or the methyl meta-aminophenylacetate) DIPEA (N, N-diisopropylethylamine) is 1:1.5:1:1.5.
Step 2, dissolving the intermediate (B1 or B2) in tetrahydrofuran in a volume ratio: methanol: to the mixed solvent of water=3:1:1, liOH h.h was added 2 O, stirring at room temperature for 3h, and detecting the reaction progress by TCL. After the reaction, the organic solvent was removed by rotary evaporation, acidified with hydrochloric acid to ph=3, and solid precipitated, filtered and naturally dried to obtain intermediate (C1 or C2).
Figure BDA0004151126830000022
Wherein the intermediate (B1 or B2) is mixed with LiOH H 2 The molar ratio of O is 1:4.
And 3, dissolving the product C1 or C2 obtained in the step 2 with podophyllotoxin under ice bath conditions, adding DCC (N, N' -dicyclohexylcarbodiimide) and DMAP (p-dimethylaminopyridine), stirring and reacting for 30 minutes, and passing through a silica gel column after the reaction is finished to obtain the target compound D1 or D2.
Figure BDA0004151126830000031
Wherein the molar ratio of (C1 or C2) to podophyllotoxin is 1:1.
The molecular structural formula of the podophyllotoxin ester derivative is shown as follows:
Figure BDA0004151126830000032
Figure BDA0004151126830000041
Figure BDA0004151126830000051
the invention proves that the podophyllotoxin ester derivative molecules have obvious antiproliferative activity on human non-small cell lung cancer cells H1975 and H1299 through in vitro tumor cell inhibition activity, and most of the compounds have half lethal concentration (IC) 50 Value) is less than 10 mu mol.L -1 In particular compound D1-1 for H1975 cells 50 The value is 0.102 mu mol.L -1 Podophyllotoxin (IC) as a parent compound thereof 50 ＝12.56μmol·L -1 ) Compared with the traditional Chinese medicine, the anti-tumor activity is improved by more than 100 times, and the detail is shown in the accompanying figures 1 and 2. In comparison of the structure-activity relationship, podophyllotoxin can only bind to tubulin (colchicine binding site), while D1-1 has good affinity with AKT1 active site in addition to the active site of podophyllotoxin, and in addition, D1-1 is more prone to bind to AKT1 protein between two targets, see FIG. 3 for details.
Compared with the prior art, the invention has the beneficial effects that:
compared with podophyllotoxin, the podophyllotoxin ester derivative has obvious tumor cell inhibiting activity, and the inhibiting activity of most novel compounds on human non-small cell lung cancer cell strains is obviously superior to that of parent molecules. In the prior art, research on podophyllotoxin does not pay attention to an AKT1 target point, but in the research, in order to further improve the anti-tumor activity of the podophyllotoxin and reduce the toxic and side effects of the podophyllotoxin, a drug molecule design is carried out on tubulin and AKT1 protein at the same time, so that a double-target molecule capable of simultaneously targeting the two target points is obtained. The research is to deeply explore the action mechanism of the medicine through a flow type, western blot and laser confocal means.
Drawings
FIG. 1, CCK8 detection method, in vitro proliferation inhibition activity diagram of podophyllotoxin ester derivatives D1-D2-10 on human lung cancer cell strains H1975 and H1299;
FIG. 2, CCK8 assay to detect the in vitro proliferation inhibitory activity of podophyllotoxin ester derivatives D1-D2-10 on human lung epithelial cell line BEAS-2B;
FIG. 3 shows an in vitro proliferation inhibition activity diagram of podophyllotoxin ester derivative D1-1 on human lung cancer cell strain H1975 detected by an EdU detection method;
FIG. 4, biological membrane layer interference (BLI) assay for the affinity of Podophyllotoxin ester derivative D1-1 for tubulin and AKT1 proteins.
Detailed Description
A method for preparing podophyllotoxin ester derivatives, which comprises the following steps:
step 1, 1.5mmol of the differently substituted phenoxyacetic acid (A) and 2.25mmol (1.5 eq) of HATU are taken in a 25mL round bottom flask, 5mL of a solution of LDMF is added, stirring and dissolving are carried out at room temperature, 1.5mmol of methyl p-aminophenylacetate (or 1.5mmol of m-aminophenylacetate) and 2.25mmol (1.5 eq) of DIPEA are added, stirring and reacting are carried out at room temperature for 6h, and TCL detects the reaction progress. After the completion of the reaction, the reaction mixture was diluted with 30mL of water, extracted with ethyl acetate 2 times, the organic phase was washed with saturated brine 2 times, dried over anhydrous sodium sulfate, and the organic solvent was removed by rotary evaporation to give a crude B1 (or B2), and 10mL of a methylene chloride solution and 930mg of silica gel powder were added to prepare a sample by spin-drying, followed by separation by column chromatography to give an intermediate (B1 or B2).
Figure BDA0004151126830000061
1mmol of intermediate (B1 or B2) was dissolved in tetrahydrofuran: methanol: to a water=3:1:1 mixed solvent (5 mL), 4mmol of LiOH H was added 2 O, stirring at room temperature for 3h, and detecting the reaction progress by TCL. After the reaction, the organic solvent was removed by rotary evaporation, and 0.1 mol. L was used -1 Acidifying hydrochloric acid to pH=3, precipitating solid, filtering, and naturally airing to obtain an intermediate (C1 or C2).
Figure BDA0004151126830000071
In a 50mL round bottom flask under ice bath, adding intermediate C1 (or C2) (0.5 mmol), DCC (1 mmol), refined dichloromethane (20 mL), DMAP (0.25 mmol) and podophyllotoxin (0.5 mmol) in sequence, stirring for 1 hr, detecting the completion of the reaction by TLC, separating by thin plate chromatography (V) Acetic acid ethyl ester ：V Petroleum ether =1:1) to give the corresponding podophyllotoxin-like derivative (D1 or D2).
Figure BDA0004151126830000072
Example 1
Figure BDA0004151126830000073
The preparation method of the compound D1-1 is the same as that of the compound D1, and the compound D1-1 is obtained by replacing the phenoxyacetic acid (A) with m-phenoxyacetic acid under the same conditions, wherein the form of the compound D1-1 is white powder, and the yield is 84%. Compound D1-1: 1 H NMR(600MHz,CDCl 3 )δ8.31(s,1H,NH),7.59(d,J＝8.3Hz,2H,Ar-H),7.31–7.24(m,3H,Ar-H),7.04(d,J＝7.9Hz,1H,Ar-H),7.01(d,J＝1.9Hz,1H,Ar-H),6.88(d,J＝8.3Hz,1H,Ar-H),6.66(s,1H,Ar-H),6.50(d,J＝17.7Hz,1H,Ar-H),6.37(d,J＝12.9Hz,2H,Ar-H),5.97(d,J＝15.7Hz,2H,O-CH 2 -O),5.86(d,J＝9.3Hz,1H,CH-O-C＝O),4.58(dd,J＝9.8,3.1Hz,3H,O-CH 2 -C＝O,Ar-CH),4.24(t,J＝8.1Hz,1H,CH 2 -O-C＝O),4.16–4.09(m,1H,CH 2 -O-C＝O),3.80(s,3H,OCH 3 ),3.73(s,6H,OCH 3 ),3.71(d,J＝1.6Hz,2H,Ar-CH 2 -C＝O),2.89(dd,J＝15.5,3.5Hz,1H,O＝C-CH),2.82–2.73(m,1H,O-CH 2 -CH).
example 2
Figure BDA0004151126830000081
The preparation method of the compound D1-2 is the same as that of the compound D1, and the compound D1-2 is obtained by replacing the phenoxyacetic acid (A) with p-chlorophenoxyacetic acid under the same conditions, wherein the form of the compound D1-2 is white powder, and the yield is 82%. Compound D1-2: 1 H NMR(600MHz,CDCl 3 )δ8.25(s,1H,NH),7.58(d,J＝8.5Hz,2H,Ar-H),7.30(dd,J＝13.4,8.7Hz,4H,Ar-H),6.94(d,J＝9.0Hz,2H,Ar-H),6.66(s,1H,Ar-H),6.53(s,1H,Ar-H),6.36(s,2H,Ar-H),5.98(dd,J＝16.3,1.2Hz,2H,O-CH 2 -O),5.87(d,J＝9.3Hz,1H,CH-O-C＝O),4.58(d,J＝4.7Hz,3H,O-CH 2 -C＝O,Ar-CH),4.24(dd,J＝9.2,7.2Hz,1H,CH 2 -O-C＝O),4.14(d,J＝9.4Hz,1H,CH 2 -O-C＝O),3.81(s,3H,OCH 3 ),3.74(s,6H,OCH 3 ),3.71(d,J＝1.9Hz,2H,Ar-CH 2 -C＝O),2.90(dd,J＝14.6,4.5Hz,1H,O＝C-CH),2.78(dt,J＝16.6,10.0Hz,1H,O-CH 2 -CH).
example 3
Figure BDA0004151126830000082
The preparation method of the compound D1-3 is the same as that of the compound D1, and the compound D1-3 is obtained by replacing the phenoxyacetic acid (A) with the p-fluorophenoxyacetic acid under the same conditions, wherein the form of the compound D1-3 is white powder, and the yield is 80%. Compounds D1-3: 1 H NMR(600MHz,CDCl 3 )δ8.36(s,1H,NH),7.57(d,J＝8.4Hz,1H,Ar-H),7.29(s,2H,Ar-H),7.12(s,2H,Ar-H),7.03(t,J＝8.6Hz,1H,Ar-H),6.94(dd,J＝7.9,5.4Hz,1H,Ar-H),6.68–6.34(m,5H,Ar-H),5.90(dd,J＝53.8,9.7Hz,3H,O-CH 2 -O,CH-O-C＝O),4.56(d,J＝3.4Hz,3H,O-CH 2 -C＝O,Ar-CH),4.11(q,J＝7.1Hz,1H,CH 2 -O-C＝O),4.01(t,J＝9.1Hz,1H,CH 2 -O-C＝O),3.79(s,3H,OCH 3 ),3.73(s,6H,OCH 3 ),3.71(d,J＝2.9Hz,2H,Ar-CH 2 -C＝O),2.81–2.75(m,2H,O＝C-CH,O-CH 2 -CH).
example 4
Figure BDA0004151126830000091
The preparation method of the compound D1-4 is the same as that of the compound D1, and the compound D1-4 is obtained by replacing the phenoxyacetic acid (A) with 2-methyl-4-chlorophenoxyacetic acid under the same conditions, wherein the form of the compound D1-4 is white powder, and the yield is 87%. Compounds D1-4: 1 HNMR(600MHz,CDCl 3 )δ8.29(s,1H,NH),7.57(d,J＝8.5Hz,2H,Ar-H),7.29(d,J＝8.5Hz,2H,Ar-H),7.19(d,J＝2.3Hz,1H,Ar-H),7.15(dd,J＝8.6,2.5Hz,1H,Ar-H),6.77(d,J＝8.7Hz,1H,Ar-H),6.66(s,1H,Ar-H),6.53(s,1H,Ar-H),6.36(s,2H,Ar-H),5.98(dd,J＝16.0,1.2Hz,2H,O-CH 2 -O),5.87(d,J＝9.3Hz,1H,CH-O-C＝O),4.58(d,J＝4.2Hz,3H,O-CH 2 -C＝O,Ar-CH),4.24(dd,J＝9.2,7.2Hz,1H,CH 2 -O-C＝O),4.18–4.12(m,1H,CH 2 -O-C＝O),3.81(s,3H,OCH 3 ),3.74(s,6H,OCH 3 ),3.72(d,J＝2.8Hz,2H,Ar-CH 2 -C＝O),2.90(dd,J＝14.6,4.5Hz,1H,O＝C-CH),2.78(ddd,J＝20.1,12.5,8.4Hz,1H,O-CH 2 -CH),2.34(s,3H,Ar-CH 3 ).
example 5
Figure BDA0004151126830000101
The preparation method of the compound D1-5 is the same as that of the compound D1, and the compound D1-5 is obtained by replacing the phenoxyacetic acid (A) with 2, 5-dimethylbenzeneoxyacetic acid under the same conditions, wherein the compound D1-5 is white powder with the yield of 79%. Compounds D1-5: 1 HNMR(600MHz,CDCl 3 )δ8.39(s,1H,NH),7.59(d,J＝8.5Hz,2H,Ar-H),7.29(d,J＝8.4Hz,2H,Ar-H),7.08(d,J＝7.6Hz,1H,Ar-H),6.78(d,J＝7.5Hz,1H,Ar-H),6.65(s,2H,Ar-H),6.52(s,1H,Ar-H),6.36(s,2H,Ar-H),5.96(dd,J＝17.5,1.2Hz,2H,O-CH 2 -O),5.85(d,J＝9.2Hz,1H,CH-O-C＝O),4.59(s,2H,O-CH 2 -C＝O),4.57(d,J＝4.4Hz,1H,Ar-CH),4.25(dd,J＝9.2,7.1Hz,1H,CH 2 -O-C＝O),4.12(dt,J＝14.1,8.6Hz,1H,CH 2 -O-C＝O),3.80(s,3H,OCH 3 ),3.73(s,6H,OCH 3 ),3.71(d,J＝2.4Hz,2H,Ar-CH 2 -C＝O),2.90–2.74(m,2H,O＝C-CH,O-CH 2 -CH),2.32(s,3H,Ar-CH 3 ),2.31(s,3H,Ar-CH 3 ).
example 6
Figure BDA0004151126830000102
The preparation method of the compound D1-6 is the same as that of the compound D1, and the compound D1-6 is obtained by replacing the phenoxyacetic acid (A) with p-isopropylphenoxyacetic acid under the same conditions as the above, and is white powder with the yield of 85%. Compounds D1-6: 1 HNMR(600MHz,CDCl 3 )δ8.33(s,1H,NH),7.59(d,J＝8.5Hz,2H,Ar-H),7.28(d,J＝8.5Hz,2H,Ar-H),7.20(d,J＝8.6Hz,2H,Ar-H),6.92(d,J＝8.7Hz,2H,Ar-H),6.65(s,1H,Ar-H),6.52(s,1H,Ar-H),6.36(s,2H,Ar-H),5.97(dd,J＝16.9,1.2Hz,2H,O-CH 2 -O),5.86(d,J＝9.3Hz,1H,CH-O-C＝O),4.59(s,2H,O-CH 2 -C＝O),4.58(d,J＝4.5Hz,1H,Ar-CH),4.25(dd,J＝9.2,7.1Hz,1H,CH 2 -O-C＝O),4.14(dd,J＝16.1,6.7Hz,1H,CH 2 -O-C＝O),3.81(s,3H,OCH 3 ),3.74(s,6H,OCH 3 ),3.71(d,J＝1.9Hz,2H,Ar-CH 2 -C＝O),2.89(dt,J＝20.8,6.5Hz,2H,O＝C-CH,O-CH 2 -CH),2.82–2.74(m,1H,CH(CH 3 ) 2 ),1.24(s,3H,CH(CH 3 ) 2 ),1.23(s,3H,CH(CH 3 ) 2 ).
example 7
Figure BDA0004151126830000111
The preparation method of the compound D1-7 is the same as that of the compound D1, and the compound D1-7 is obtained by replacing the phenoxyacetic acid (A) with the p-isobutylphenoxyacetic acid under the same conditions as the other conditions, and the yield is 82%. Compounds D1-7: 1 HNMR(600MHz,CDCl 3 )δ8.30(s,1H,NH),7.51(d,J＝8.4Hz,1H,Ar-H),7.28(d,J＝8.7Hz,2H,Ar-H),7.20(d,J＝7.2Hz,2H,Ar-H),7.06(s,1H,Ar-H),6.84(d,J＝8.7Hz,1H,Ar-H),6.50(d,J＝81.1Hz,1H,Ar-H),6.33(t,J＝36.9Hz,4H,Ar-H),5.88(t,J＝12.5Hz,3H,O-CH 2 -O,CH-O-C＝O),4.52–4.45(m,3H,O-CH 2 -C＝O,Ar-CH),4.20–4.00(m,2H,CH 2 -O-C＝O),3.72(s,3H,OCH 3 ),3.65(s,6H,OCH 3 ),3.63(d,J＝2.6Hz,2H,Ar-CH 2 -C＝O),2.75–2.66(m,2H,O＝C-CH,O-CH 2 -CH),1.23(s,9H,C(CH 3 ) 3 ).
example 8
Figure BDA0004151126830000112
The preparation method of the compound D1-8 is the same as that of the compound D1, and the compound D1-8 is obtained by replacing the phenoxyacetic acid (A) with the p-methylphenoxyacetic acid under the same conditions as the other conditions, and is white powder with the yield of 78%. Compounds D1-8: 1 HNMR(600MHz,CDCl 3 )δ8.35(s,1H,NH),7.59(d,J＝8.4Hz,2H,Ar-H),7.27(d,J＝8.5Hz,2H,Ar-H),7.13(d,J＝8.4Hz,2H,Ar-H),6.88(d,J＝8.5Hz,2H,Ar-H),6.65(s,1H,Ar-H),6.51(s,1H,Ar-H),6.36(s,2H,Ar-H),5.96(d,J＝16.7Hz,2H,O-CH 2 -O),5.85(d,J＝9.2Hz,1H,CH-O-C＝O),4.56(s,3H,O-CH 2 -C＝O,Ar-CH),4.26–4.21(m,1H,CH 2 -O-C＝O),4.12(dt,J＝11.5,8.5Hz,1H,CH 2 -O-C＝O),3.80(s,3H,OCH 3 ),3.73(s,6H,OCH 3 ),3.70(s,2H,Ar-CH 2 -C＝O),2.86(dd,J＝14.6,4.4Hz,1H,O＝C-CH),2.77(ddd,J＝16.6,9.9,7.3Hz,1H,O-CH 2 -CH),2.30(s,3H,CH 3 ).
example 9
Figure BDA0004151126830000121
The preparation method of the compound D1-9 is the same as that of the compound D1, and the compound D1-9 is obtained by replacing the phenoxyacetic acid (A) with 2, 3-dimethylbenzeneoxyacetic acid under the same conditions, wherein the form of the compound D1-9 is white powder, and the yield is 83%. Compounds D1-9: 1 HNMR(600MHz,CD 2 Cl 2 )δ8.36(s,1H,NH),7.59(d,J＝8.4Hz,2H,Ar-H),7.29(d,J＝8.4Hz,2H,Ar-H),7.09(t,J＝7.9Hz,1H,Ar-H),6.89(d,J＝7.6Hz,1H,Ar-H),6.73(d,J＝8.1Hz,1H,Ar-H),6.65(s,1H,Ar-H),6.52(s,1H,Ar-H),6.36(s,2H,Ar-H),5.98(d,J＝16.4Hz,2H,O-CH 2 -O),5.87(d,J＝9.3Hz,1H,CH-O-C＝O),4.60(s,2H,O-CH 2 -C＝O),4.58(d,J＝4.5Hz,1H,Ar-CH),4.25(dd,J＝9.1,7.3Hz,1H,CH 2 -O-C＝O),4.15(t,J＝8.6Hz,1H,CH 2 -O-C＝O),3.81(s,3H,OCH 3 ),3.74(s,6H,OCH 3 ),3.71(d,J＝2.5Hz,2H,Ar-CH 2 -C＝O),2.90(dd,J＝14.5,4.5Hz,1H,O＝C-CH),2.83–2.75(m,1H,O-CH 2 -CH),2.32(s,3H,CH 3 ),2.28(s,3H,CH 3 ).
example 10
Figure BDA0004151126830000122
The preparation method of the compound D1-10 is the same as that of the compound D1, and the o-chlorophenoxyacetic acid is replaced by the phenoxyacetic acid (A) with different substitutions, and other conditions are unchanged, so that the compound D1-10 is obtained in the form of white powder with the yield of 75%. Compounds D1-10: 1 H NMR(600MHz,CDCl 3 )δ8.70(s,1H,NH),7.62(d,J＝8.4Hz,2H,Ar-H),7.53(d,J＝8.6Hz,1H,Ar-H),7.45(dd,J＝7.9,1.4Hz,1H,Ar-H),7.37–7.34(m,1H,Ar-H),7.30(d,J＝8.5Hz,3H,Ar-H),6.65(s,1H,Ar-H),6.52(s,1H,Ar-H),6.36(s,2H,Ar-H),5.98(d,J＝18.5Hz,2H,O-CH 2 -O),5.87(d,J＝9.3Hz,1H,CH-O-C＝O),4.66(s,2H,O-CH 2 -C＝O),4.58(d,J＝4.4Hz,1H,Ar-CH),4.27(dd,J＝9.2,7.2Hz,1H,CH 2 -O-C＝O),4.18–4.13(m,1H,CH 2 -O-C＝O),3.81(s,3H,OCH 3 ),3.74(s,6H,OCH 3 ),3.72(d,J＝2.1Hz,2H,Ar-CH 2 -C＝O),2.90(dd,J＝14.6,4.5Hz,1H,O＝C-CH),2.85–2.73(m,1H O-CH 2 -CH).
example 11
Figure BDA0004151126830000131
The preparation method of the compound D2-1 is the same as that of the compound D2, and the compound D2-1 is obtained by replacing the phenoxyacetic acid (A) with m-phenoxyacetic acid under the same conditions, wherein the form of the compound D2-1 is white powder, and the yield is 85%. Compound D2-1: 1 H NMR(600MHz,CDCl 3 )δ8.23(s,1H,NH),7.73(s,1H,Ar-H),7.42(d,J＝9.2Hz,1H,Ar-H),7.36–7.29(m,2H,Ar-H),7.10(d,J＝7.7Hz,1H,Ar-H),7.06(dd,J＝7.6,1.4Hz,1H,Ar-H),7.02(dd,J＝4.7,2.6Hz,1H,Ar-H),6.89(dd,J＝8.3,2.3Hz,1H,Ar-H),Ar-H,6.69(s,1H,Ar-H),6.53(s,1H,Ar-H),6.37(s,2H,Ar-H),5.96(dd,J＝11.1,1.3Hz,2H,O-CH 2 -O),5.88(d,J＝9.2Hz,1H,CH-O-C＝O),4.59(s,3H,Ar-CH,O-CH 2 -C＝O),4.30(dd,J＝9.2,7.0Hz,1H,CH 2 -O-C＝O),4.19–4.14(m,1H,CH 2 -O-C＝O),3.81(s,3H,OCH 3 ),3.75(d,J＝4.4Hz,2H,Ar-CH 2 -C＝O),3.74(s,6H,OCH 3 ),2.93–2.78C(m,2H,O＝C-CH,O-CH 2 -CH).
example 12
Figure BDA0004151126830000141
The preparation method of the compound D2-2 is the same as that of the compound D2, and the phenoxyacetic acid (A) substituted by different groups is replaced by the p-chlorophenoxyacetic acid, and other conditions are unchanged, so that the compound D2-2 is obtained in the form of white powder with the yield of 81%. Compound D2-2: 1 H NMR(600MHz,CDCl 3 )δ8.30(s,1H,NH),7.72(s,1H,Ar-H),7.42(d,J＝7.1Hz,1H,Ar-H),7.35–7.28(m,3H,Ar-H),7.09(d,J＝7.6Hz,1H,Ar-H),6.93(d,J＝9.0Hz,2H,Ar-H),6.68(s,1H,Ar-H),6.52(s,1H,Ar-H),6.36(s,2H,Ar-H),5.96(dd,J＝11.2,1.2Hz,2H,O-CH 2 -O),5.87(d,J＝9.2Hz,1H,CH-O-C＝O),4.58(d,J＝4.9Hz,3H,Ar-CH,O-CH 2 -C＝O),4.29(dd,J＝9.2,7.1Hz,1H,CH 2 -O-C＝O),4.18–4.13(m,1H,CH 2 -O-C＝O),3.80(s,3H,OCH 3 ),3.75(d,J＝3.9Hz,2H,Ar-CH 2 -C＝O),3.73(s,6H,OCH 3 ),2.90(dd,J＝14.6,4.5Hz,1H,O＝C-CH),2.86–2.77(m,1H,O-CH 2 -CH).
example 13
Figure BDA0004151126830000142
The preparation method of the compound D2-3 is the same as that of the compound D2, and the compound D2-3 is obtained by replacing the phenoxyacetic acid (A) with the p-fluorophenoxyacetic acid under the same conditions, wherein the form of the compound D2-3 is white powder, and the yield is 80%. Compound D2-3: 1 H NMR(600MHz,CDCl 3 )δ8.30(s,1H,NH),7.73(s,1H,Ar-H),7.42(dd,J＝8.1,1.1Hz,1H,Ar-H),7.33(t,J＝7.8Hz,1H,Ar-H),7.09(d,J＝7.6Hz,1H,Ar-H),7.06–7.02(m,2H,Ar-H),6.95(dd,J＝9.2,4.2Hz,2H,Ar-H),6.69(s,1H,Ar-H),6.52(s,1H,Ar-H),6.37(s,2H,Ar-H),5.96(dd,J＝11.3,1.2Hz,2H,O-CH 2 -O),5.88(d,J＝9.2Hz,1H,CH-O-C＝O),4.58(d,J＝4.4Hz,1H,Ar-CH),4.57(s,2H,O-CH 2 -C＝O),4.30(dd,J＝9.2,7.0Hz,1H,CH 2 -O-C＝O),4.19–4.14(m,1H,CH 2 -O-C＝O),3.80(s,3H,OCH 3 ),3.75(d,J＝4.1Hz,2H,Ar-CH 2 -C＝O),3.73(s,6H,OCH 3 ),3.49–3.43(m,1H,O＝C-CH),2.91(dd,J＝14.6,4.5Hz,1H,O-CH 2 -CH).
example 14
Figure BDA0004151126830000151
The preparation method of the compound D2-4 is the same as that of the compound D2, and the compound D2-4 is obtained by replacing the phenoxyacetic acid (A) with 2-methyl-4-chlorophenoxyacetic acid under the same conditions, wherein the compound D2-4 is white powder with the yield of 75%. Chemical treatmentCompounds D2-4: 1 H NMR(600MHz,CDCl 3 )δ8.29(s,1H,NH),7.75(s,1H,Ar-H),7.38–7.34(m,2H,Ar-H),7.19(d,J＝2.4Hz,1H,Ar-H),7.15(dd,J＝8.6,2.5Hz,1H,Ar-H),7.11–7.08(m,1H,Ar-H),6.77(d,J＝8.7Hz,1H,Ar-H),6.69(s,1H,Ar-H),6.52(s,1H,Ar-H),6.37(s,2H,Ar-H),5.95(dd,J＝8.5,1.2Hz,2H,O-CH 2 -O),5.87(d,J＝9.2Hz,1H,CH-O-C＝O),4.58(d,J＝4.4Hz,1H,Ar-CH),4.57(s,2H,O-CH 2 -C＝O),4.30(dd,J＝9.2,7.0Hz,1H,CH 2 -O-C＝O),4.16(t,J＝9.8Hz,1H,CH 2 -O-C＝O),3.80(s,3H,OCH 3 ),3.75(d,J＝4.5Hz,2H,Ar-CH 2 -C＝O),3.73(s,6H,OCH 3 ),2.93–2.78(m,2H,O＝C-CH,O-CH 2 -CH),2.33(s,3H,CH 3 ).
example 15
Figure BDA0004151126830000152
The preparation method of the compound D2-5 is the same as that of the compound D2, and the compound D2-5 is obtained by replacing the phenoxyacetic acid (A) with 2, 5-dimethylbenzeneoxyacetic acid under the same conditions, wherein the compound D2-5 is white powder with the yield of 78%. Compound D2-5: 1 H NMR(600MHz,CDCl 3 )δ8.38(d,J＝16.1Hz,1H,NH),7.77(s,1H,Ar-H),7.56(s,1H,Ar-H),7.42–7.30(m,2H,Ar-H),7.09(d,J＝7.5Hz,2H,Ar-H),6.79(d,J＝7.5Hz,1H,Ar-H),6.69(s,1H,Ar-H),6.67(d,J＝4.2Hz,1H,Ar-H),6.53(s,1H,Ar-H),6.37(s,1H,Ar-H),5.95(dd,J＝5.3,1.2Hz,2H,O-CH 2 -O),5.88(d,J＝9.2Hz,1H,CH-O-C＝O),4.59(s,3H,Ar-CH,O-CH 2 -C＝O),4.33–4.15(m,1H,CH 2 -O-C＝O),4.13(q,J＝7.1Hz,1H,CH 2 -O-C＝O),3.81(s,3H,OCH 3 ),3.76(d,J＝5.6Hz,2H,Ar-CH 2 -C＝O),3.74(s,6H,OCH 3 ),3.20(td,J＝9.6,4.4Hz,1H,O＝C-CH),2.94–2.79(m,1H,O-CH 2 -CH),2.33(s,3H,Ar-CH 3 ),2.32(s,3H,Ar-CH 3 ).
example 16
Figure BDA0004151126830000161
The preparation method of the compound D2-6 is the same as that of the compound D2, and the compound D2-6 is obtained by replacing the phenoxyacetic acid (A) with p-isopropylphenoxyacetic acid under the same conditions as the above, and is white powder with the yield of 73%. Compound D2-6: 1 H NMR(600MHz,CDCl 3 )δ8.34(s,1H,NH),7.74(s,1H,Ar-H),7.43(d,J＝9.1Hz,1H,Ar-H),7.32(t,J＝7.8Hz,1H,Ar-H),7.20(d,J＝8.6Hz,2H,Ar-H),7.08(d,J＝7.6Hz,1H,Ar-H),6.92(d,J＝8.6Hz,2H,Ar-H),6.68(s,1H,Ar-H),6.52(s,1H,Ar-H),6.37(s,2H,Ar-H),5.95(dd,J＝10.5,1.0Hz,2H,O-CH 2 -O),5.87(d,J＝9.1Hz,1H,CH-O-C＝O),4.58(d,J＝3.4Hz,3H,Ar-CH,O-CH 2 -C＝O),4.30(dd,J＝9.3,7.0Hz,1H,CH 2 -O-C＝O),4.16(t,J＝9.8Hz,1H,CH 2 -O-C＝O),3.80(s,3H,OCH 3 ),3.74(d,J＝7.9Hz,8H,Ar-CH 2 -C＝O,OCH 3 ),2.92–2.87(m,2H,O＝C-CH,CH(CH 3 ) 2 ),2.87–2.78(m,1H,O-CH 2 -CH),1.24(s,3H,CH(CH 3 ) 2 ),1.23(s,3H,CH(CH 3 ) 2 ).
example 17
Figure BDA0004151126830000162
The preparation method of the compound D2-7 is the same as that of the compound D2, and the different substituted phenoxyacetic acid (A) is replaced by the p-bromophenoxyacetic acid, and other conditions are unchanged, so that the compound D2-7 is obtained in the form of white powder with the yield of 76%. Compounds D2-7: 1 H NMR(600MHz,CDCl 3 )δ8.20(s,1H,NH),7.65(s,1H,Ar-H),7.37(d,J＝8.8Hz,2H,Ar-H),7.29–7.23(m,2H,Ar-H),7.03–6.99(m,1H,Ar-H),6.81(d,J＝9.0Hz,2H,Ar-H),6.61(s,1H,Ar-H),6.45(s,1H,Ar-H),6.29(s,2H,Ar-H),5.88(dd,J＝11.3,1.2Hz,2H,O-CH 2 -O),5.80(d,J＝9.2Hz,1H,CH-O-C＝O),4.51(d,J＝4.4Hz,1H,Ar-CH),4.49(s,2H,O-CH 2 -C＝O),4.22(dd,J＝9.2,7.0Hz,1H,CH 2 -O-C＝O),4.11–4.05(m,1H,CH 2 -O-C＝O),3.73(s,3H,OCH 3 ),3.67(d,J＝3.8Hz,2H,Ar-CH 2 -C＝O),3.66(s,6H,OCH 3 ),2.82(dd,J＝14.6,4.5Hz,1H,O＝C-CH),2.75(ddd,J＝21.6,12.4,8.7Hz,1H,O-CH 2 -CH).
example 18
Figure BDA0004151126830000171
The preparation method of the compound D2-8 is the same as that of the compound D2, and the compound D2-8 is obtained by replacing the phenoxyacetic acid (A) with the p-methoxyphenoxyacetic acid under the same conditions, wherein the form of the compound D2-8 is white powder, and the yield is 77%. Compounds D2-8: 1 H NMR(600MHz,CDCl 3 )δ8.37(s,1H,NH),7.74(s,1H,Ar-H),7.42(d,J＝8.3Hz,1H,Ar-H),7.32(t,J＝7.9Hz,1H,Ar-H),7.08(d,J＝7.6Hz,1H,Ar-H),6.92(d,J＝9.1Hz,2H,Ar-H),6.86(d,J＝9.0Hz,2H,Ar-H),6.68(s,1H,Ar-H),6.51(s,1H,Ar-H),6.36(s,2H,Ar-H),5.95(d,J＝10.9Hz,2H,O-CH 2 -O),5.86(d,J＝9.1Hz,1H,CH-O-C＝O),4.57(d,J＝4.0Hz,1H,Ar-CH),4.53(s,2H,O-CH 2 -C＝O),4.29(t,J＝8.1Hz,1H,CH 2 -O-C＝O),4.15(t,J＝9.5Hz,1H,CH 2 -O-C＝O),3.80(s,3H,OCH 3 ),3.77(s,3H,OCH 3 ),3.74(d,J＝4.9Hz,2H,Ar-CH 2 -C＝O),3.73(s,6H,OCH 3 ),2.88(dd,J＝14.6,4.3Hz,1H,O＝C-CH),2.85–2.77(m,1H,O-CH 2 -CH).
example 19
Figure BDA0004151126830000181
The preparation method of the compound D2-9 is the same as that of the compound D2, and the compound D2-9 is obtained by replacing the phenoxyacetic acid (A) with the m-methoxyphenoxyacetic acid under the same conditions, wherein the form of the compound D2-9 is white powder, and the yield is 81%. Compounds D2-9: 1 H NMR(600MHz,CDCl 3 )δ8.33(s,1H,NH),7.73(s,1H,Ar-H),7.43(d,J＝9.1Hz,1H,Ar-H),7.32(t,J＝7.8Hz,1H,Ar-H),7.23(t,J＝8.2Hz,1H,Ar-H),7.08(d,J＝7.6Hz,1H,Ar-H),6.68(s,1H,Ar-H),6.61(dd,J＝8.3,2.0Hz,1H,Ar-H),6.56(dt,J＝4.4,2.1Hz,2H,Ar-H),6.51(s,1H,Ar-H),6.36(s,2H,Ar-H),5.94(d,J＝10.6Hz,2H,O-CH 2 -O),5.85(d,J＝9.1Hz,1H,CH-O-C＝O),4.57(d,J＝6.2Hz,3H,Ar-CH,O-CH 2 -C＝O),4.29(dd,J＝9.1,7.0Hz,1H,CH 2 -O-C＝O),4.14(t,J＝9.7Hz,1H,CH 2 -O-C＝O),3.80(s,6H,OCH 3 ),3.74(d,J＝4.9Hz,2H,Ar-CH 2 -C＝O),3.73(s,6H,OCH 3 ),2.88(dd,J＝14.6,4.4Hz,1H,O＝C-CH),2.85–2.77(m,1H,O-CH 2 -CH).
example 20
Figure BDA0004151126830000182
The preparation method of the compound D2-10 is the same as that of the compound D2, and the phenoxyacetic acid (A) substituted by different groups is replaced by phenoxyacetic acid, and other conditions are unchanged, so that the compound D2-10 is obtained in the form of white powder with the yield of 88%. Compounds D2-10: 1 HNMR(600MHz,CDCl 3 )δ8.29(s,1H,NH),7.71(d,J＝8.3Hz,1H,Ar-H),7.36(t,J＝9.2Hz,1H,Ar-H),7.34–7.29(m,3H,Ar-H),7.04(dd,J＝16.7,8.3Hz,2H,Ar-H),6.97(dd,J＝8.0,3.9Hz,2H,Ar-H),6.68(d,J＝1.9Hz,1H,Ar-H),6.52(d,J＝1.9Hz,1H,Ar-H),6.37(d,J＝2.3Hz,2H,Ar-H),5.98–5.92(m,2H,O-CH 2 -O),5.86(d,J＝9.1Hz,1H,CH-O-C＝O),4.78(qd,J＝6.7,1.5Hz,1H,O-CH(CH 3 )-C＝O),4.57(d,J＝4.3Hz,1H,Ar-CH),4.29(t,J＝8.0Hz,1H,CH 2 -O-C＝O),4.14(t,J＝8.4Hz,1H,CH 2 -O-C＝O),3.80(s,3H,OCH 3 ),3.73(s,2H,Ar-CH 2 -C＝O),3.73(s,6H,OCH 3 ),2.89(dd,J＝14.5,4.4Hz,1H,O＝C-CH),2.82(tdd,J＝16.1,9.9,6.5Hz,1H,O-CH 2 -CH),1.63(d,J＝6.8Hz,3H,CH 3 ).
example 21: application of podophyllotoxin ester derivative molecule of formula I
The in vitro tumor cell inhibition activity research of the podophyllotoxin ester derivatives of formula I by using human lung cancer cell strains H1975 and H1299 as detection strains and using a CCK-8 colorimetric method as a detection method shows that the novel structural derivatives have obvious in vitro tumor cell inhibition activity, and the result is shown in figure 1. Meanwhile, the derivative pairProliferation inhibition effect of human lung epithelial cell strain BASE-2B is not obvious, and IC (integrated circuit) 50 Values are all greater than 80 mu mol.L -1 The toxicity of the derivative to normal cells is obviously lower than that of podophyllotoxin with a parent nuclear structure, and the result is shown in figure 2.
TABLE 1 Podophyllotoxin ester derivatives have anti-proliferative activity against human non-small cell lung cancer cells
Figure BDA0004151126830000191
In addition, the result of EdU antiproliferative experiments on the active optimal compound D1-1 shows that D1-1 can significantly reduce the proportion of EdU positive cells, and shows superior antiproliferative activity compared with podophyllotoxin, and the result is shown in figure 3.
Example 22: compound D1-1 can target tubulin and AKT1 protein simultaneously
The affinity of D1-1 for tubulin (colchicine binding site) and AKT1 (covalent allosteric site (G4N binding site)) was detected separately using the biological membrane layer interference technique (BLI). The results show that D1-1 has a strong affinity for both AKT1 and tubulin, wherein the affinity for AKT1 (K D ＝3.328×10 -6 M) is slightly stronger than the affinity for tubulin (K) D ＝6.28×10 -5 M) is selected from the group consisting of; its parent nuclear structure podophyllotoxin (PPT) has high affinity for tubulin (K) D ＝7.65×10 -5 M) and the affinity for AKT1 was almost zero, see figure 4.
According to the conclusion, the compounds have application prospects as tubulin or/and AKT1 inhibitors, and can be prepared into antitumor drugs.

Claims (4)

1. A class of tubulin/AKT 1 double-targeting podophyllotoxin derivatives is characterized in that: the general structural formula of the podophyllotoxin derivative is as follows:
Figure FDA0004151126820000011
wherein take outThe selection range of the substituents is as follows: r is R 1 、R 2 、R 3 、R 4 、R 5 Each independently selected from H, cl, F, CH (CH) 3 ) 2 ,C(CH 3 ) 3 ,CH 3 Br or OCH 3 ；R 6 =h or CH 3 。
2. A class of tubulin/AKT 1 dual-targeted podophyllotoxin derivatives according to claim 1, wherein: the podophyllotoxin derivative is one of the following structural formulas:
Figure FDA0004151126820000012
Figure FDA0004151126820000021
Figure FDA0004151126820000031
3. use of a class of tubulin/AKT 1 dual-targeting podophyllotoxin derivatives according to claim 1 or 2 for the preparation of tubulin or/and AKT1 inhibitors.
4. Use of a class of tubulin/AKT 1 dual-targeting podophyllotoxin derivatives according to claim 1 or 2 for the preparation of an antitumor medicament.
CN202310319389.5A 2023-03-29 2023-03-29 tubulin/AKT 1 double-targeting podophyllotoxin derivative and application thereof Pending CN116284033A (en)

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