Verapamil derivative for enhancing sensitivity of tumor cells to anti-cancer drugs and preparation of verapamil derivative

Abstract

The invention belongs to the technical field of medicinal chemistry, and particularly relates to a verapamil derivative for enhancing the sensitivity of tumor cells to anti-cancer drugs and a preparation method of the verapamil derivative. According to the application of the verapamil derivative and / or the pharmaceutically acceptable salt of the verapamil derivative in preparation of drugs for enhancing the sensitivity of tumor cells to chemotherapeutic drugs or reversing the chemotherapeutic drug resistance of the tumor cells, the verapamil derivative is 5-[(3, 4-dimethoxyphenethyl) (methyl) amino]-2-(3, 4-dimethoxyphenyl)-2-isopropyl valeronitrile. The invention provides the application of the verapamil derivative in reversing tumor chemotherapy drug tolerance and enhancing sensitivity to malignant solid tumors for the first time, and provides a synthesis method of the verapamil derivative. The safe concentration of the verapamil derivative is higher than that of parent verapamil, and a new solution is provided for solving the problem of insufficient curative effect caused by concentration limitation of verapamil.

Description

Technical Field

[0001] This invention belongs to the field of medicinal chemistry technology, specifically relating to a verapamil derivative that enhances the sensitivity of tumor cells to anticancer drugs and its preparation. Background Technology

[0002] Malignant tumors are among the leading diseases affecting human health and threatening human life worldwide. They are now the second leading cause of death and are difficult to treat. Chemotherapy and targeted therapy are the main means of prolonging the survival of patients with malignant tumors, but their effectiveness is limited by tumor drug resistance. Therefore, exploring ways to overcome tumor cell resistance to chemotherapy drugs remains of great significance for improving the clinical efficacy of treatment for malignant tumors.

[0003] Tumor cell drug resistance manifests in two forms: single-drug resistance and multidrug resistance, with multidrug resistance being more common. Multidrug resistance (MDR) is the phenomenon where tumor cells, while resistant to one anticancer drug, develop cross-resistance to other anticancer drugs with different structures and mechanisms of action. The development of drug resistance is mainly related to various factors such as changes in intracellular drug concentration and distribution, activation of intracellular antioxidant systems, activation of DNA damage repair systems, and extracellular matrix activity. Tumor cell MDR can be divided into two main types: endogenous resistance, which is the innate ability of tumor cells to resist drug activity and is genetically inherent; and acquired resistance, which refers to tumor cells initially being sensitive to drugs, but gradually developing increased resistance over time with chemotherapy.

[0004] Verapamil can be used to reverse tumor drug resistance. In vitro experiments have demonstrated that verapamil increases the efficacy of chemotherapy drugs and reverses innate and acquired resistance to chemotherapy drugs by inhibiting the PG-P glycoprotein in tumor cell membranes. However, despite the potential of verapamil to reverse tumor drug resistance in vitro and in animal models, it faces some challenges in clinical application: the effective concentration of verapamil to increase the efficacy of chemotherapy drugs is 6–10 μmol / L, and the maximum tolerated concentration of verapamil for cardiovascular toxicity in humans is 2 μmol / L. Therefore, various clinical trials of verapamil in combination with chemotherapy for the treatment of malignant tumors have been terminated.

[0005] Modifying or altering verapamil to further enhance its reversal effect, increase the sensitivity of tumor cells to anticancer drugs, improve the efficacy of chemotherapy drugs, and reduce the dosage or side effects of verapamil is a powerful way to overcome the limitations of verapamil's clinical application. Summary of the Invention

[0006] To address the aforementioned technical problems, this invention first provides the use of verapamil derivatives and / or their pharmaceutically acceptable salts in the preparation of drugs that enhance the sensitivity of tumor cells to chemotherapeutic drugs or reverse chemotherapeutic resistance in tumor cells. The structural formula of the verapamil derivative is as follows: .

[0007] Preferably, the tumor cells are derived from any one or a combination of several of the following: gastric cancer, esophageal cancer, liver cancer, colorectal cancer, and osteosarcoma.

[0008] Preferably, the chemotherapy drug is 5-fluorouracil, oxaliplatin, or epirubicin.

[0009] Preferably, the drug resistance is multidrug resistance.

[0010] Preferably, pharmaceutically acceptable salts of verapamil derivatives include salts formed by verapamil derivatives with any one of inorganic acids, organic acids, alkali metals, alkaline earth metals, or basic amino acids.

[0011] Preferably, the inorganic acid is any one of hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, and hydrobromic acid; the organic acid is any one of maleic acid, fumaric acid, tartaric acid, lactic acid, citric acid, acetic acid, methanesulfonic acid, p-toluenesulfonic acid, adipic acid, palmitic acid, and tannic acid; the alkali metal is any one of lithium, sodium, and potassium; the alkaline earth metal is any one of calcium and magnesium; and the basic amino acid is lysine.

[0012] The present invention further provides the use of a composition of verapamil derivative with 5-fluorouracil and / or oxaliplatin and / or epirubicin in the preparation of a drug that enhances the sensitivity of tumor cells to chemotherapeutic drugs or reverses the chemotherapeutic resistance of tumor cells; wherein the verapamil derivative is 5-[(3,4-dimethoxyphenethyl)(methyl)amino]-2-(3,4-dimethoxyphenyl)-2-isopropylpentanonitrile, with the following structural formula: .

[0013] This invention also provides a chemotherapeutic drug sensitizer comprising a pharmaceutically effective dose of a verapamil derivative, or a pharmaceutically acceptable salt of a pharmaceutically effective dose of a verapamil derivative; the structural formula of the verapamil derivative is: .

[0014] Preferably, the effective dose is 10%, 20%, 30%, 50%, or 70% of the mass fraction of the verapamil derivative as a chemotherapeutic drug sensitizer.

[0015] Preferably, it also includes a pharmaceutically acceptable carrier, which includes one or more excipients with functions such as excipients, stabilizers, antioxidants, colorants, diluents, and sustained-release agents; such as starch, lipids, waxes, dextrin, sucrose, lactose, microcrystalline cellulose, gelatin, citric acid, inorganic salts, hydroxypropyl methylcellulose, hydroxyethyl cellulose, etc.

[0016] Finally, this invention provides a method for synthesizing the verapamil derivative as described above, comprising the following steps: S1. Trifluoroacetic acid was added dropwise to the THF suspension of NaBH4 and verapamil at 0°C and stirred overnight at room temperature; S2. The reaction is quenched by adding water to the reaction system of step S1 at a temperature below 10°C. After vacuum concentration of the reactants, they are extracted with dichloromethane, the organic phases are combined, dried and purified to obtain the desired verapamil derivative.

[0017] Preferably, in step S1, the molar ratio of trifluoroacetic acid, NaBH4 and verapamil is 2:4:1.

[0018] The synthesis path can be represented as follows:

[0019] In the presence of trifluoroacetic acid (TFA), sodium borohydride (NaB) The target product was obtained by reducing and amination of the cyano group (-CN).

[0020] The above-described preparation route is primarily for illustrative purposes and not for limiting the invention.

[0021] The beneficial effects of this invention are as follows: In previous studies, the inventors' research group achieved good clinical results by perfusing verapamil 25 mg and chemotherapy drugs into the target artery, and by perfusing verapamil, 5-FU, and DDP into the pleural and peritoneal cavities. However, these are essentially local treatments, and target artery perfusion is a minimally invasive treatment under X-ray guidance. Moreover, some target artery perfusion treatments are difficult to achieve, which limits the clinical application of verapamil in the treatment of malignant tumors.

[0022] Verapamil enhances the efficacy of chemotherapy drugs and reverses their cardiovascular toxicity. Unlike other drugs, verapamil contains groups that act as calcium channel binding agents and groups that bind to P-GP glycoproteins associated with cell membrane resistance. Based on this mechanistic analysis, the inventors amino-modified the cyano group of verapamil, discovering that one verapamil derivative (5-[(3,4-dimethoxyphenylethyl)(methyl)amino]-2-(3,4-dimethoxyphenyl)-2-isopropylpentanonitrile) enhances the effects of chemotherapy drugs. Experiments show that the verapamil derivative, at baseline application concentrations, exhibits sensitizing capabilities comparable to or superior to the parent compound verapamil.

[0023] This application is the first to propose that the verapamil derivative 5-[(3,4-dimethoxyphenylethyl)(methyl)amino]-2-(3,4-dimethoxyphenyl)-2-isopropylpentanonitrile has the use in reversing tumor resistance to chemotherapy drugs and enhancing sensitization in malignant solid tumors, and verifies the anti-tumor effect of the verapamil derivative in combination with chemotherapy drugs.

[0024] The verapamil derivative 5-[(3,4-dimethoxyphenylethyl)(methyl)amino]-2-(3,4-dimethoxyphenyl)-2-isopropylpentanonitrile provided in this application exhibits a significantly improved safe concentration compared to the parent compound verapamil, offering a wider range of dosage options for subsequent combination chemotherapy and fundamentally avoiding the efficacy limitations caused by concentration restrictions of verapamil. At a concentration of 30 μM, the verapamil derivative is non-toxic to nine types of tumor cells, demonstrating broad tumor cell compatibility. Traditional verapamil, due to its cardiovascular toxicity, has reached in vitro effective sensitization concentrations far exceeding human tolerance levels. However, the verapamil derivative, at a concentration of 30 μM, remains within the cellular safety range, and experiments have shown no cardiovascular toxicity-related risks. This overcomes the limitation of traditional verapamil where "effective concentration equals toxic concentration," laying a safe foundation for clinical application and providing a superior solution for overcoming chemotherapy resistance and improving chemotherapy efficacy.

[0025] This application provides a method for synthesizing the verapamil derivative 5-[(3,4-dimethoxyphenylethyl)(methyl)amino]-2-(3,4-dimethoxyphenyl)-2-isopropylpentanonitrile. This method is simple and easy to operate, and can be industrialized. The 5-[(3,4-dimethoxyphenylethyl)(methyl)amino]-2-(3,4-dimethoxyphenyl)-2-isopropylpentanonitrile involved in this invention has the potential to be developed into a new anticancer drug. Attached Figure Description

[0026] Figure 1The results of safety tests of the prepared verapamil derivatives on nine cell lines are shown in the figure. a~i represent the results of the liver cancer cell line HePG2, the esophageal cancer cell line KYSE-150, the gastric cancer cell lines HGC-27, MKN-45, AGS, BGC-823, MGC-803, MKN-1 and osteosarcoma cell line MG-63, respectively.

[0027] Figure 2 The results of a sensitization test of verapamil derivatives in combination with chemical drugs on liver cancer cells.

[0028] Figure 3 This is the result of a sensitization test of verapamil derivatives in combination with chemical drugs on esophageal cancer cells.

[0029] Figures 4-9 The results of a sensitization test of verapamil derivatives in combination with chemical drugs on different gastric cancer cells.

[0030] Figure 10 The results are from a sensitization assay of osteosarcoma cells using verapamil derivatives in combination with chemical drugs.

[0031] Figure 1-10 In the graph, the horizontal axis represents the corresponding drug dosage, and the vertical axis represents cell viability. Detailed Implementation

[0032] Unless otherwise stated, the terms used herein have the meanings conventionally understood by those skilled in the art. Unless otherwise specified, all raw materials, reagents, instruments, and equipment used herein are commercially available or can be prepared using existing methods.

[0033] The technical solution of the present invention will be described in more detail below with reference to the embodiments.

[0034] Example 1 Synthesis of 5-[(3,4-dimethoxyphenethyl)(methyl)amino]-2-(3,4-dimethoxyphenyl)-2-isopropylpentanonitrile

[0035] TFA (0.15 mL, 2 mmol) was added dropwise at 0 °C to a 20 mL THF suspension of NaBH4 (152 mg, 4 mmol) and verapamil (454 mg, 1 mmol). The reaction mixture was stirred overnight at room temperature. The reaction was carefully quenched with water below 10 °C, concentrated to dryness under vacuum, and extracted with dichloromethane. The combined organic phases were dried over anhydrous sodium sulfate, evaporated under vacuum, and purified by rapid column chromatography to give the target product 5-[(3,4-dimethoxyphenethyl)(methyl)amino]-2-(3,4-dimethoxyphenyl)-2-isopropylpentanonitrile (206 mg).

[0036] 1 H NMR (400 MHz, CDCl3) ppm 0.81 (d, J=6.72 Hz, 3 H) 1.13 - 1.20 (m, 4 H) 1.37 (m, 2 H) 1.48 - 1.56 (m, 1 H) 1.78 - 1.86 (m, 1 H) 2.01 - 2.15 (m, 2 H) 2.21 (s, 3 H) 2.32 - 2.39 (m, 2 H) 2.42 (m, 2 H) 2.46 - 2.54 (m, 2H) 2.64 - 2.71 (m, 2 H) 3.82 - 3.87 (m, 12 H) 6.69 - 6.73 (m, 2 H) 6.75 -6.79 (m, 1 H) 6.83 - 6.86 (m, 2 H) 6.89 - 6.95 (m, 1 H). HRMS (ESI, m / z):calculated for C 27 H 42 N₂O₄ [M+H] + 459.6025; found 459.6142.

[0037] Database comparison revealed that patent DE3143356A1 discloses a series of verapamil derivatives, including the verapamil derivative of this application. That application states that the verapamil derivative exerts its antiarrhythmic effect through sodium channel antagonism. This application proposes a new function of the verapamil derivative and provides a novel synthetic method.

[0038] Example 2 The CCK8 kit was used to detect the inhibitory activity of 5-[(3,4-dimethoxyphenylethyl)(methyl)amino]-2-(3,4-dimethoxyphenyl)-2-isopropylpentanonitrile and chemotherapeutic drugs on tumor cell proliferation.

[0039] Experimental materials: 5-[(3,4-dimethoxyphenylethyl)(methyl)amino]-2-(3,4-dimethoxyphenyl)-2-isopropylpentanonitrile (hereinafter referred to as verapamil derivative) was synthesized according to Example 1, with a purity of not less than 95%. Gastric cancer (HGC-27, MKN-45, AGS, BGC-823, MGC-803, MKN-1), liver cancer (HePG2), esophageal cancer (KYSE-150), and osteosarcoma (MG-63) cell lines were provided by Anhui Medical University. 5-Fluorouracil, oxaliplatin, and epirubicin were purchased from Shanghai Jingchun Biochemical Technology Co., Ltd., with a purity greater than 99%. The CCK8 kit was purchased from Biosharp Life Sciences.

[0040] Experimental methods: 1. Cell resuscitation 1) Remove the cryovials from the liquid nitrogen tank and immerse them directly in 37°C warm water, shaking them occasionally to thaw them as quickly as possible.

[0041] 2) Remove the cryopreservation tube from the 37 ℃ water bath, aspirate 1 ML of cell suspension with a pipette, inject it into a centrifuge tube and add 2 ML of culture medium, mix and centrifuge at low speed, discard the supernatant, and wash once more with culture medium.

[0042] 3) After appropriately diluting the culture medium, inoculate it into culture flasks and incubate at 37 ℃. Change the culture medium the next day and continue culturing. Subculture when the culture reaches a certain density.

[0043] 2. Cell passage culture

[0044] The tumor cell line used was cultured in high-glucose DMEM medium containing 10% fetal bovine serum. Cell growth was observed daily. When the cells reached approximately 90% confluence (adherent cells) in the culture flask, they were passaged at a ratio of 1:3 to 1:5, approximately every 2-4 days. The method is as follows: 1) Wash the cells three times with 1× phosphate buffer.

[0045] 2) Add 1-2 ml of 0.25% trypsin digestion solution and incubate at 37°C for several minutes. Wait until cell separation occurs.

[0046] 3) Stop digestion with a suitable culture medium containing 10% fetal bovine serum. Aliquot the cells into new culture flasks and continue culturing.

[0047] 3. Cell cryopreservation

[0048] 1) Take cells cultured to the logarithmic growth phase, digest them with trypsin, collect them in centrifuge tubes, count them, and centrifuge.

[0049] 2) Discard the trypsin and the old culture medium, add the prepared cryopreservation solution, and the final cell concentration in the cryopreservation solution should be 0.5-1×10⁻⁶. 7 / ml. Gently pipette to homogenize the cells, then aliquot them into sterile cryovials, adding 1-1.5ml to each tube.

[0050] Place the cryovials in a cryopreservation box at -80 °C, and after 5 hours transfer them to a liquid nitrogen tank for storage.

[0051] 4. CCK8 assay for cell drug sensitivity

[0052] 1) Safety test

[0053] Human tumor cells were seeded into 96-well plates at a density of 5000 cells / well. After cell adhesion, the culture medium was removed, and the cells were washed twice with PBS. Fresh culture medium supplemented with 10% FBS and different concentrations of 5-[(3,4-dimethoxyphenylethyl)(methyl)amino]-2-(3,4-dimethoxyphenyl)-2-isopropylpentanonitrile (100 μL per well) was used, and the cells were incubated at 37 °C and 5% CO2 for 24 hours. Six concentration gradients of 5-[(3,4-dimethoxyphenylethyl)(methyl)amino]-2-(3,4-dimethoxyphenyl)-2-isopropylpentanonitrile (40, 30, and 20 μmol / L) were used. After incubation, the liquid in each well was discarded, and 10 μL of CCK8 solution and 90 μL of serum-free culture medium were added to each well of the 96-well plate. The plates were then incubated for another 2 hours. Then, the 96-well plate was placed in a microplate reader and the absorbance value (OD) was measured at 450 nm. 450 (Value). The blank group consisted of culture medium only, without cells; the control group consisted of cells without the drug. Cell inhibition rate = 1 - (experimental group OD). 450 - Blank group OD 450 ) / (Control group OD 450 - Blank group OD 450 ).

[0054] The safety range of 5-[(3,4-dimethoxyphenethyl)(methyl)amino]-2-(3,4-dimethoxyphenyl)-2-isopropylpentanonitrile in tumor cells is as follows: Figure 1 As shown in the figure, 5-[(3,4-dimethoxyphenylethyl)(methyl)amino]-2-(3,4-dimethoxyphenyl)-2-isopropylpentanonitrile is non-toxic to all tested tumor cells at concentrations below 30 μM. Therefore, in the cell drug sensitivity assay, the verapamil derivative 5-[(3,4-dimethoxyphenylethyl)(methyl)amino]-2-(3,4-dimethoxyphenyl)-2-isopropylpentanonitrile was selected at a concentration of 30 μM to eliminate interference from the compound itself on the experimental results.

[0055] 2) Inhibition rate experiment

[0056] The tumor cell lines to be tested were seeded into 96-well cell culture plates at a density of 5000 cells / well. The plates were then placed in a 37°C, 5% CO2 cell culture incubator and cultured until the cells were fully adherent. The culture medium was then aspirated, and the cells were washed twice with PBS. The following solutions were prepared using fresh culture medium containing 10% FBS: Control group: culture medium only; drug-only groups: 5-fluorouracil (5-Fu, 20 μM), oxaliplatin (Oxa, 10 μM), epirubicin (1 μM); verapamil derivative-only groups (final concentrations of 20 μM and 30 μM); combination drug groups: 5-fluorouracil (20 μM) + verapamil derivative (20 μM and 30 μM), oxaliplatin (10 μM) + verapamil derivative (20 μM and 30 μM), epirubicin (1 μM) + verapamil derivative (20 μM and 30 μM).

[0057] Add 100 μL of the corresponding drug solution to each well, place the 96-well plate in a 37°C, 5% CO2 cell culture incubator, and incubate for 24 hours to evaluate the ability of the derivatives to enhance the anti-tumor cell proliferation of the three drugs.

[0058] After incubation, discard the liquid in each well. Add 10 μL of CCK8 solution and 90 μL of serum-free culture medium to each well of the 96-well plate, and incubate the plate for another 2 hours. Then, measure the absorbance (OD) of the 96-well plate at 450 nm using a microplate reader. 450 (Value). The blank group was the group with culture medium but no cells, and the control group was the group with cells but no drugs.

[0059] Cell inhibition rate = 1 - (experimental group OD) 450 - Blank group OD 450 ) / (Control group OD 450 - Blank group OD 450 ).

[0060] All experiments were repeated three times. The results were analyzed and plotted using SPSS statistical analysis software. The results are as follows: Figure 2-10 As shown.

[0061] It can be seen that, regardless of whether the target is liver cancer, esophageal cancer, gastric cancer, or osteosarcoma cells, verapamil derivatives, when used in combination with 5-fluorouracil, oxaliplatin, and epirubicin, can effectively reduce tumor cell survival rates, and the effects are highly consistent. At a concentration of 20 μM, when verapamil derivatives are combined with the three chemotherapy drugs, the reduction in survival rates of the nine tested tumor cell types is basically equivalent to the effect of 20 μM traditional verapamil combined with chemotherapy drugs. In some cell types (such as HepG2 and HGC-27), the survival rate of the derivative group decreased more significantly, indicating that the verapamil derivatives provided in this application have a sensitizing ability roughly equivalent to that of traditional verapamil. Furthermore, when the concentration of verapamil derivatives is increased from 20 μM to 30 μM, the survival rate of the tested cell lines is further reduced, while traditional verapamil, due to its toxicity limitations, cannot enhance its sensitizing effect by increasing the concentration. In summary, with the increase of verapamil derivative concentration, the ability of 5-fluorouracil, oxaliplatin, and epirubicin to inhibit tumor cell proliferation was enhanced, comparable to or superior to verapamil, indicating that verapamil derivatives have the ability to enhance the anti-tumor cell proliferation ability of chemotherapeutic drugs.

[0062] Example 3 Acute toxicity test of 5-[(3,4-dimethoxyphenethyl)(methyl)amino]-2-(3,4-dimethoxyphenyl)-2-isopropylpentanonitrile

[0063] Sixty rats were randomly divided into 10 groups. Each group was administered different concentrations of verapamil derivatives and different concentrations of verapamil by gavage. The mortality of the rats was observed after 7 days. The administration details and results are shown in Table 1.

[0064] Table 1. Mortality rate of rats 7 days after gavage administration of verapamil derivatives and verapamil

[0065] It can be seen that, under gavage administration, the lethal dose of verapamil derivative is much higher than that of verapamil (the dose at which verapamil derivative achieves 100% mortality is 900 mg / kg, while that of verapamil is only 320 mg / kg); no deaths were observed in the low-dose range (500 mg / kg for verapamil derivative and 60 mg / kg for verapamil), but the upper limit of the safe dose of verapamil derivative is much higher than that of verapamil. This proves that the amino-modified verapamil derivative 5-[(3,4-dimethoxyphenylethyl)(methyl)amino]-2-(3,4-dimethoxyphenyl)-2-isopropylpentanonitrile provided in this application significantly reduces the toxicity of the parent verapamil, expands the safe range, and significantly increases safety.

[0066] In summary, the verapamil derivative provided in this application can maintain a low mortality rate even at higher doses, indicating that it has a wide safety range between effective and toxic doses. It can overcome the dosage limitations caused by the toxicity of traditional verapamil and avoid the limitations of cardiovascular toxicity and local treatment of traditional verapamil. It provides a new approach for verapamil to enhance the sensitivity of tumor cells to chemotherapeutic drugs and / or reverse tumor multidrug resistance.

[0067] The above are merely preferred embodiments of the present invention and are not intended to limit the scope of the invention. Although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art should understand that any modifications, equivalent substitutions, and improvements made within the spirit and principles of the present invention should be included within the scope of protection of the present invention.

Claims

1. The use of verapamil derivatives and / or their pharmaceutically acceptable salts in the preparation of medicaments for enhancing the sensitivity of tumor cells to chemotherapeutic drugs or reversing chemotherapeutic resistance in tumor cells, wherein the structural formula of the verapamil derivative is: 。 2. The application as described in claim 1, characterized in that, The tumor cells are derived from any one or a combination of several of the following: gastric cancer, esophageal cancer, liver cancer, colorectal cancer, and osteosarcoma.

3. The application as described in claim 1, characterized in that, The chemotherapy drugs are 5-fluorouracil, oxaliplatin, and epirubicin.

4. The application as described in claim 1, characterized in that, The drug resistance mentioned is multidrug resistance.

5. The application as described in claim 1, characterized in that, Pharmaceutically acceptable salts of verapamil derivatives include salts formed by verapamil derivatives with any one of inorganic acids, organic acids, alkali metals, alkaline earth metals, or basic amino acids.

6. The application as described in claim 5, characterized in that, The inorganic acid is any one of hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, and hydrobromic acid; the organic acid is any one of maleic acid, fumaric acid, tartaric acid, lactic acid, citric acid, acetic acid, methanesulfonic acid, p-toluenesulfonic acid, adipic acid, palmitic acid, and tannic acid; the alkali metal is any one of lithium, sodium, and potassium; the alkaline earth metal is any one of calcium and magnesium; and the basic amino acid is lysine.

7. The use of a composition of verapamil derivatives with 5-fluorouracil and / or oxaliplatin and / or epirubicin in the preparation of a drug that enhances the sensitivity of tumor cells to chemotherapeutic drugs or reverses chemotherapeutic resistance in tumor cells; the structural formula of the verapamil derivative is: 。 8. A chemotherapy drug sensitizer, characterized in that, The product comprises a pharmaceutically effective dose of a verapamil derivative, or a pharmaceutically acceptable salt of a pharmaceutically effective dose of a verapamil derivative; the structural formula of the verapamil derivative is: 。 9. The method for synthesizing verapamil derivatives as described in claim 1, characterized in that, Includes the following steps: S1. Trifluoroacetic acid was added dropwise to the THF suspension of NaBH4 and verapamil at 0°C and stirred overnight at room temperature; S2. The reaction is quenched by adding water to the reaction system of step S1 at a temperature below 10°C. After vacuum concentration of the reactants, they are extracted with dichloromethane, the organic phases are combined, dried and purified to obtain the desired verapamil derivative.

10. The method for synthesizing verapamil derivatives as described in claim 8, characterized in that, In step S1, the molar ratio of trifluoroacetic acid, NaBH4, and verapamil is 2:4:1.

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