A kind of tanshinone- secondary amine derivative and its application in preparing anti-breast cancer drugs

Abstract

The application belongs to the technical field of pharmaceutical chemistry, and proposes a class of amine derivatives of pterostilbene and the application of the amine derivatives in the preparation of anti-breast cancer drugs. The chemical structure of the amine derivatives of pterostilbene is shown as formula (I), and R is an amine compound. The method for preparing the amine derivatives of pterostilbene has the characteristics of easy availability of raw materials and simple operation. At the same time, the in-vitro anti-breast cancer activity test results show that most amine derivatives of pterostilbene (2a-2c, 2e, 2g, 2i, 2l and 2m) have good inhibitory effects on breast cancer cells MDA-MB-231 (IC 50 = 7.92-26.42 μM) and MCF-7 (IC 50 = 7.84-25.78 μM). The pterostilbene compound is expected to be used as an active ingredient for preparing a lead drug for treating / preventing breast cancer, and has a pharmaceutical prospect.

Description

Technical Field

[0001] The present invention belongs to the field of medicinal chemistry, and particularly relates to a preparation method of a pterostilbene-secondary amine hybrid and its application in the field of breast cancer. Background Art

[0002] Breast cancer (BC) is one of the most common malignancies in women worldwide, with the highest morbidity and mortality rates among female malignancies. Triple-negative breast cancer (TNBC) is the most aggressive subtype. Due to its lack of expression of estrogen receptor (ER), human epidermal growth factor receptor 2 (HER2), and progesterone receptor (PR), TNBC suffers from poor clinical treatment efficacy, poor prognosis, and high recurrence rates. Currently, conventional chemotherapy remains an important cornerstone of breast cancer treatment. Unfortunately, drug resistance, side effects, and selectivity significantly impact the efficacy of chemotherapeutic agents. To overcome these challenges, biomacromolecules such as tubulin, cyclin-dependent kinases (CDKs), epidermal growth factor (EGF), and Ras are considered attractive targets for anti-tumor drugs. Therefore, the discovery of novel lead anti-breast cancer drug molecules is a critical task and a key development direction.

[0003] Pterostilbene (PTE) is a natural polyphenol found in plants such as rosewood, blueberries, nuts, and grape leaves. Chemically, PTE contains an additional dimethoxy group, making it a homologue of resveratrol. Pharmacologically, PTE exhibits antioxidant, anti-inflammatory, antifungal, and hypoglycemic properties. In recent years, PTE has been widely used in the treatment of various cancer types, including prostate, liver, lung, gastric, and colon cancers. Preliminary mechanistic studies have revealed that PTE can inhibit the growth and proliferation of cancer cells by inducing apoptosis, cell cycle arrest, autophagy, and DNA damage. Notably, PTE has important biological functions in breast cancer. Consequently, several studies have reported the anti-breast cancer activities of PTE and its derivatives. These findings suggest that PTE could serve as an effective lead drug molecule for breast cancer. Summary of the Invention

[0004] This study, based on pterostilbene as the basic skeleton, provides a method for preparing pterostilbene-secondary amine hybrids, aiming to broaden the structural types of pterostilbene derivatives. Furthermore, the antiproliferative activity of the target product against MDA-MB-231 and MCF-7 cells was evaluated, with the goal of identifying novel lead molecules for anti-breast cancer treatment.

[0005] In order to achieve the purpose of the present invention, the technical solutions adopted are as follows:

[0006] The pterostilbene-secondary amine derivatives of the present invention have a structure as shown in general formula (I):

[0007]

[0008] Specifically, R is selected from one of amine substances such as N-methylpiperazine, tetrahydropyrrole, piperidine, morpholine, di-n-propylamine, diisobutylamine, piperazine, N-acetylpiperazine, 1-(2-hydroxyethyl)piperazine, diallylamine, N-phenylpiperazine, 4-piperidinylpiperidine or N-[4-(trifluoromethyl)benzyl]piperazine.

[0009] The chemical structure of pterostilbene-secondary amine derivatives is one of the following:

[0010]

[0011] The pterostilbene-secondary amine derivative of formula (I) of the present invention is prepared by the following route:

[0012]

[0013] Reagents and reaction conditions: Pterostilbene, epoxybromolane, potassium carbonate, acetonitrile, 80°C, 5h. (ii) Secondary amine compounds, anhydrous methanol, 65°C, 8h.

[0014] Preferably, the experimental steps are as follows:

[0015] (i) Pterostilbene and anhydrous potassium carbonate are dissolved in acetonitrile, and epibromopropane is added dropwise with stirring. The mixture is heated in an oil bath and refluxed. After completion of the reaction, the reaction solution is cooled to room temperature. After suction filtration, the filtrate is concentrated and extracted with ethyl acetate. The organic layers are combined and the ethyl acetate is evaporated under reduced pressure. An appropriate amount of diethyl ether is then added to precipitate a white solid, Intermediate 1. This operation is repeated for 2-3 times for recrystallization.

[0016] (ii) Compound 1 was dissolved in anhydrous methanol and stirred at 65°C. An appropriate amount of a secondary amine was added dropwise to the system and stirring was continued for 8 hours. After the reaction of the starting materials was complete, the methanol was removed under reduced pressure, and the mixture was extracted with ethyl acetate. The organic layer was collected, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The mixture was separated and purified by flash column chromatography (dichloromethane and methanol as eluents) to obtain derivatives 2a-2m of formula (I).

[0017] Beneficial effects of the present invention:

[0018] This invention provides novel pterostilbene analogs. Activity screening results show that most derivatives (2a-2c, 2e, 2g, 2i, 2l, and 2m) exhibit strong inhibitory activity against breast cancer cells (MDA-MB-231 and MCF-7). These compounds have the potential to be developed as lead anti-BC drugs. Furthermore, the corresponding synthesis methods for the provided derivative structures are provided, featuring simple reaction steps and high yields. DETAILED DESCRIPTION

[0019] The present invention will be further described in conjunction with the embodiments. The following embodiments are only used to more clearly illustrate the technical solutions of the present invention and are not intended to limit the scope of protection of the present invention.

[0020] Preparation of intermediate 1 and derivatives 2a-2m:

[0021]

[0022] Reagents and reaction conditions: (i) pterostilbene, epibromopropane, potassium carbonate, acetonitrile, 805h; (ii) secondary amine compound, anhydrous methanol, 65℃, 8h

[0023] Example 1

[0024] Intermediate 1:

[0025] To a round-bottom flask, pterostilbene (1000 mg, 3.9 mM), anhydrous potassium carbonate (952.6 mg, 7.8 mM), and acetonitrile solution were added sequentially. The reaction system was stirred at 80°C. An appropriate amount of epibromohydrin (801.6 mg, 5.9 mM) was added dropwise while stirring, and reflux was continued for 5 h. After the reaction was complete as monitored by TLC, the potassium carbonate was removed by filtration, and the filtrate was concentrated. Then, the mixture was extracted with ethyl acetate (3 × 30 mL), the organic layers were combined, washed with distilled water and saturated brine, the EtOAc layer was dried over anhydrous Na2SO4, and concentrated under reduced pressure. An appropriate amount of diethyl ether was added dropwise until a white solid precipitated. Recrystallization was repeated 2-3 times to obtain Intermediate 1.

[0026] (E)-2-((4-(3,5-dimethoxyphenylvinyl)phenoxy)methyl)oxirane (1): yield 50.2%, 1H NMR (300MHz, CDCl3) δ (ppm): 7.43 (d, J = 8.7Hz, 2H), 7.03 (d, J = 16.2Hz, 1H), 6.90 (d, J = 10.6Hz, 2H), 6.89 (d, J = 5.6Hz, 1H), 6.65 (d, J = 2.2Hz, 2H),6.37(t,J=4.5Hz,1H),4.22(dd,J=14.3Hz,1H),3.96(m,1H),3.82(s,6H),2.72(s,2H),3.36(s,1H),2.31(t,J=9.2Hz,1H),2.82(m,2H). 13 C NMR (75MHz, CDCl3) δ (ppm): 161.0, 158.3, 139.6, 130.5, 128.6, 127.8, 126.9, 114.9, 104.4, 99.7, 68.8, 55.4, 50.1, 44.7.

[0027] Example 2

[0028] 2a:

[0029] Intermediate 1 (57.5 mg, 0.18 mM) and N-methylpiperazine (27.66 mg, 0.28 mM) were placed in a 20 mL Shrek tube and dissolved in anhydrous methanol (2 mL). The reaction system was refluxed at 65°C for 8 h. After completion of the reaction, the mixture was cooled to room temperature and extracted with ethyl acetate (3 × 10 mL), washed sequentially with distilled water and saturated brine. The EtOAc layer was dried over anhydrous Na2SO4, and the crude product was eluted by silica gel column chromatography (dichloromethane:methanol = 10:1) and concentrated under reduced pressure to obtain derivative 2a.

[0030] (E)-1-(4-(3,5-dimethoxyphenylvinyl)phenoxy)-3-(4-methylpiperazin-1-yl)propan-2-ol (2a): white solid, yield 56.9%, 1 H NMR (300MHz, CDCl3) δ (ppm): 7.43 (d, J = 8.7Hz, 2H), 7.03 (d, J = 16.2Hz, 1H), 6.90 (d, J = 8.3Hz, 2H), 6.89 (d, J = 8.2Hz, 1H), 6.64 (d, J =2.3Hz,2H),6.37(t,J=4.5Hz,1H),4.09(m,1H),3.99(d,J=5.0Hz,2H),3.82(s,6H),2.72(s,2H),2.61-2.42(m,8H).2.31(s,3H). 13C NMR (75MHz, CDCl3) δ (ppm): 161.0 (2C), 158.5, 139.6, 130.2, 128.6, 127.8 (2C), 126 .7,114.8(2C),104.4(2C),99.7,70.4,65.5,61.1,55.3(2C),54.1(2C),45.9(2C).

[0031] Example 3

[0032] 2b:

[0033] The synthesis method was the same as that of Example 2, except that tetrahydropyrrole was used instead of N-methylpiperazine. The target product 2b was obtained by eluting with silica gel column chromatography (dichloromethane:methanol=10:1).

[0034] (E)-1-(4-(3,5-dimethoxyphenylvinyl)phenoxy)-3-(pyrrolidin-1-yl)propan-2-ol (2b): pale yellow solid, yield 91.3%, 1 H NMR (300MHz, CDCl3) δ (ppm): 7.42 (d, J = 8.7Hz, 2H), 7.02 (d, J = 16.2Hz, 1H), 6.90 (d, J = 8.6Hz, 2H), 6.88 (d, J = 7.9Hz, 1H), 6.6 4(d,J=2.4Hz,2H),6.37(t,J=4.7Hz,1H),4.20-4.10(m,3H),3.81(s,6H),2.92-2.76(m,3H),2.69-2.60(m,3H),1.83(m,4H). 13 C NMR (75MHz, CDCl3) δ (ppm): 161.0 (2C), 158.5, 139.6, 130.2, 128.7, 127.8 (2C), 126 .7,114.8(2C),104.4(2C),99.7,70.5,67.2,58.7,55.3(2C),54.4(2C),23.6(2C).

[0035] Example 4

[0036] 2c:

[0037] The synthesis method was the same as that of Example 2, except that piperidine was used instead of N-methylpiperazine. The target product 2c was obtained by eluting with silica gel column chromatography (dichloromethane:methanol=10:1).

[0038] (E)-1-(4-(3,5-dimethoxyphenylvinyl)phenoxy)-3-(piperidin-1-yl)propan-2-ol (2c): white solid, yield 92.1%, 1 HNMR (400MHz, CDCl3) δ (ppm): 7.42 (d, J = 8.8Hz, 2H), 7.02 (d, J = 16.2Hz, 1H), 6.91 (d, J = 8.8Hz, 2H), 6.90 (d, J = 10.0Hz, 1H), 6.64 (d, J = 2.3Hz, 2H) ,6.37(t,J=4.6Hz,1H),4.09(m,1H),3.98(dd,J=2.5,2.5Hz,2H),3.81( s,6H),2.62(m,2H),2.50(m,2H),2.40(m,2H),1.60(m,4H),1.46(m,2H). 13 C NMR (101MHz, CDCl3) δ (ppm): 161.0 (2C), 158.6, 139.7, 130.2, 128.7, 127.8 (2C), 126.7 ,114.8(2C),104.4(2C),99.7,70.6,65.4,61.2,55.4(2C),54.8(2C),26.0(2C),24.2.

[0039] Example 5

[0040] 2d:

[0041] The synthesis method was the same as that of Example 2, except that morpholine was used instead of N-methylpiperazine. The target product 2d was obtained by eluting with silica gel column chromatography (dichloromethane:methanol=10:1).

[0042] (E)-1-(4-(3,5-dimethoxyphenylvinyl)phenoxy)-3-morpholinopropan-2-ol (2d): white solid, yield 89.7%, 1 H NMR (400MHz, CDCl3) δ (ppm): 7.43 (d, J = 8.8Hz, 2H), 7.03 (d, J = 16.2Hz, 1H), 6.91 (d, J = 8.8Hz, 2H), 6.90 (d, J = 7.6Hz, 1H), 6.64 (d, J = 2.3H z,2H),6.37(t,J=4.4Hz,1H),4.11(m,1H),3.99(d,J=4.1Hz,2H),3.82(s,6H),3.75-3.70(m,4H),2.67(m,2H),2.55(m,2H),2.47(m,2H). 13C NMR (101MHz, CDCl3) δ (ppm): 161.0 (2C), 158.5, 139.6, 130.3, 128.6, 127.8 (2C), 12 6.8,114.8(2C),104.4(2C),99.7,70.3,67.0(2C),65.5,61.1,55.4(2C),53.8(2C).

[0043] Example 6

[0044] 2e:

[0045] The synthesis method was the same as that of Example 2, except that di-n-propylamine was used instead of N-methylpiperazine. The target product 2e was obtained by eluting with silica gel column chromatography (dichloromethane:methanol=10:1).

[0046] (E)-1-(4-(3,5-dimethoxyphenylvinyl)phenoxy)-3-(dipropylamino)propan-2-ol (2e): white solid, yield 79.5%, 1 HNMR (300MHz, CDCl3) δ (ppm): 7.42 (d, J = 8.3Hz, 2H), 7.02 (d, J = 16.2Hz, 1H), 6.92 (d, J = 8.1Hz, 2H), 6.88 (d, J = 16.2Hz, 1H), 6.64 (brs, 2H ),6.36(d,J=2.1Hz,1H),3.99(m,3H),3.81(s,6H),2,57(m,2H),2.54-2.37(m,4H),1.48(tq,J=13.8,6.9Hz,4H),0.89(t,J=7.3Hz,6H). 13 C NMR (75MHz, CDCl3) δ (ppm): 161.0 (2C), 158.7, 139.7, 130.1, 128.7, 127.8 (2C), 126.6, 1 14.8(2C),104.4(2C),99.6,70.6,66.0,57.2,56.3(2C),55.3(2C),20.3(2C),11.8(2C).

[0047] Example 7

[0048] 2f:

[0049] The synthesis method was the same as that of Example 2, except that diisobutylamine was used instead of N-methylpiperazine. The target product 2f was obtained by eluting with silica gel column chromatography (dichloromethane:methanol=10:1).

[0050] (E)-1-(diisobutylamino)-3-(4-(3,5-dimethoxyphenyl)phenoxy)propan-2-ol (2f): white solid, yield 79.5%, 1 H NMR (400MHz, CDCl3) δ (ppm): 7.43 (d, J = 8.8Hz, 2H), 7.03 (d, J = 16.2Hz, 1H), 6.91 (d, J = 8.8Hz, 2H), 6.90 (d, J = 10.1Hz, 1H), 6.64 (d, J = 2.3Hz, 2H), 6. 37(t,J=4.5Hz,1H),4.01(m,3H),3.82(s,6H),2.67-2.44(m,2H),2.23(d ,J=7.1Hz,4H),1.78(m,2H),0.94(d,J=6.5Hz,6H),0.89(d,J=6.7Hz,6H). 13 C NMR (101MHz, CDCl3) δ (ppm): 161.0 (2C), 158.7, 139.7, 130.2, 128.7, 127.8 (2C), 126.7, 114.8 (2C),104.4(2C),99.7,70.5,66.2,64.1(2C),58.6,55.4(2C),26.3(2C),21.1(2C),20.9(2C).

[0051] Example 8

[0052] 2g:

[0053] The synthesis method was the same as that in Example 2, except that piperazine was used instead of N-methylpiperazine. The target product (2 g) was obtained by eluting with silica gel column chromatography (dichloromethane:methanol=10:1).

[0054] (E)-1-(4-(3,5-dimethoxyphenylvinyl)phenoxy)-3-(piperazin-1-yl)propan-2-ol (2 g): white solid, yield 82.8%, 1 H NMR (400MHz, CDCl3) δ (ppm): 7.41 (d, J = 8.9Hz, 2H), 7.01 (d, J = 16.2Hz, 1H), 6.89 (d, J = 8.8Hz, 2H), 6.88 (d, J = 24.2Hz, 1H), 6.63 (d, J =2.2Hz,2H),6.36(t,J=4.5Hz,1H),4.10(m,1H),3.97(brd,J=4.9Hz,2H),3.80(s,6H),2.94(m,4H),2.66(m,2H),2.56-2.44(m,4H). 13C NMR (101MHz, CDCl3) δ (ppm): 161.0 (2C), 158.5, 139.6, 130.2, 128.6, 127.8 (2C), 12 6.7,114.8(2C),104.4(2C),99.7,70.4,65.5,61.1,55.3(2C),54.1(2C),45.9(2C).

[0055] Example 9

[0056] 2h:

[0057] The synthesis method was the same as that of Example 2, except that 1-acylpiperazine was used instead of N-methylpiperazine. The target product 2h was obtained by eluting with silica gel column chromatography (dichloromethane:methanol=10:1).

[0058] (E)-1-(4-(3-(4-(3,5-dimethoxyphenylvinyl)phenoxy)-2-hydroxypropyl)piperazin-1-yl)ethan-1-one (2h): white solid, yield 82.8%, 1 H NMR (400MHz, CDCl3) δ (ppm): 7.43 (d, J = 8.0 Hz, 2H), 7.02 (d, J = 16.0 Hz, 1H), 6. 91(d,J=8.70Hz,2H),6.90(d,J=16.0Hz,1H),6.64(d,J=4.0Hz,2H),6.37(t,J= 8.0Hz,1H),4.12(m,1H),4.01(d,J=8.0Hz,2H),3.81(s,6H),3.64(m,2H),3.47 (m,2H),2.60-2.56(m,2H),2.55-2.50(m,2H),2.49-2.40(m,2H),2.08(s,3H). 13 C NMR (101MHz, CDCl3) δ (ppm): 169.0, 161.0 (2C), 158.4, 139.6, 130.4, 128.6, 127.8 (2C), 126 .8,114.8(2C),104.4(2C),99.7,70.2,65.9,60.5,55.4(2C),53.5,53.0,46.3,41.4,21.3.

[0059] Example 10

[0060] 2i:

[0061] The synthesis method was the same as that of Example 2, except that 1-(2-hydroxyethyl)piperazine was used instead of N-methylpiperazine. The target product 2i was obtained by eluting with silica gel column chromatography (dichloromethane:methanol=10:1).

[0062] (E)-1-(4-(3,5-dimethoxyphenylvinyl)phenoxy)-3-(4-(2-hydroxyethyl)piperazin-1-yl)propan-2-ol (2i): white solid, yield 90.2%, 1 H NMR (400MHz, CDCl3) δ (ppm): 7.42 (d, J = 8.8Hz, 2H), 7.03 (d, J = 16.0Hz, 1H), 6.91 (d, J = 6.8Hz, 2H), 6.90 (d, J = 8.4Hz, 1H), 6.64 (d, J = 2.3Hz ,2H),6.37(t,J=4.5Hz,1H),4.12(m,1H),3.99(d,J=4.8Hz,2H),3.82(s,6H),3.62(brt,J=10.76Hz,2H),2.72(m,2H),2.61-2.50(m,10H). 13 C NMR (101MHz, CDCl3) δ (ppm): 161.0 (2C), 158.5, 139.6, 130.3, 128.7, 127.8 (2C), 126.8, 1 14.8(2C),104.4(2C),99.7,70.4,65.6,60.4,59.3,57.8,55.4(2C),53.3(2C),52.9(2C).

[0063] Example 11

[0064] 2j:

[0065] The synthesis method was the same as that of Example 2, except that diallylamine was used instead of N-methylpiperazine. The target product 2j was obtained by eluting with silica gel column chromatography (dichloromethane:methanol=10:1).

[0066] (E)-1-(Diallylamino)-3-(4-(3,5-dimethoxyphenylvinyl)phenoxy)propan-2-ol (2j): pale yellow solid, yield 55.7%, 1H NMR (400MHz, CDCl3) δ (ppm): 7.42 (d, J = 8.9 Hz, 2H), 7.03 (d, J = 16.1 Hz, 1H), 6.91 (d,J=8.8Hz,2H),6.89(d,J=5.4Hz,1H),6.64(d,J=2.3Hz,2H),6.37(t,J=4.5Hz, 1H),5.87(m,1H),5.82(m,1H),5.23-5.18(m,4H),4.08(m,1H),3.99(d,J=9.6Hz, 2H),3.82(s,6H),3.62(brt,J=15.8Hz,1H),3.3(m,2H),3.1(m,2H),2.65(m,2H). 13 CNMR (75MHz, CDCl3) δ (ppm): 161.0 (2C), 158.5, 139.6, 134.3, 130.1, 128.7, 127.8 (2C), 12 6.7,118.8,114.7(2C),104.3(2C),99.6,70.3,65.9,57.0,55.4(2C),55.3(2C),29.7(2C).

[0067] Example 12

[0068] 2k:

[0069] The synthesis method was the same as that of Example 2, except that N-phenylpiperazine was used instead of N-methylpiperazine. The target product 2k was obtained by eluting with silica gel column chromatography (dichloromethane:methanol=10:1).

[0070] (E)-1-(4-(3,5-dimethoxyphenylvinyl)phenoxy)-3-(4-phenylpiperazin-1-yl)propan-2-ol (2k): pale yellow solid, yield 53.4%, 1 H NMR (400MHz, CDCl3) δ (ppm): 7.42 (d, J = 8.8Hz, 2H), 7.25 (dd, J = 18.7Hz, 2H), 7.02 (d, J = 16.3Hz, 1H), 6.91 (m, 4H), 6.86 (t, J = 13.6Hz, 1H ),6.64(d,J=2.4Hz,2H),6.37(t,J=4.6Hz,1H),4.13(m,1H),4.01(d,J=5.0Hz,2H),3.81(s,6H),3.20(m,4H),2.82(m,2H),2.61(m,4H). 13C NMR (75MHz, CDCl3) δ (ppm): 161.0 (2C), 158.5, 151.2, 139.7, 130.3, 129.2 (2C), 128.7, 127.9 (2C), 12 6.7,120.0,116.2(2C),114.8(2C),104.4(2C)99.6,70.3,65.6,60.5,55.4(2C),55.3(2C),49.3(2C).

[0071] Example 13

[0072] 2l:

[0073] The synthesis method was the same as that of Example 2, except that 4-piperidinylpiperidine was used instead of N-methylpiperazine. The target product 21 was obtained by eluting with silica gel column chromatography (dichloromethane:methanol=10:1).

[0074] (E)-1-([1,4'-bipiperidinyl]-1'-yl)-3-(4-(3,5-dimethoxyphenylvinyl)phenoxy)propan-2-ol (21): pale yellow solid, yield 61.8%, 1 H NMR (400MHz, CDCl3) δ (ppm): 7.42 (d, J = 8.8 Hz, 2H), 7.02 (d, J = 16.3 Hz, 1H), 6.91 (d,J=8.8Hz,2H),6.89(d,J=7.6Hz,1H),6.64(d,J=2.4Hz,1H),6.36(t,J=4.6Hz ,1H),4.07(m,1H),4.01(d,J=4.9Hz,2H),3.81(s,6H),3.05(m,1H),2.92(m,1H) ,2.53(m,6H),2.29(m,2H),1.99(m,1H),1.84(m,2H),1.62(m,6H),1.44(m,2H). 13 C NMR (75MHz, CDCl3) δ (ppm): 161.0 (2C), 158.6, 139.6, 130.0, 128.7, 127.8 (2C), 126.7, 114.8 (2C), 1 04.3(2C),99.6,70.4,65.6,62.6,60.3,55.4(2C),55.0,52.0,50.2(2C)28.0,27.7,25.9(2C),24.5.

[0075] Example 14

[0076] 2m:

[0077] The synthesis method was the same as that in Example 2, except that N-[4-(trifluoromethyl)benzyl]piperazine was used instead of N-methylpiperazine. The target product 2m was obtained by elution through silica gel column chromatography (dichloromethane:methanol=10:1).

[0078] (E)-1-(4-(3,5-dimethoxybenzoyl)phenoxy)-3-(4-(4-(tris(trifluoromethyl)benzyl)piperazin-1-yl)propazin-1-yl) (2m): white solid, yield 83.1%, 1 H NMR (400MHz, CDCl3) δ (ppm): 7.57 (d, J = 8.1Hz, 2H), 7.42 (d, J = 5.4Hz, 2H), 7.42 (d, J = 6.4Hz, 2H), 7.03 (d, J = 16.3Hz, 1H), 6.90 (t, J = 16.2Hz, 3H), 6.65 (d ,J=2.2Hz,2H),6.37(t,J=4.5Hz,1H),4.10(m,1H),3.99(d,J=4.3Hz,2H),3. 82(s,6H),3.55(s,2H),2.64(m,4H),2.53(m,2H),2.51(m,2H),1.26(s,1H). 13 C NMR (101MHz, CDCl3) δ (ppm): 161.0 (2C), 158.5, 142.4, 139.6, 130.2, 129.5 (2C), 128.6, 127.8 (2C), 125.6, 12 5.2,125.2,125.2,125.2,122.9,114.8(2C),104.3(2C),99.6,70.3,65.5,62.3,60.4,55.3(2C),53.1,29.7. 19 F NMR (376MHz, CDCl3) δ (ppm): -62.30.

[0079] The products obtained in Examples 1-14 were tested for their anti-breast cancer activity

[0080] Test Example 1

[0081] Anti-breast cancer activity experiment

[0082] 1. Experimental principle:

[0083] Under the action of the electron carrier 1-methoxy-5-methylphenazinium dimethyl sulfate (1-Methoxy PMS), 2-(2-methoxy-4-nitrophenyl)-3-(4-nitrophenyl)-5-(2,4-disulfonic acid benzene)-2H-tetrazole monosodium salt (WST-8) can be reduced by dehydrogenases in the mitochondria of living cells to a highly water-soluble orange-red formazan product. This product has a significant absorbance at a wavelength of 450nm, and the absorbance is positively correlated with the number of living cells, that is, the higher the absorbance value, the more living cells there are. Therefore, the absorbance value can be detected by a microplate reader, and then the IC value of the drug can be calculated using software. 50 value.

[0084] 2. Experimental methods:

[0085] The human breast cancer cell lines (MDA-MB-231 and MCF-7) involved in the present invention were purchased from the cell bank of Shanghai Institute of Cell Biology, Chinese Academy of Sciences, and were passaged and preserved in this laboratory.

[0086] Breast cancer cells MDA-MB-231 and MCF-7 were cultured in DMEM supplemented with 10% fetal bovine serum, 1% L-glutamine, and 100 U / mL penicillin / streptomycin in a 37°C incubator with 5% CO2. Anti-breast cancer activity screening was performed as follows:

[0087] (1) MDA-MB-231 and MCF-7 cells in the logarithmic growth phase were cultured at a rate of 3-5×10 cells per well. 3 Cells were seeded at a density of 100 μL / well in a 96-well plate, and 100 μL of cell suspension was added to each well. The plates were then incubated overnight in an incubator. (2) Drugs were prepared using DMSO solution to achieve final concentrations of 1, 3, 10, 30, and 100 μM. After the cells adhered, drugs were added sequentially according to a concentration gradient. Three replicates were set for each concentration, and an equal volume of DMSO was added as a blank control.

[0088] (3) Incubate in a 5% CO2, 37°C incubator for 48 h, and then add 10 μL of CCK-8 reagent to each well.

[0089] (4) After 2 h of pretreatment, the OD value at a wavelength of 450 nm was detected by an enzyme-labeled instrument. The IC value of the compound was calculated using SPSS 13.0 software according to formula (1). 50 value.

[0090] Cell proliferation inhibition rate (%) = [OD 450 (Blank control group)-OD 450 (drug group)] / OD 450 (blank control group) × 100% formula (1)

[0091] 3. Experimental results:

[0092] Most of the compounds (1, 2a-2c, 2e, 2g-2j, 2l and 2m) prepared in the present invention have an inhibitory effect on two breast cancer cell lines MDA-MB-231 (IC 50 =7.92-113.05 μM) and MCF-7 (IC 50 =7.84-107.20 μM) showed different degrees of inhibitory effects, and the results are shown in Table 1.

[0093] Table 1 Growth inhibitory activity of some compounds on MAD-MB-231 and MCF-7 cells

[0094]

[0095] 4. Experimental summary:

[0096] According to IC 50 The data showed that compared with the prototype drug PTE, derivatives 2c, 2l and 2m had good anti-proliferative ability against MDA-MB-231 and MCF-7, with IC 50 The values ​​were between 7.92-9.75μM and 7.84-11.34μM, respectively. In addition, preliminary structure-activity relationships showed that: (1) the introduction of secondary amine compounds containing saturated linear alkanes at the side chain end is beneficial to improving their anti-BC ability (2evs.1, 2f, 2j, PTE); (2) the introduction of piperidine at the side chain end will significantly enhance the inhibitory efficacy of the derivatives against breast cancer cells (2c, 2l vs. 1, 2a, 2b, 2d-2k, 2m, PTE); (3) the substitution of electron-donating groups on the piperazine ring helps to maintain or improve the anti-BC activity (2a, 2i, 2m vs. 1, 2h, 2k, PTE; 2a, 2i, 2m vs. 2g, PTE). This provides a valuable reference for subsequent studies on the derivatization of pterostilbene. Therefore, the pterostilbene derivatives described in the present invention can be used to prepare drugs for the treatment or prevention of breast cancer.

Claims

1. Use of a pterostilbene-secondary amine derivative in the preparation of an anti-breast cancer drug, characterized in that: The chemical structure of pterostilbene-secondary amine derivatives is one of the following: ； 。 2. The use according to claim 1, characterized in that: Application of the pterostilbene-secondary amine derivatives in the preparation of drugs against triple-negative breast cancer.

3. The use according to claim 1, characterized in that: The pterostilbene-secondary amine derivatives are used in preparing drugs for treating breast cancer cells MDA-MB-231.

4. The use according to claim 1, characterized in that: The pterostilbene-secondary amine derivatives are used in preparing drugs for treating breast cancer cells MCF-7.

Images