Boron-functionalized berberine derivative, preparation method thereof and application of boron-functionalized berberine derivative in preparation of anti-breast cancer drugs

Abstract

The invention discloses a boron-functionalized berberine derivative, a preparation method thereof and application of the boron-functionalized berberine derivative in preparation of anti-breast cancer drugs, and belongs to the technical field of medicinal chemistry and medicine. The structure of the boron-functionalized berberine derivative is shown as a general formula (I), and the boron-functionalized berberine derivative is obtained by connecting an aromatic or heterocyclic segment containing a boric acid (or boric acid ester) group to the ninth site of a berberine parent nucleus through an ether bond, an ester bond or an amido bond. In-vitro activity tests show that the boron-functionalized berberine derivative has good proliferation inhibition activity on triple negative breast cancer (MDA-MB-468) and estrogen receptor positive breast cancer (MCF-7) cells, the selectivity index (SI) is higher than that of parent berberine and a control drug 5-fluorouracil, and a wider treatment window is shown. The boron functionalized berberine derivative has the advantages of novel structure, good activity and high selectivity, and can be used for preparing high-efficiency and low-toxicity anti-breast cancer drugs.

Description

Technical Field

[0001] This invention relates to the fields of medicinal chemistry and pharmaceutical technology, specifically to a boron-functionalized berberine derivative, its preparation method, and its use in the preparation of anti-breast cancer drugs. Background Technology

[0002] Natural products and their structural analogs have always been an important source for anticancer drug development. Berberine, also known as berberine alkaloid, is an isoquinoline alkaloid isolated from medicinal plants such as Coptis chinensis. As a basic drug for treating bacterial gastrointestinal infections, it has been applied clinically and is included in the National Essential Medicines List, providing a good clinical safety basis for its use as a lead compound. In recent years, research has continuously revealed new pharmacological effects of berberine in metabolic diseases, neurodegenerative diseases, and tumors. Particularly in breast cancer research, berberine has been shown to inhibit cancer cell proliferation, invasion, and metastasis, indicating that it is an ideal pharmacologically active framework for anti-breast cancer. Nevertheless, berberine still has some limitations, such as: 1) insufficient killing efficacy against cancer cells; 2) poor selectivity for normal cells, leading to potentially high toxicity; and 3) less than ideal pharmacokinetic properties. These factors limit its direct clinical translation into antitumor applications.

[0003] Boric acid groups, as important pharmacophores, have attracted much attention in drug design. This structure can exert antitumor effects by forming reversible covalent bonds with threonine residues at the active site of serine proteases, inhibiting proteasome activity. This effect has been verified in marketed drugs such as bortezomib. Therefore, introducing boric acid groups into other pharmacophores to endow them with new mechanisms of action or improve their properties is a reasonable drug design strategy.

[0004] Currently, there are no reports on obtaining berberine derivatives with both good antitumor activity and selectivity by linking an aromatic or heterocyclic fragment containing boric acid (or borate ester) to the 9 position of the berberine core via ether, ester, or amide bonds. Summary of the Invention

[0005] To address the shortcomings of existing technologies, particularly the limitations of natural berberine compounds in antitumor activity and selectivity, this invention aims to provide a class of novel, highly active, and highly selective boron-functionalized berberine derivatives for tumor cells, offering valuable lead compounds for the development of breast cancer therapeutics. Furthermore, this invention also provides an efficient and universal synthetic method for these compounds.

[0006] This invention provides a class of boron-functionalized berberine derivatives represented by general formula (I).

[0007] Where X is selected from O (oxygen atom) or NH (imino), Y is selected from CH2 (methylene) or O=C (carbonyl), and Z is selected from Br - (bromine anion) or Cl - (Chloride anion); [B] is selected from -B(OH)2 (boronic acid group), or a cyclic borate ester group protected by a diol (such as pinacol); Ar is selected from substituted or unsubstituted phenyl or five-membered heteroaryl; the R-substituted group is selected from halogen, nitro or alkoxy.

[0008] Preferably, the [B] is attached to the ortho, meta, or para position of the phenyl group.

[0009] The present invention also provides a method for preparing the boron-functionalized berberine derivative, the key of which is: using commercially available berberine and its 9-position demethylated product (berberine red) as starting materials, and carrying out nucleophilic substitution or condensation reactions with haloalkanes (for forming ether bonds), carboxylic acids (for forming ester bonds), or acyl chlorides (for forming amide bonds) containing boric acid or borate ester groups under alkaline conditions, and obtaining the target product after separation and purification.

[0010] The specific structure is shown below: Structure of boron-functionalized berberine derivatives (spectral data are shown in the examples). .

[0011] The specific synthesis route is shown below: The synthetic routes for compounds 3a-c and 4a-c are shown below: .

[0012] The synthetic route for compound 5a-j is shown below: .

[0013] The synthetic route for compounds 8a-b is shown below: .

[0014] The present invention further provides the application of the boron-functionalized berberine derivative in the preparation of anti-breast cancer drugs.

[0015] Preferably, the breast cancer includes triple-negative breast cancer (TNBC) and estrogen receptor-positive (ER+) breast cancer.

[0016] The in vitro antitumor activity assay was conducted using the MTT assay to evaluate the inhibitory activity and selectivity of the boron-functionalized berberine derivatives of this invention on the proliferation of TNBC cell lines (MDA-MB-468, Hs578T), ER+ breast cancer cell line (MCF-7), human glioma cells (U251), and normal human embryonic kidney cells (HEK-293).

[0017] Experimental results show that the boron-functionalized berberine derivatives of this invention exhibit a selective inhibitory effect on breast cancer cell lines. Specifically, their toxicity to U251 cells is lower than that to breast cancer cells, demonstrating good selectivity. Meanwhile, their toxicity to HEK-293 cells is generally lower than that of berberine and the control drug 5-fluorouracil. Among the boron-functionalized berberine derivatives, compounds 5d and 4c exhibit the best activity. Compound 5d shows the most prominent activity, with a half-maximal inhibitory concentration (IC50) against MDA-MB-468 cells. 50 As low as 4.2 m Compound M, and with a selectivity index (SI) of 2.5 for MDA-MB-468 cells, indicates that its cytotoxicity against cancer cells is 2.5 times that against normal cells, a value superior to berberine (SI = 0.58) and the control drug 5-fluorouracil (SI = 0.24). Compound 4c also exhibited good activity and selectivity, with an IC50 of 2.5 against MCF-7 cells. 50 The value is 16.7 m M, SI was 1.02, which was superior to berberine (SI = 0.06) and the control drug 5-fluorouracil (SI = 0.23). The experimental results are shown in Table 1.

[0018] Table 1. IC50 of boronized berberine derivatives against various breast cancer cell lines and normal cell lines 50 Value and selectivity index

[0019] a SI1 = IC 50 (HEK-293) / IC 50 (MDA-MB-468); b SI2 = IC 50 (HEK-293) / IC 50 (MCF-7)

[0020] Compared with the prior art, the beneficial effects of the present invention are as follows: (1) For the first time, a boric acid (ester) pharmacophore was introduced into berberine at position 9 through multiple linking arms, creating a new type of borated berberine hybrid molecule.

[0021] (2) In vitro antitumor activity experiments showed that the anti-breast cancer cell activity of several compounds of the present invention was superior to or equivalent to that of parent berberine and control drugs. For example, compound 5d showed an effect on the IC50 of MDA-MB-468 cells. 50 It is 4.2 m M, superior to 5-fluorouracil and comparable to berberine; compound 4c showed IC50 activity in MCF-7 cells.50 It is 16.7 m M is superior to berberine and comparable to 5-fluorouracil.

[0022] (3) Several compounds of the present invention (such as 5d, 4c, 8b, 5f) have higher selectivity indices for cancer cells and normal cells than berberine and 5-fluorouracil, indicating lower toxicity and a wider therapeutic window. Detailed Implementation

[0023] The present invention will be further described below with reference to embodiments, but these are not intended to limit the scope of the invention.

[0024] In addition, it should be noted that the compounds in the specification are all boron-functionalized berberine derivatives with different structures.

[0025] Example 1: Synthesis of compound 3a-c (9-O-(benzyl borate)berberine)

[0026] Berberine 2 (see structural formula 2 in the synthetic routes of compounds 3a-c and 4a-c) (0.5 mmol, 1.0 equivalent) and benzyl bromide borate (0.55 mmol, 1.1 equivalent) were dissolved in acetonitrile (25 mL). Anhydrous potassium carbonate (1.0 mmol, 2.0 equivalent) was added, and the mixture was stirred at room temperature for 12 hours. The solvent was then removed by concentration under reduced pressure. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol, 15:1 to 10:1, v / v) to give the yellow solid product 3a-c.

[0027] Compound 3a, yield 40%, mp 263-264 °C. 1 H NMR (400 MHz, DMSO- d 6 ) d : 9.73 (s,1H), 8.93 (s, 1H),8.20 (d, J = 9.2 Hz, 1H), 8.08 (s, 2H), 8.00 (d, J = 9.2 Hz, 1H), 7.81 (d, J = 8.0 Hz, 2H),7.77 (s, 1H), 7.55 (d, J = 8.4 Hz, 2H), 7.08 (s,1H), 6.17 (s, 2H), 5.36 (s, 2H), 4.91 (t, J = 6.4 Hz, 2H), 4.07 (s, 3H), 3.19(t, J= 6.4 Hz, 2H). 13 C NMR (100 MHz, DMSO- d 6 ) d : 151.2, 150.4, 148.2, 145.9,142.5, 138.7, 137.9, 134.7, 133.4, 131.2, 128.2, 127.0, 124.3, 122.3, 120.9,120.7, 109.0, 106.0, 102.6, 75.8, 57.6, 55.9, 26.9. HRMS (ESI): m / z calcd for[C 26 H 23 BNO6] + 456.1613, found 456.1618.

[0028] Compound 3b, yield 39%, mp 258-259 °C. 1 H NMR (400 MHz, DMSO- d 6 ) d : 9.71 (s,1H), 8.92 (s, 1H), 8.20 (d, J = 9.2 Hz, 1H),8.08 (s, 2H), 8.01-7.99 (m, 2H),7.77-7.75 (m, 2H), 7.61 (d, J = 7.6 Hz, 1H), 7.35 (t, J = 7.6 Hz, 1H), 7.08(s, 1H), 6.17 (s, 2H), 5.36 (s, 2H), 4.90 (t, J = 6.4 Hz, 2H), 4.09 (s, 3H), 3.20-3.17 (m, 2H). 13 C NMR (100 MHz, DMSO- d 6 ) d: 151.3, 150.4, 148.2, 145.9,142.6, 137.8, 135.8, 135.3, 134.7, 133.4, 131.7, 128.0, 127.0, 124.3, 122.4,120.9, 120.7, 109.0, 106.0, 102.6, 76.2, 57.6, 55.9, 26.9. HRMS (ESI): m / z calcd for [C 26 H 23 BNO6] + 456.1613, found 456.1618.

[0029] Compound 3c, yield 54%, mp 215-216 °C. 1 H NMR (400 MHz, DMSO- d 6 ) d : 9.57 (s,1H), 8.92 (s, 1H), 8.26 (s, 2H), 8.16 (d, J = 9.2 Hz, 1H), 7.96 (d, J = 9.2Hz, 1H), 7.75 (s, 1H), 7.61-7.57 (m, 2H), 7.40 (t, J = 7.6 Hz, 1H), 7.33 (t, J = 7.6 Hz, 1H), 7.07 (s, 1H), 6.16 (s, 2H), 5.55 (s, 2H), 4.84 (t, J = 6.4Hz, 2H), 4.07 (s, 3H), 3.20 (t, J = 6.4 Hz, 2H). 13 C NMR (100 MHz, DMSO- d 6 ) d:150.9, 150.2, 148.1, 145.7, 142.7, 140.5, 137.7, 134.2, 133.4, 131.0, 129.5,129.5, 127.9, 127.1, 123.8, 122.1, 120.8, 120.6, 108.9, 105.8, 102.6, 76.0,57.5, 56.0, 26.8. HRMS (ESI): m / z calcd for [C 26 H 23 BNO6] + 456.1613, found456.1614.

[0030] Example 2: Synthesis of compound 4a-c (9-O-(boronate benzyl)berberine)

[0031] Compound 3 (see structural formula 3 in the synthetic routes of compounds 3a-c and 4a-c) (0.1 mmol, 1.0 equivalent) and pinacol (1.0 mmol, 10.0 equivalent) were dissolved in N,N-dimethylformamide (2 mL). Anhydrous sodium sulfate (0.3 mmol, 3.0 equivalent) was added, and the mixture was stirred at room temperature for 9 hours. The solvent was then removed by concentration under reduced pressure. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol, 20:1, v / v) to give the yellow solid product 4a-c.

[0032] Compound 4a, yield 55%, mp 222-223 °C. 1 H NMR (400 MHz, DMSO- d 6 ) d : 9.74 (s,1H), 8.92 (s, 1H), 8.20 (d, J = 9.2 Hz, 1H), 8.00 (d, J = 9.2 Hz, 1H), 7.78(s, 1H), 7.69 (d, J = 7.2 Hz, 2H), 7.59 (d, J = 7.6 Hz, 2H), 7.09 (s, 1H), 6.17 (s, 2H), 5.39 (s, 2H), 4.91 (t, J = 6.0 Hz, 2H), 4.07 (s, 3H), 3.19 (t, J= 6.0 Hz, 2H). 1.28 (s, 12H). 13 C NMR (100 MHz, DMSO- d 6 ) d : 151.1, 150.4,148.2, 145.8, 142.4, 140.3, 137.9, 135.0, 133.4, 131.2, 128.5, 127.1, 124.3,122.3, 120.9, 120.7, 109.0, 106.0, 102.6, 84.3, 75.6, 57.6, 55.9, 26.9, 25.2. HRMS (ESI): m / z calcd for [C 32 H 33 BNO6] + 538.2395, found 538.2401.

[0033] Compound 4b, yield 51%, mp 227-228 °C. 1 H NMR (400 MHz, DMSO- d 6 ) d : 9.75 (s,1H), 8.95 (s, 1H), 8.22 (d, J = 9.2 Hz, 1H), 8.03 (d, J = 9.2 Hz, 1H), 7.87(s, 1H), 7.79 (s, 1H), 7.75 (d, J = 7.6 Hz, 1H), 7.66 (d, J = 7.2 Hz, 1H), 7.45 (t, J = 7.6 Hz, 1H), 7.09 (s, 1H), 6.18 (s, 2H), 5.34 (s, 2H), 4.91 (t, J = 6.4 Hz, 2H), 4.08 (s, 3H), 3.20 (t, J = 6.4 Hz, 2H). 1.29 (s, 12H). 13 C NMR (100 MHz, DMSO-) d 6 ) d: 151.4, 150.4, 148.2, 145.9, 142.7, 137.9, 136.6, 135.3,134.9, 133.4, 132.4, 131.2, 128.6, 127.0, 124.4, 122.4, 120.9, 120.8, 109.0,106.0, 102.6, 84.3, 76.1, 57.5, 55.9, 26.9, 25.2. HRMS (ESI): m / z calcd for[C 32 H 33 BNO6] + 538.2395, found 538.2402.

[0034] Compound 4c, yield 46%, mp 239-240 °C. 1 H NMR (400 MHz, DMSO- d 6 ) d : 9.52 (s,1H), 8.95 (s, 1H), 8.23 ​​(d, J = 9.2 Hz, 1H), 8.02 (d, J = 9.2 Hz, 1H), 7.79(s, 1H), 7.76-7.72 (m, 2H), 7.56 (t, J = 7.6 Hz, 1H), 7.38 (t, J = 7.6 Hz,1H), 7.08 (s, 1H), 6.17 (s, 2H), 5.62 (s, 2H), 4.83 (t, J = 6.8 Hz, 2H), 4.03(s, 3H), 3.16 (t, J = 6.4 Hz, 2H). 1.19 (s, 12H). 13 C NMR (100 MHz, DMSO- d 6 ) d:150.9, 150.3, 148.2, 145.7, 143.2, 142.9, 137.9, 135.9, 133.5, 131.7, 131.1,129.1, 127.9, 127.4, 124.0, 122.1, 120.8, 120.7, 108.9, 105.9, 102.6, 84.1,75.4, 57.7, 55.9, 26.8, 25.0. HRMS (ESI): m / z calcd for [C 32 H 33 BNO6] + 538.2395, found 538.2400.

[0035] Example 3: Synthesis of compound 5a-j (9-O-(substituted benzoyl borate)berberine)

[0036] Berberine 2 (see structural formula 2 in the synthetic route of compounds 5a-j) (0.5 mmol, 1.0 equivalent) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (0.75 mmol, 1.5 equivalent) were dissolved in acetonitrile (25 mL). Benzoic acid substituted borate (0.75 mmol, 1.5 equivalent) and 4-dimethylaminopyridine (0.075 mmol, 0.15 equivalent) were added sequentially. The reaction mixture was heated to 80°C and stirred under reflux for 14 hours. After cooling, the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol, 20:1 to 10:1, v / v) to give yellow solid products 5a-5j.

[0037] Compound 5a, yield 45%, mp 269-270 °C. 1 H NMR (400 MHz, DMSO- d 6 ) d : 10.01 (s,1H), 9.17 (s, 1H), 8.44 (s, 2H), 8.35 (d, J = 9.2 Hz, 1H), 8.30 (d, J = 9.2Hz, 1H), 8.21 (d, J = 7.6 Hz, 2H), 8.08 (d, J = 7.6 Hz, 2H), 7.85 (s, 1H), 7.08 (s, 1H), 6.18 (s, 2H), 4.92 (t, J= 6.4 Hz, 2H), 4.02 (s, 3H), 3.20 (t, J = 6.4 Hz, 2H). 13 C NMR (100 MHz, DMSO- d 6 ) d : 164.1, 151.0, 150.5, 148.2,145.1, 138.7, 135.1, 134.1, 133.5, 131.4, 129.7, 129.6, 127.8, 126.4, 121.8,121.3, 120.9, 109.0, 106.2, 102.7, 57.8, 55.8, 26.7. HRMS (ESI): m / z calcd for[C 26 H 21 BNO7] + 470.1406, found 470.1409.

[0038] Compound 5b, yield 35%, mp 232-233 °C. 1 H NMR (400 MHz, DMSO- d 6 ) d : 10.02 (s,1H), 9.13 (s, 1H), 8.63 (s, 2H), 8.39 (d, J = 7.6 Hz, 1H), 8.34 (d, J = 8.8Hz, 1H), 8.28 (d, J = 9.2 Hz, 1H), 8.07 (s, 1H), 8.01 (d, J = 8.0 Hz, 1H),7.82 (s, 1H), 7.08 (s, 1H), 6.18 (s, 2H), 4.95 (t, J = 6.0 Hz, 2H), 4.05 (s, 3H), 3.21 (t, J = 6.4 Hz, 2H). 13 C NMR (100 MHz, DMSO- d 6 ) d: 162.1, 150.7,150.5, 148.2, 144.9, 138.6, 137.0, 133.7, 133.6, 133.5, 133.3, 132.5, 131.3,128.4, 127.6, 126.3, 121.5, 121.2, 120.8, 108.9, 106.0, 102.6, 57.8, 55.8,26.6. HRMS (ESI): m / z calcd for [C 26 H 20 BClNO7] + 504.1016, found 504.1019.

[0039] Compound 5c, yield 44%, mp 226-227 °C. 1 H NMR (400 MHz, DMSO- d 6 ) d : 9.86 (s,1H), 9.09 (s, 1H), 8.48 (s, 2H), 8.32 (d, J = 9.2 Hz, 1H), 8.25 (d, J = 9.2Hz, 1H), 8.12 (d, J = 7.6 Hz, 1H), 7.82 (s, 1H), 7.73 (s, 1H), 7.57 (d, J =7.6 Hz, 1H), 7.08 (s, 1H), 6.17 (s, 2H), 4.93 (t, J = 6.4 Hz, 2H), 4.03 (s, 3H), 3.94 (s, 3H), 3.20 (t, J = 6.4 Hz, 2H). 13 C NMR (100 MHz, DMSO- d 6 ) d:162.5, 159.7, 151.1, 150.5, 148.2, 145.0, 138.6, 134.3, 133.5, 131.9, 131.4,127.3, 126.5, 126.3, 121.8, 121.2, 120.9, 118.6, 118.5, 109.0, 106.1, 102.7, 57.8, 56.5, 55.9, 26.7. HRMS (ESI): m / z calcd for [C 27 H 23 BNO8] + 500.1511, found 500.1519.

[0040] Compound 5d, yield 49%, mp 207-208 °C. 1 H NMR (400 MHz, DMSO- d 6 ) d : 9.91 (s,1H), 9.12 (s, 1H), 8.83 (s, 2H), 8.44 (s, 1H), 8.40 (d, J = 7.6 Hz, 1H),8.37-8.34 (m, 2H), 8.29 (d, J = 9.2 Hz, 1H), 7.83 (s, 1H), 7.10 (s, 1H), 6.18(s, 2H), 4.94 (t, J = 6.4 Hz, 2H), 4.10 (s, 3H), 3.22 (t, J = 6.4 Hz, 2H). 13 CNMR (100 MHz, DMSO- d 6 ) d : 161.8, 151.0, 150.6, 148.8, 148.3, 144.5, 139.0,138.9, 133.6, 132.9, 131.5, 131.0, 129.4, 128.1, 126.6, 124.5, 121.3, 120.8,109.0, 106.1, 102.7, 58.0, 56.1, 26.7. HRMS (ESI): m / z calcd for [C 26 H 20BN2O9] + 515.1256, found 515.1260.

[0041] Compound 5e, yield 46%, mp 282-283 °C. 1 H NMR (400 MHz, DMSO- d 6 ) d : 10.04 (s,1H), 9.10 (s, 1H), 8.68 (s, 2H), 8.34 (d, J = 9.2 Hz, 1H), 8.28 (d, J = 9.6Hz, 1H), 8.16 (s, 1H), 8.12 (d, J = 7.6 Hz, 1H), 7.83 (s, 1H), 7.73 (d, J =6.4 Hz, 1H), 7.09 (s, 1H), 6.18 (s, 2H), 4.91 (t, J = 6.4 Hz, 2H), 4.03 (s, 3H), 3.20 (t, J = 6.4 Hz, 2H). 13 C NMR (100 MHz, DMSO-) d 6 ) d : 163.0, 150.8,150.5, 148.3, 145.1, 138.7, 137.0, 134.8, 133.9, 133.5, 131.4, 130.0, 128.3,127.7, 126.4, 121.6, 121.2, 120.9, 109.0, 106.1, 102.7, 57.9, 55.8, 26.7. HRMS (ESI): m / z calcd for [C 26 H 20 BClNO7] + 504.1016, found 504.1021.

[0042] Compound 5f, yield 67%, mp 259-260 °C. 1 H NMR (400 MHz, DMSO- d 6 ) d: 10.08 (s,1H), 9.09 (s, 1H), 8.89 (s, 1H), 8.57 (s, 2H), 8.34 (d, J = 9.2 Hz, 1H), 8.27(d, J = 9.6 Hz, 1H), 8.13 (d, J = 8.0 Hz, 1H), 7.82 (s, 1H), 7.72 (d, J = 8.0Hz, 1H), 7.08 (s, 1H), 6.18 (s, 2H), 4.96 (t, J = 6.8 Hz, 2H), 4.06 (s, 3H),3.21 (t, J = 6.4 Hz, 2H). 13 C NMR (100 MHz, DMSO- d 6 ) d : 162.2, 150.8, 150.5,148.3, 145.0, 140.8, 139.4, 138.7, 136.4, 133.9, 133.5, 131.4, 131.3, 127.6,126.5, 126.4, 121.6, 121.2, 120.9, 109.0, 106.1, 102.7, 57.9, 55.8, 26.7. HRMS(ESI): m / z calcd for [C 26 H 20 BClNO7] + 504.1016, found 504.1018。

[0043] Compound 5g, yield 54%, mp 250 - 251 °C。 1 H NMR (400 MHz, DMSO- d 6 ) d : 9.91 (s,1H), 9.09 (s, 1H), 8.69 (s, 1H), 8.33 (d, J = 9.2 Hz, 1H), 8.26 - 8.23 (m, 3H),8.16 (d, J = 8.4 Hz, 1H), 7.82 (s, 1H), 7.29 (d, J= 8.4 Hz, 1H), 7.09 (s,1H), 6.18 (s, 2H), 4.95 (t, J = 6.4 Hz, 2H), 4.03 (s, 3H), 3.94 (s, 3H), 3.20(t, J = 6.4 Hz, 2H). 13 C NMR (100 MHz, DMSO-) d 6 ) d : 162.4, 162.1, 151.0, 150.4,148.2, 145.0, 142.1, 139.6, 138.5, 134.4, 133.5, 131.3, 127.1, 126.4, 121.8,121.1, 120.8, 116.4, 112.4, 108.9, 106.0, 102.6, 57.7, 56.5, 55.8, 26.7. HRMS(ESI): m / z calcd for [C 27 H 23 BNO8] + 500.1511, found 500.1514.

[0044] Compound was tested for 5 hours, yield 33%, mp 271-272 °C. 1 H NMR (400 MHz, DMSO- d 6 ) d : 10.02 (s,1H), 9.09 (s, 1H), 8.64 (s, 2H), 8.34-8.32 (m, 2H), 8.27 (d, J = 9.2 Hz, 1H), 8.19 (d, J = 8.4 Hz, 1H), 7.81 (s, 1H), 7.69 (d, J = 8.4 Hz, 1H), 7.08 (s,1H), 6.17 (s, 2H), 4.92 (t, J = 6.4 Hz, 2H), 4.02 (s, 3H), 3.20 (t, J = 6.4Hz, 2H). 13 C NMR (100 MHz, DMSO-d 6 ) d : 163.4, 150.8, 150.4, 148.2, 145.0,143.3, 138.6, 136.5, 133.9, 133.4, 132.6, 131.3, 129.8, 127.5, 126.3, 126.2,121.6, 121.1, 120.8, 108.9, 106.0, 102.6, 57.8, 55.7, 26.6. HRMS (ESI): m / z calcd for [C 26 H 20 BClNO7] + 504.1016, found 504.1022.

[0045] Compound 5i, yield 68%, mp 259-260 °C. 1 H NMR (400 MHz, DMSO- d 6 ) d : 9.96 (s,1H), 9.09 (s, 1H), 8.45 (s, 1H), 8.32-8.24 (m, 3H), 8.02 (s, 2H), 7.81 (s,1H), 7.24 (d, J = 8.8 Hz, 1H), 7.07 (s, 1H), 6.17 (s, 2H), 4.93 (t, J = 6.4Hz, 2H), 4.01 (s, 3H), 3.95 (s, 3H), 3.19 (t, J = 6.4 Hz, 2H). 13 C NMR (100MHz, DMSO- d 6 ) d : 168.6, 163.8, 151.0, 150.5, 148.2, 145.0, 138.6, 138.5,135.2, 134.4, 133.5, 131.4, 127.3, 12 6.3, 121.9, 121.2, 120.9, 120.0, 111.3,108.9, 106.1, 102.7, 57.8, 55.8, 26.7. HRMS (ESI): m / zcalcd for [C 27 H 23 BNO8] + 500.1511, found 500.1515.

[0046] Compound 5j, yield 20%, mp 232-233 ℃. 1 H NMR (400 MHz, DMSO- d 6 ) d : 9.97 (s,1H), 9.09 (s, 1H), 8.76 (s, 2H), 8.32 (d, J = 9.2 Hz, 1H), 8.26 (d, J = 9.2Hz, 1H), 8.16 (s, 1H), 7.90 (s, 1H), 7.81 (s, 1H), 7.08 (s, 1H), 6.17 (s,2H), 4.92 (t, J = 6.4 Hz, 2H), 4.03 (s, 3H), 3.20 (t, J = 6.4 Hz, 2H). 13 C NMR (100 MHz, DMSO-) d 6 ) d : 159.4, 151.1, 150.5, 148.2, 144.9, 138.7, 137.1, 137.0,135.4, 133.6, 133.5, 131.4, 127.7, 126.4, 121.8, 121.2, 120.9, 108.9, 106.1,102.7, 57.9, 55.8, 26.7. HRMS (ESI): m / z calcd for [C 24 H 19 BNO7S] + 476.0970, found 476.0976.

[0047] Example 4: Synthesis of compound 8a-b (9-N-(benzoyl borate)berberine)

[0048] Compound 7 (see structural formula 7 in the synthetic route of compounds 8a-b) (0.5 mmol, 1.0 equivalent) and benzoyl borate chloride (0.75 mmol, 1.5 equivalent) were dissolved in acetonitrile (25 mL). Pyridine (0.75 mmol, 1.5 equivalent) was added, and the reaction mixture was heated to 80°C and stirred under reflux for 12 hours. After cooling, the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol, 20:1, v / v) to give yellow solid products 8a-8b.

[0049] Compound 8a, yield 31%, mp 275-276 °C. 1 H NMR (400 MHz, DMSO- d 6 ) d : 10.56 (s,1H), 9.78 (s, 1H), 9.04 (s, 1H), 8.31 (s, 2H), 8.25 (s, 2H), 8.12 (d, J = 7.6Hz, 2H), 7.98 (d, J = 7.6 Hz, 2H), 7.81 (s, 1H), 7.08 (s, 1H), 6.17 (s, 2H), 4.96 (t, J = 6.0 Hz, 2H), 4.01 (s, 3H), 3.21-3.16 (m, 2H). 13 C NMR (100 MHz, DMSO- d 6 ) d : 166.9, 155.4, 150.4, 148.2, 144.6, 138.0, 135.3, 134.5, 133.8,131.2, 128.3, 127.7, 125.8, 124.9, 122.5, 121.3, 121.0, 108.9, 106.1, 102.6,57.5, 55.7, 26.8. HRMS (ESI): m / z calcd for [C 26 H 22 BN2O6] + 469.1565, found469.1571.

[0050] Compound 8b, yield 40%, mp 268-269 °C. 1 H NMR (400 MHz, DMSO-d 6 ) d : 10.58 (s,1H), 9.80 (s, 1H), 9.01 (s, 1H), 8.67 (s, 1H), 8.29 (s, 2H), 8.21 (s, 3H),8.06 (d, J = 7.6 Hz, 1H), 7.77 (s, 1H), 7.55 (t, J = 7.6 Hz, 1H), 7.07 (s,1H), 6.14 (s, 2H), 4.96 (t, J = 6.8 Hz, 2H), 3.98 (s, 3H), 3.18 (t, J = 6.0Hz, 2H). 13 C NMR (100 MHz, DMSO- d 6 ) d : 167.2, 155.4, 150.4, 148.2, 146.6,138.1, 138.0, 134.8, 133.8, 133.2, 131.2, 130.4, 128.2, 127.9, 125.8, 124.9,122.6, 121.3, 121.0, 108.9, 106.1, 102.6, 57.5, 55.7, 26.8. HRMS (ESI): m / z calcd for [C 26 H 22 BN2O6] + 469.1565, found 469.1570.

[0051] The above description is merely a preferred embodiment of the present invention and is not intended to limit the invention. Various modifications and variations can be made to the present invention by those skilled in the art. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the scope of protection of the present invention.

Claims

1. A boron-functionalized berberine derivative, characterized in that, Its chemical structural formula is shown in general formula (I): 。 2. The boron-functionalized berberine derivative according to claim 1, characterized in that, X is O (oxygen atom) or NH (imino).

3. The boron-functionalized berberine derivative according to any one of claims 1-2, characterized in that, The Y is CH2 (methylene) or O=C (carbonyl).

4. The boron-functionalized berberine derivative according to any one of claims 1-2, characterized in that, Z is Br - (bromine anion) or Cl - (Chloride anion).

5. The boron-functionalized berberine derivative according to any one of claims 1-2, characterized in that, The [B] is -B(OH)2, the Ar is a substituted or unsubstituted phenyl or five-membered heteroaryl group, and the R-substituted group is a halogen, nitro or alkoxy group.

6. The boron-functionalized berberine derivative according to any one of claims 1-2, characterized in that, The [B] is a cyclic borate ester group protected by pinacol.

7. A method for preparing boron-functionalized berberine derivatives according to any one of claims 1-6, characterized in that, Using a berberine derivative with a free 9-hydroxyl group as a raw material, it reacts with a haloalkane, carboxylic acid, or acyl chloride derivative containing boric acid or borate ester groups under alkaline conditions or in the presence of a condensing agent to generate a compound of general formula (I).

8. Use of the boron-functionalized berberine derivative as described in any one of claims 1-6 in the preparation of an anti-breast cancer drug.

9. The use according to claim 8, characterized in that, The breast cancers mentioned include triple-negative breast cancer and estrogen receptor-positive breast cancer.

Images