Triphenylphosphine derivative with pancreatic cancer resisting activity as well as synthesis method and application of triphenylphosphine derivative

Abstract

The invention discloses a triphenylphosphine derivative with pancreatic cancer resisting activity as well as a synthesis method and application thereof, relates to the technical field of organic synthesis and medicinal chemistry, and aims to overcome the core defects of insufficient CPI-613 mitochondrial targeting, low target exposure, limited pancreatic cancer resisting activity and narrow therapeutic window in the prior art. The novel triphenylphosphine derivative developed by conjugating an alpha-lipoic acid active mother nucleus and a mitochondrial targeting group triphenylphosphine cation (TPP < + >) has multiple beneficial technical effects.

Description

Technical Field

[0001] This invention relates to the fields of organic synthesis and medicinal chemistry, specifically to a triphenylphosphine derivative with anti-pancreatic cancer activity, its synthesis method, and its applications. Background Technology

[0002] Pancreatic cancer is a highly malignant digestive system tumor, with a 5-year overall survival rate of only 7%–10%, ranking last among common malignant tumors. The disease has an insidious onset, and most patients are diagnosed at an advanced stage, losing the opportunity for radical surgery. First-line chemotherapy regimens, with gemcitabine as the core, have limited efficacy, and almost all patients develop acquired resistance. 70% of patients who undergo radical surgery relapse within two years. Current treatments are insufficient to improve long-term survival, making the development of anti-pancreatic cancer drugs with novel mechanisms a critical clinical challenge.

[0003] Tumor metabolic reprogramming is one of the core hallmarks of malignant tumors. Recent studies have confirmed that tumor cells possess high metabolic plasticity. Mitochondria, as the core hub of cellular energy metabolism and signal transduction, are crucial for tumor cell proliferation, survival, and drug resistance. Targeting mitochondrial metabolism has become an important research direction for the treatment of malignant tumors. The pyruvate dehydrogenase complex (PDC) is the core rate-limiting enzyme connecting glycolysis and the mitochondrial tricarboxylic acid cycle. Its abnormal activation is closely related to pancreatic cancer proliferation, chemotherapy resistance, and poor prognosis. PDC inhibitors, such as CPI-613 (devimistat), can simultaneously inhibit the activity of PDC and α-ketoglutarate dehydrogenase, disrupting mitochondrial metabolic homeostasis in tumor cells. They have shown clear anti-pancreatic cancer activity in preclinical studies; however, this drug failed to reach the expected treatment endpoint in a phase III clinical trial for pancreatic cancer. The core reason is its lack of tumor mitochondrial-specific targeting ability, failing to maintain an effective therapeutic concentration at the target site, thus severely limiting its anti-tumor efficacy.

[0004] Triphenylphosphine cation (TPP) + Mitochondrial targeting groups are widely used lipophilic mitochondrial targeting groups. By leveraging the significantly higher mitochondrial membrane potential of tumor cells compared to normal cells, selective targeting and enrichment of tumor mitochondria can be achieved. This increases the concentration of the target drug while reducing toxic side effects, making it a mature technology for improving the drug-likeness of mitochondrial target drugs.

[0005] Currently, no existing technology has been found to combine the α-lipoic acid active core of CPI-613 with TPP. +There are reports on the construction of triphenylphosphine derivatives with both mitochondrial targeting and highly effective anti-pancreatic cancer activity through mitochondrial-targeting group conjugation. Based on this, this invention addresses the core deficiencies of existing technologies by developing a novel mitochondrial-targeting triphenylphosphine-modified α-lipoic acid derivative. It also provides a simple, controllable, and industrially suitable synthetic method and clarifies its application in the preparation of anti-pancreatic cancer drugs, offering a novel drug option for targeted therapy of pancreatic cancer. Summary of the Invention

[0006] To address the aforementioned shortcomings of the prior art, this invention provides a triphenylphosphine derivative with anti-pancreatic cancer activity, its synthesis method, and its applications.

[0007] To achieve the above-mentioned objectives, the technical solution adopted by this invention is as follows: A triphenylphosphine derivative with anti-pancreatic cancer activity is provided, characterized in that the structure of the triphenylphosphine derivative is shown in the following formula TM; ; in,( ) n The n in the figure is 4~10, that is, the carbon chain length is 4~10; the triphenylphosphine derivative has a dual-targeting mechanism of action on the mitochondrial oxidative phosphorylation function of tumor cells, which can block the tricarboxylic acid cycle pathway mediated by pyruvate dehydrogenase complex while inhibiting the molecular chaperone function of tumor necrosis factor receptor-associated protein 1, thereby interfering with the operation of the mitochondrial respiratory chain.

[0008] Furthermore, when n is 5, the structure of the triphenylphosphine derivative is shown in Formula 6 below; ; When n is 6, the structure of the triphenylphosphine derivative is shown in Formula 17 below; .

[0009] The present invention also provides a method for synthesizing the above-mentioned triphenylphosphine derivative with anti-pancreatic cancer activity, comprising the following steps: S1: Weigh the synthetic substrate, triphenylphosphine and acetonitrile, mix them, and reflux and stir at 95°C for 36 h; S2: After the reaction is complete, the solvent is removed by vacuum concentration, and the concentrated product is purified by chromatography to obtain the triphenylphosphine derivative. When n is 4 in the triphenylphosphine derivative, the substrate for synthesis is 7-bromo-1,3-bis(benzylthio)heptane; When n is 5 in the triphenylphosphine derivative, the substrate for synthesis is 8-bromo-1,3-bis(benzylthio)octane, with the structural formula shown in Formula 5 below; ; When n is 6 in the triphenylphosphine derivative, the substrate for synthesis is 9-bromo-1,3-bis(benzylthio)nonane, with the structural formula shown in Formula 16 below; ; When n is 7 in the triphenylphosphine derivative, the substrate for synthesis is 10-bromo-1,3-bis(benzylthio)decane; When n is 8 in the triphenylphosphine derivative, the substrate for synthesis is 11-bromo-1,3-bis(benzylthio)undecane; When n is 9 in the triphenylphosphine derivative, the substrate for synthesis is 12-bromo-1,3-bis(benzylthio)dodecane; When n is 10 in the triphenylphosphine derivative, the substrate for synthesis is 13-bromo-1,3-bis(benzylthio)tridecane.

[0010] Furthermore, in step S1, the ratio of the synthetic substrate, triphenylphosphine, and acetonitrile is 0.5 mmol: 0.75 mmol: 20 mL.

[0011] Furthermore, in step S2, the eluent used in column chromatography separation and purification is a mixture of dichloromethane and methanol, and the volume ratio of dichloromethane to methanol is 50~20:1.

[0012] Furthermore, the method for synthesizing 8-bromo-1,3-bis(benzylthio)octane is as follows: A1: 5 mmol of α-lipoic acid, 10 mL of 0.5 M sodium hydroxide solution, 25 mmol of sodium borohydride, and 40 mL of tetrahydrofuran were placed in a double-necked flask and stirred at 40 °C for about 1.5 h under nitrogen protection. After the reaction was complete, 10 mL of 1 M sodium hydroxide solution and 10 mmol of benzyl bromide were added to the system, and the mixture was stirred at 40 °C for 4 h. After the reaction was completed by TLC monitoring, hydrochloric acid was added dropwise to the reaction system for acidification, and the pH of the system was adjusted to 2. Subsequently, the reaction system was extracted with dichloromethane and saturated brine, and the extraction was repeated 2-3 times. All organic phases were combined, dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. Finally, the first intermediate product was obtained by column chromatography using dichloromethane as the eluent. A2: Take 2.38 mmol of the first intermediate obtained from A1, dissolve it in 1-2 mL of redistilled tetrahydrofuran, and cool it to 0℃ to obtain the first intermediate-THF solution; add 7.1 mmol of lithium aluminum hydride and 5 mL of tetrahydrofuran to a double-necked flask, cool it to 0℃ under nitrogen protection, and slowly add the first intermediate-THF solution. Stir at room temperature for 3 h; monitor the reaction by TLC until it is complete, cool the reaction system to 0℃ again, slowly add Na2SO4 to the reaction system, and continue stirring for 15 min after no obvious bubbles emerge to ensure complete quenching; filter the quenched reaction solution under reduced pressure, and concentrate the filtrate under reduced pressure to obtain the second intermediate; A3: Take 1.97 mmol of the second intermediate obtained from A2, 2.96 mmol of carbon tetrabromide, and 10 mL of redistilled tetrahydrofuran and add them to a double-necked flask. Under nitrogen protection, place the flask in an ice bath and stir. After the reaction system cools to 0°C, slowly add 2.96 mmol of triphenylphosphine and stir overnight at room temperature. After the reaction is completed by TLC monitoring, concentrate under reduced pressure to remove the solvent, and use petroleum ether:ethyl acetate at a volume ratio of 80:1 as the eluent for column chromatography to obtain 8-bromo-1,3-bis(benzylthio)octane.

[0013] Furthermore, the synthesis method of the 7-bromo-1,3-bis(benzylthio)heptane, 9-bromo-1,3-bis(benzylthio)nonane, 10-bromo-1,3-bis(benzylthio)decane, 11-bromo-1,3-bis(benzylthio)undecane, 12-bromo-1,3-bis(benzylthio)dodecane or 13-bromo-1,3-bis(benzylthio)tridecane is as follows: B1: 1.94 mmol of 1,3-propanedithiol, 2.03 mmol of acetone, 35 mg of p-toluenesulfonic acid, 2.54 mmol of anhydrous magnesium sulfate and 40 mL of toluene were added to a round-bottom flask and reacted at 125 °C for 24 h. The reaction was monitored by TLC until it was complete. The system solution was cooled to room temperature, diluted with water, and then extracted with dichloromethane and saturated brine. The extraction was repeated 2-3 times. The solution was dried with Na2SO4 and concentrated under reduced pressure to obtain the third intermediate product. B2: Take 5.29 mmol of the third intermediate obtained from B1 and 100 mL of methanol and add them to a double-necked flask. Under nitrogen protection, cool the system to 0°C and add 1.13 mL of sodium periodate aqueous solution with a concentration of 1 g / mL. Place the reaction system at room temperature for 5 h. After the reaction is completed by TLC monitoring, collect the filtrate by vacuum filtration, concentrate under reduced pressure to remove the solvent, and then extract the reaction system with dichloromethane and saturated brine. Repeat the extraction 2-3 times. Dry with Na2SO4, concentrate under reduced pressure, and then separate and purify the colorless liquid fourth intermediate by column chromatography using dichloromethane:ethyl acetate with a volume ratio of 50:1 as the eluent. B3: Add 10 mL of dichloromethane, 2.75 mmol of imidazole and 1.1 mmol of triisopropylchlorosilane to a double-necked flask, then add 1.1 mmol of 4-bromobutanol, 6-bromohexanol, 7-bromoheptanol, 8-bromooctanol, 9-bromononanol or 10-bromodecanol. React at room temperature for 12 h. After the reaction is complete, monitor the reaction by TLC. Dilute with water, then extract the reaction system with dichloromethane and saturated brine. Repeat the extraction 2-3 times. Dry with Na2SO4, concentrate under reduced pressure, and use petroleum ether as eluent for column chromatography to obtain the fifth intermediate product. B4: 4.37 mmol of the fourth intermediate obtained from B2 and 20 mL of redistilled tetrahydrofuran were added to a double-necked flask. The system temperature was lowered to -78 °C under nitrogen protection. Then, 10.93 mmol of N,N,N',N'-tetramethylethylenediamine and 8.74 mmol of diisopropylaminolithium were added sequentially. After stirring at -78 °C for 20 min, 6.56 mmol of the fifth intermediate obtained from B3 was added. After stirring for another 30 min, the reaction system was placed at room temperature for 3.5 h. The reaction was monitored by TLC until it was complete. Under ice bath conditions, 15 mL of saturated ammonium chloride aqueous solution was added dropwise to the system. After the addition was complete, the mixture was stirred for 15 min to ensure complete quenching. The reaction system was then extracted with ethyl acetate and saturated brine. The extraction was repeated 2-3 times and dried with Na2SO4. The sixth intermediate was obtained by column chromatography using petroleum ether:ethyl acetate at a volume ratio of 5:1 as the eluent. B5: Take 3.09 mmol of the sixth intermediate obtained from B4 and 20 mL of acetonitrile and add them to a double-necked flask. Under nitrogen protection, add 0.14 mL of 2 mol / L hydrochloric acid dropwise. Stir at room temperature for 40 h. After the reaction is completed by TLC monitoring, cool the system to room temperature, concentrate under reduced pressure, and purify by column chromatography using dichloromethane:methanol at a volume ratio of 20:1 as the eluent to obtain the seventh intermediate. B6: Take 0.38 mmol of the seventh intermediate obtained from B5, 10 mL of tetrahydrofuran, 15.2 mg of 0.5 mol / L sodium hydroxide aqueous solution, and 1.9 mmol of sodium borohydride, and add them to a double-necked flask. Under nitrogen protection, react at 40 °C for 1.5 h. Then, add 15.2 mg of 1 mol / L sodium hydroxide aqueous solution and 0.76 mmol of benzyl bromide to the reaction system in sequence, and continue to react at 40 °C for 3 h. After the reaction is completed, adjust the pH to weakly acidic with saturated ammonium chloride aqueous solution. Then, extract the reaction system with ethyl acetate and saturated brine, repeat the extraction 2-3 times, and dry with anhydrous Na2SO4. Use petroleum ether:ethyl acetate at a volume ratio of 5:1 as the eluent for column chromatography to obtain the eighth intermediate. B7: Take 1.97 mmol of the eighth intermediate obtained from B6, 2.96 mmol of carbon tetrabromide, and 10 mL of redistilled tetrahydrofuran and add them to a double-necked flask. Under nitrogen protection, place the flask in an ice bath and stir. After the reaction system cools to 0°C, slowly add 2.96 mmol of triphenylphosphine and stir overnight at room temperature. After the reaction is completed by TLC monitoring, concentrate under reduced pressure to remove the solvent, and use petroleum ether:ethyl acetate at a volume ratio of 80:1 as the eluent for column chromatography to obtain 7-bromo-1,3-bis(benzylthio)heptane, 9-bromo-1,3-bis(benzylthio)nonane, 10-bromo-1,3-bis(benzylthio)decane, 11-bromo-1,3-bis(benzylthio)undecane, 12-bromo-1,3-bis(benzylthio)dodecane, or 13-bromo-1,3-bis(benzylthio)tridecane.

[0014] The present invention also provides the application of the above-mentioned triphenylphosphine derivative in the preparation of antitumor drugs.

[0015] The beneficial effects of this invention are as follows: This invention addresses the core shortcomings of existing technologies, such as insufficient mitochondrial targeting of CPI-613, low target exposure, limited anti-pancreatic cancer activity, and narrow therapeutic window. It addresses these shortcomings by combining the α-lipoic acid active core with the mitochondrial targeting group triphenylphosphine cation (TPP). + The novel triphenylphosphine derivatives developed through conjugation have achieved several beneficial technical effects. In vitro experiments have confirmed that the compounds of this invention exhibit potent inhibitory activity against the proliferation of various human pancreatic cancer cell lines, with a half-maximal inhibitory concentration (IC50) more than one order of magnitude lower than that of CPI-613, and overall activity comparable to gemcitabine, a first-line clinical chemotherapy drug. The synthetic method of this invention uses commercially available raw materials, has a short reaction route, mild and controllable conditions, good intermediate stability, simple post-processing and purification operations, high yield of the target product, requires no special production equipment, is easy to scale up for industrial production, and has good prospects for industrial application. Attached Figure Description

[0016] Figure 1 A schematic diagram of the synthetic route for 8-bromo-1,3-bis(benzylthio)octane; Figure 2 This is a schematic diagram of the synthetic route for 9-bromo-1,3-bis(benzylthio)nonane. Detailed Implementation

[0017] The specific embodiments of the present invention are described below to enable those skilled in the art to understand the present invention. However, it should be understood that the present invention is not limited to the scope of the specific embodiments. For those skilled in the art, various changes are obvious as long as they are within the spirit and scope of the present invention as defined and determined by the appended claims. All inventions utilizing the concept of the present invention are protected.

[0018] Unless otherwise specified, all raw materials used in the embodiments of this invention are of conventional analytical grade.

[0019] Example 1 Synthesis of the substrate When the substrate is 8-bromo-1,3-bis(benzylthio)octane, the following method is used: Figure 1 The synthetic route shown below has the following specific steps: A1: Compound 1 (1.03 g, 5.0 mmol), i.e., α-lipoic acid, sodium hydroxide aqueous solution (10.00 mL, 0.5 M), and NaBH4 (946 mg, 25.0 mmol) were added to a 100 mL double-necked flask. Then, THF (40 mL) was added as the reaction solvent. The mixture was stirred at 40 °C for approximately 1.5 h under N2 protection. Next, NaOH (10.0 mL, 1 M) and Compound 2 (1.29 mL, 10.0 mmol), i.e., BrBn, were added sequentially to the system. The mixture was stirred at 40 °C for 4 h. After the reaction was complete as monitored by TLC, hydrochloric acid was added dropwise to acidify the system and adjust the pH to 2. The reaction system was then extracted with dichloromethane (DCM) and saturated brine, repeated 2-3 times. All organic phases were combined, dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. Column chromatography separation and purification (pure DCM) yielded the first intermediate (1.26 g), namely compound 3, which was a white solid powder with a yield of 64.9%.

[0020] A2: Compound 3 (927 mg, 2.38 mmol) was dissolved in redistilled THF (1-2 mL) to obtain the first intermediate-THF solution, which was then cooled to 0 °C for later use. LiAlH4 (300 mg, 7.10 mmol) and THF (5 mL) were added to a 50 mL double-necked flask. Under nitrogen protection, the mixture was cooled to 0 °C, and the first intermediate-THF solution was slowly added. The mixture was stirred at room temperature for 3 h. After the reaction was complete as monitored by TLC, the reaction system was cooled to 0 °C again. Slightly moistened Na2SO4 was slowly added to the reaction system. After no obvious bubbles emerged, stirring was continued for 15 min to ensure complete quenching. The quenched reaction solution was filtered under reduced pressure using a sintered glass funnel lined with diatomaceous earth. The filter cake was washed several times with EA, and all filtrate was collected and concentrated under reduced pressure to obtain the second intermediate (856 mg), i.e., compound 4. The second intermediate was a colorless oily liquid with a yield of 96%.

[0021] A3: Compound 4 (739 mg, 1.97 mmol), CBr4 (981.4 mg, 2.96 mmol), and redistilled DCM (10 mL) were added to a 50 mL double-necked flask. The mixture was stirred in an ice bath under N2 protection. After the reaction system cooled to 0 °C, PPh3 (776.2 mg, 2.96 mmol) was slowly added, and the mixture was stirred overnight at room temperature. The reaction was monitored by TLC until complete. The solvent was removed by concentration under reduced pressure, and the mixture was purified by column chromatography (PE:EA = 80:1) to give 8-bromo-1,3-bis(benzylthio)octane (615 mg), i.e., compound 5, 8-bromo-1,3-bis(benzylthio)octane, a pale yellow oily liquid with a yield of 71.4%.

[0022] When synthesizing 9-bromo-1,3-bis(benzylthio)nonane as the substrate, the following method is used: Figure 2 The synthetic route shown below has the following specific steps: B1: Compound 7 (0.19 mL, 1.94 mmol), i.e., 1,3-propanedithiol, compound 8 (0.16 mL, 2.03 mmol), i.e., acetone, p-TsOH (35 mg, 0.203 mmol), MgSO4 (305 mg, 2.54 mmol), and toluene (40 mL) were added to a 100 mL round-bottom flask and reacted at 125 °C for 24 h. After the reaction was completed by TLC, the system solution was cooled to room temperature, diluted with water, and then extracted with dichloromethane (DCM) and saturated brine. The extraction was repeated 2-3 times. The solution was dried over Na2SO4 and concentrated under reduced pressure to obtain the third intermediate (187 mg), i.e., compound 9. The third intermediate was a colorless liquid with a yield of 35.1%.

[0023] B2: Compound 9 (785 mg, 5.29 mmol) and methanol (100 mL) were added to a 250 mL double-necked flask. After nitrogen protection, the system was cooled to 0 °C, and then an aqueous solution of NaIO4 (1.13 g, 5.29 mmol) was added. The reaction system was placed at room temperature for 5 h. After the reaction was completed by TLC monitoring, the filtrate was collected by vacuum filtration, concentrated under reduced pressure to remove the solvent, and then extracted with dichloromethane (DCM) and saturated brine. The extraction was repeated 2-3 times. The mixture was dried over Na2SO4, concentrated under reduced pressure, and purified by column chromatography (DCM:EA = 50:1) to obtain the fourth intermediate (765 mg), namely compound 10. The fourth intermediate was a colorless liquid with a yield of 88.0%.

[0024] B3: Compound 11 (200 mg, 1.10 mmol), i.e., 6-bromohexanol, DCM (10 mL), Imidazole (187 mg, 2.75 mmol), and TIPS-Cl (0.24 mL, 1.10 mmol) were added to a 100 mL double-necked flask and reacted at room temperature for 12 h. After the reaction was completed by TLC, water was added for dilution, and then the reaction system was extracted with dichloromethane (DCM) and saturated brine. The extraction was repeated 2-3 times. The mixture was dried over Na2SO4, concentrated under reduced pressure, and purified by column chromatography (pure PE) to obtain the fifth intermediate (304 mg), i.e., compound 12. The fifth intermediate was a colorless liquid with a yield of 81.6%.

[0025] B4: Compound 10 (718 mg, 4.37 mmol) and redistilled THF (20 mL) were added to a 250 mL double-necked flask. Under nitrogen protection, the mixture was cooled in a low-temperature cold trap. When the system temperature dropped to -78 °C, TEMED (1.68 mL, 10.93 mmol) and LDA (4.37 mL, 8.74 mmol) were added sequentially. After stirring at -78 °C for 20 min, compound 12 (2.21 g, 6.56 mmol) was added, and stirring continued for 30 min. The reaction system was then allowed to react at room temperature for 3.5 h. The reaction was monitored by TLC until completion. Under ice bath conditions, saturated NH4Cl aqueous solution (15 mL) was added dropwise to the system, stirring for 15 min to ensure complete quenching. Subsequently, the reaction system was extracted with ethyl acetate (EA) and saturated brine, repeated 2-3 times, and dried over Na2SO4. Column chromatography separation and purification (PE∶EA=5∶1) yielded the sixth intermediate (1.30 g), namely compound 13. The sixth intermediate was a colorless liquid with a yield of 70.7%.

[0026] B5: Compound 13 (1.30 g, 3.09 mmol) and MeCN (20 mL) were added to a 100 mL double-necked flask. Under nitrogen protection, HCl (2N, 0.14 mL, 0.28 mmol) was added dropwise, and the mixture was stirred at room temperature for 40 h. After the reaction was completed by TLC monitoring, the system was cooled to room temperature, concentrated under reduced pressure, and purified by column chromatography (DCM:MeOH = 20:1) to obtain the seventh intermediate (379 mg), namely compound 14. The seventh intermediate was a colorless liquid with a yield of 59.5%.

[0027] B6: Compound 14 (77 mg, 0.38 mmol), THF (10 mL), sodium hydroxide aqueous solution (15.2 mg, 0.38 mmol / L, 0.76 mL), and NaBH4 (72 mg, 1.90 mmol) were added to a 50 mL double-necked flask. After nitrogen protection, the mixture was reacted at 40 °C for 1.5 h. Then, sodium hydroxide aqueous solution (15.2 mg, 0.38 mmol / L, 0.38 mL) and BrBn (0.1 mL, 0.76 mmol) were added sequentially, and the reaction was continued at 40 °C for 3 h. After the reaction was completed, the pH was adjusted to weakly acidic with saturated NH4Cl. The reaction system was then extracted with ethyl acetate (EA) and saturated brine, and the extraction was repeated 2-3 times. The mixture was then dried over anhydrous Na2SO4. Column chromatography separation and purification (PE∶EA=5∶1) yielded the eighth intermediate (78.7 mg, 0.20 mmol), namely compound 15. The eighth intermediate was a colorless liquid with a yield of 54.2%.

[0028] B7: Compound 15 (1.97 mmol), CBr4 (981.4 mg, 2.96 mmol), and redistilled DCM (10 mL) were added to a 50 mL double-necked flask. The mixture was stirred in an ice bath under N2 protection. After the reaction system cooled to 0 °C, PPh3 (776.2 mg, 2.96 mmol) was slowly added, and the mixture was stirred overnight at room temperature. The reaction was monitored by TLC until complete. The solvent was removed by concentration under reduced pressure, and the mixture was purified by column chromatography (PE:EA = 80:1) to give 9-bromo-1,3-bis(benzylthio)nonane, i.e., compound 16. 9-bromo-1,3-bis(benzylthio)nonane is a pale yellow oily liquid with a yield of 96.0%.

[0029] The synthetic methods for 7-bromo-1,3-bis(benzylthio)heptane, 10-bromo-1,3-bis(benzylthio)decane, 11-bromo-1,3-bis(benzylthio)undecane, 12-bromo-1,3-bis(benzylthio)dodecane, or 13-bromo-1,3-bis(benzylthio)tridecane are similar to those for 9-bromo-1,3-bis(benzylthio)nonane, the difference being the type of compound 11. When 7-bromo-1,3-bis(benzylthio)heptane is to be synthesized, compound 11 is 4-bromobutanol; when 10-bromo-1,3-bis(benzylthio)decane is to be synthesized... Compound 11 is 7-bromoheptanol; when 11-bromo-1,3-bis(benzylthio)undecane is to be synthesized, compound 11 is 8-bromooctanol; when 12-bromo-1,3-bis(benzylthio)dodecane is to be synthesized, compound 11 is 9-bromononanol; when 13-bromo-1,3-bis(benzylthio)tridecane is to be synthesized, compound 11 is 10-bromodecanol; and the ratio of compound 11, DCM, Imidazole and TIPS-Cl in step B3 is 1.10 mmol: 10 mL: 2.75 mmol: 1.10 mmol.

[0030] Example 2 Preparation of triphenylphosphine derivatives The structure of the triphenylphosphine derivative is shown in the following formula TM; ; in,( ) n The n in the figure is 4~10, that is, the carbon chain length is 4~10; the triphenylphosphine derivative has a dual-targeting mechanism of action on the mitochondrial oxidative phosphorylation function of tumor cells, which can block the tricarboxylic acid cycle pathway mediated by pyruvate dehydrogenase complex while inhibiting the molecular chaperone function of tumor necrosis factor receptor-associated protein 1, thereby interfering with the operation of the mitochondrial respiratory chain.

[0031] When n is 5, the structure of the triphenylphosphine derivative is shown in Formula 6 below; ; The method for synthesizing the compound of Formula 6 is as follows: Compound 5 (218.8 mg, 0.5 mmol) prepared in Example 1, namely 8-bromo-1,3-bis(benzylthio)octane, PPh3 (196.7 mg, 0.75 mmol), and MeCN (20 mL) were added to a 100 mL double-necked flask. The mixture was heated to 95 °C, refluxed, and stirred for 36 h. The solvent was removed by concentration under reduced pressure, and the solution was purified by column chromatography (DCM:MeOH = 50~20:1) to obtain a pale yellow liquid (276 mg), with a yield of 79.0%. Its NMR data are as follows: 1 H NMR 1 H NMR (400 MHz, Chloroform- d) δ 7.92-7.64 (m, 15H), 7.31-7.21 (m, 10H), 3.89-3.77 (m, 3H), 3.65 (s, 2H), 3.60 (s, 2H), 2.60-2.42(m, 4H), 1.71-1.64 (m, 2H), 1.62-1.55 (m, 2H), 1.48-1.37 (m, 2H), 1.33-1.23(m, 2H). 13 C NMR (151 MHz, Chloroform- d ) δ 138.51 (d, J = 29.2 Hz), 135.04 (d, J = 3.0 Hz), 133.58, 133.51, 130.54, 130.46, 128.84, 128.79, 128.43, 128.36,126.84 (d, J = 14.5 Hz), 118.22 (d, J = 86.0 Hz), 44.44, 36.31, 35.00, 34.40,34.18, 30.11 (d, J = 16.1 Hz), 28.72, 26.18, 22.55, 22.38 (d, J = 42.8 Hz).HRMS (ESI): calcd. for C 40 H 44 BrPS2[M-Br] + : 619.2617, found: 619.2622. That is, the light yellow liquid is a phenylphosphine derivative when n is 5.

[0032] When n is 6, the structure of the triphenylphosphine derivative is shown in Formula 17 below; .

[0033] The method for synthesizing the compound of Formula 17 is as follows: Compound 16 (0.5 mmol) prepared in Example 1, namely 9-bromo-1,3-bis(benzylthio)nonane, PPh3 (196.7 mg, 0.75 mmol), and MeCN (20 mL) were added to a 100 mL double-necked flask. The mixture was heated to 95 °C, refluxed, and stirred for 36 h. The solvent was removed by concentration under reduced pressure, and the solution was purified by column chromatography (DCM:MeOH = 50~20:1) to obtain a pale yellow liquid (276 mg), with a yield of 96.0%. Its NMR data are as follows: 1H NMR (400 MHz, Chloroform- d ) δ 7.82-7.61 (m, 15H), 7.25-7.10 (m, 10H), 3.70-3.62 (m, 2H), 3.60 (s, 2H), 3.56 (s, 2H), 2.52-2.38 (m,3H), 1.71-1.59 (m, 3H), 1.41-1.30 (m, 2H), 1.30-1.18 (m, 4H), 1.18-1.09 (m, 3H). 13 C NMR (151 MHz, Chloroform- d ) δ 138.47 (d, J = 24.4 Hz), 135.04 (d, J =3.0 Hz), 133.62, 133.55, 130.54, 130.46, 128.85, 128.79, 128.45, 128.37,126.86 (d, J = 13.6 Hz), 118.19 (d, J = 85.7 Hz), 44.26, 36.27, 34.94, 34.48,34.27, 30.17 (d, J = 15.8 Hz), 29.66, 28.76 (d, J = 26.4 Hz), 26.06, 22.76,22.43 (d, J = 3.9 Hz). HRMS (ESI): calcd. for C 41 H 46 BrPS2[M-Br] + : 633.2773, found: 633.2782. That is, the light yellow liquid is a phenylphosphine derivative when n is 6.

[0034] Phenylenol derivatives with n = 4, 7, 8, 9, or 10 were synthesized using the same method, with a substrate, triphenylphosphine, and acetonitrile ratio of 0.5 mmol: 0.75 mmol: 20 mL. Column chromatography was used as the eluent for purification, employing a mixture of dichloromethane and methanol, with a volume ratio of dichloromethane to methanol ranging from 50 to 20:1.

[0035] Example 3: Verification of the tumor-inhibiting effect of triphenylphosphine derivatives The two triphenylphosphine derivatives prepared in Example 2, namely compound 6 and compound 17, were validated using the MTT colorimetric method. The inhibitory effects of compound 6, compound 17, and the existing common antitumor drugs gemcitabine (Gem) and CPI-613 on tumor cells PANC-1, MIAPaCa-2, BxPC-3, Aspc-1, CFPC-1, and Panco2 were investigated.

[0036] Specifically: when the cell confluence is 80%~90%, the cells are placed at a density of 3~6 × 10⁶ cells per well. 3 Cells were seeded at a density of 1000 cells / well in 96-well plates. The plates were incubated for 24 hours in a humidified, 37°C, 5% CO2 incubator. Then, solutions of the compound at gradient concentrations were added to the plates, and the plates were returned to the incubator for further incubation. After 48 hours, the drug-containing medium was removed, and complete medium containing 0.5 mg / mL MTT was added for another 4 hours of incubation. The suspension was then removed, and 100 μL of DMSO was added to dissolve the blue-purple crystals, followed by shaking for 15 minutes. The absorbance was measured at 490 nm using a microplate reader. Cell viability was calculated using Excel. Cell viability = (OD value of treatment group - OD value of blank group / (OD value of solvent control group - OD value of blank group) × 100%). A concentration-effect curve was plotted with drug concentration on the x-axis and cell viability on the y-axis. A regression equation was obtained using GraphPadPrism 10 to determine the 50% inhibiting concentration (IC50). 50 The final IC obtained from the experiment 50 This is the average of three independent experiments. The results are shown in Table 1 below; Table 1

[0037] As shown in Table 1, the two triphenylphosphine derivatives prepared in this invention have significantly greater inhibitory effects on tumor cells PANC-1, MIAPaCa-2, BxPC-3, Aspc-1, CFPC-1, and Panco2 than CPI-613; and their inhibitory effects on tumor cells PANC-1 and BxPC-3 are greater than those on Gem, while their inhibitory effects on the other tumor cells are close to those on Gem.

Claims

1. A triphenylphosphine derivative with anti-pancreatic cancer activity, characterized in that, The structure of the triphenylphosphine derivative is shown in the following formula TM; ； in,( ) n The n in the figure is 4~10, that is, the carbon chain length is 4~10; the triphenylphosphine derivative has a dual-targeting mechanism of action on the mitochondrial oxidative phosphorylation function of tumor cells. It can block the tricarboxylic acid cycle pathway mediated by pyruvate dehydrogenase complex while inhibiting the molecular chaperone function of tumor necrosis factor receptor-associated protein 1, thereby interfering with the operation of the mitochondrial respiratory chain.

2. The triphenylphosphine derivative with anti-pancreatic cancer activity according to claim 1, characterized in that, When n is 5, the structure of the triphenylphosphine derivative is shown in Formula 6 below; ； When n is 6, the structure of the triphenylphosphine derivative is shown in Formula 17 below; 。 3. A method for synthesizing the triphenylphosphine derivative with anti-pancreatic cancer activity as described in claim 1, characterized in that, The following steps are used: S1: Weigh the synthetic substrate, triphenylphosphine and acetonitrile, mix them, and reflux and stir at 95°C for 36 h; S2: After the reaction is complete, the solvent is removed by vacuum concentration, and the concentrated product is purified by chromatography to obtain the triphenylphosphine derivative. When n is 4 in the triphenylphosphine derivative, the substrate for synthesis is 7-bromo-1,3-bis(benzylthio)heptane; When n is 5 in the triphenylphosphine derivative, the substrate for synthesis is 8-bromo-1,3-bis(benzylthio)octane, with the structural formula shown in Formula 5 below; ； When n is 6 in the triphenylphosphine derivative, the substrate for synthesis is 9-bromo-1,3-bis(benzylthio)nonane, with the structural formula shown in Formula 16 below; ； When n is 7 in the triphenylphosphine derivative, the substrate for synthesis is 10-bromo-1,3-bis(benzylthio)decane; When n is 8 in the triphenylphosphine derivative, the substrate for synthesis is 11-bromo-1,3-bis(benzylthio)undecane; When n is 9 in the triphenylphosphine derivative, the substrate for synthesis is 12-bromo-1,3-bis(benzylthio)dodecane; When n is 10 in the triphenylphosphine derivative, the substrate for synthesis is 13-bromo-1,3-bis(benzylthio)tridecane.

4. The synthesis method according to claim 3, characterized in that, In step S1, the ratio of the synthetic substrate, triphenylphosphine, and acetonitrile is 0.5 mmol: 0.75 mmol: 20 mL.

5. The synthesis method according to claim 3, characterized in that, In step S2, the eluent used in column chromatography separation and purification is a mixture of dichloromethane and methanol, and the volume ratio of dichloromethane to methanol is 50~20:

1.

6. The synthesis method according to claim 3, characterized in that, The method for synthesizing the 8-bromo-1,3-bis(benzylthio)octane is as follows: A1: 5 mmol of α-lipoic acid, 10 mL of 0.5 M sodium hydroxide solution, 25 mmol of sodium borohydride, and 40 mL of tetrahydrofuran were placed in a double-necked flask and stirred at 40 °C for about 1.5 h under nitrogen protection. After the reaction was complete, 10 mL of 1 M sodium hydroxide solution and 10 mmol of benzyl bromide were added to the system, and the mixture was stirred at 40 °C for 4 h. After the reaction was completed by TLC monitoring, hydrochloric acid was added dropwise to the reaction system for acidification, and the pH of the system was adjusted to 2. Subsequently, the reaction system was extracted with dichloromethane and saturated brine, and the extraction was repeated 2-3 times. All organic phases were combined, dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. Finally, the first intermediate product was obtained by column chromatography using dichloromethane as the eluent. A2: Take 2.38 mmol of the first intermediate obtained from A1, dissolve it in 1-2 mL of redistilled tetrahydrofuran, and cool it to 0℃ to obtain the first intermediate-THF solution; add 7.1 mmol of lithium aluminum hydride and 5 mL of tetrahydrofuran to a double-necked flask, cool it to 0℃ under nitrogen protection, and slowly add the first intermediate-THF solution. Stir at room temperature for 3 h; monitor the reaction by TLC until it is complete, cool the reaction system to 0℃ again, slowly add Na2SO4 to the reaction system, and continue stirring for 15 min after no obvious bubbles emerge to ensure complete quenching; filter the quenched reaction solution under reduced pressure, and concentrate the filtrate under reduced pressure to obtain the second intermediate; A3: Take 1.97 mmol of the second intermediate obtained from A2, 2.96 mmol of carbon tetrabromide, and 10 mL of redistilled tetrahydrofuran and add them to a double-necked flask. Under nitrogen protection, place the flask in an ice bath and stir. After the reaction system cools to 0°C, slowly add 2.96 mmol of triphenylphosphine and stir overnight at room temperature. After the reaction is completed by TLC monitoring, concentrate under reduced pressure to remove the solvent, and use petroleum ether:ethyl acetate at a volume ratio of 80:1 as the eluent for column chromatography to obtain 8-bromo-1,3-bis(benzylthio)octane.

7. The synthesis method according to claim 3, characterized in that, The synthesis methods for the aforementioned 7-bromo-1,3-bis(benzylthio)heptane, 9-bromo-1,3-bis(benzylthio)nonane, 10-bromo-1,3-bis(benzylthio)decane, 11-bromo-1,3-bis(benzylthio)undecane, 12-bromo-1,3-bis(benzylthio)dodecane, or 13-bromo-1,3-bis(benzylthio)tridecane are as follows: B1: 1.94 mmol of 1,3-propanedithiol, 2.03 mmol of acetone, 35 mg of p-toluenesulfonic acid, 2.54 mmol of anhydrous magnesium sulfate and 40 mL of toluene were added to a round-bottom flask and reacted at 125 °C for 24 h. The reaction was monitored by TLC until it was complete. The system solution was cooled to room temperature, diluted with water, and then extracted with dichloromethane and saturated brine. The extraction was repeated 2-3 times. The solution was dried with Na2SO4 and concentrated under reduced pressure to obtain the third intermediate product. B2: Take 5.29 mmol of the third intermediate obtained from B1 and 100 mL of methanol and add them to a double-necked flask. Under nitrogen protection, cool the system to 0°C and add 1.13 mL of sodium periodate aqueous solution with a concentration of 1 g / mL. Place the reaction system at room temperature for 5 h. After the reaction is completed by TLC monitoring, collect the filtrate by vacuum filtration, concentrate under reduced pressure to remove the solvent, and then extract the reaction system with dichloromethane and saturated brine. Repeat the extraction 2-3 times. Dry with Na2SO4, concentrate under reduced pressure, and then separate and purify the colorless liquid fourth intermediate by column chromatography using dichloromethane:ethyl acetate with a volume ratio of 50:1 as the eluent. B3: Add 10 mL of dichloromethane, 2.75 mmol of imidazole and 1.1 mmol of triisopropylchlorosilane to a double-necked flask, then add 1.1 mmol of 4-bromobutanol, 6-bromohexanol, 7-bromoheptanol, 8-bromooctanol, 9-bromononanol or 10-bromodecanol. React at room temperature for 12 h. After the reaction is complete, monitor the reaction by TLC. Dilute with water, then extract the reaction system with dichloromethane and saturated brine. Repeat the extraction 2-3 times. Dry with Na2SO4, concentrate under reduced pressure, and use petroleum ether as eluent for column chromatography to obtain the fifth intermediate product. B4: 4.37 mmol of the fourth intermediate obtained from B2 and 20 mL of redistilled tetrahydrofuran were added to a double-necked flask. The system temperature was lowered to -78 °C under nitrogen protection. Then, 10.93 mmol of N,N,N',N'-tetramethylethylenediamine and 8.74 mmol of diisopropylaminolithium were added sequentially. After stirring at -78 °C for 20 min, 6.56 mmol of the fifth intermediate obtained from B3 was added. After stirring for another 30 min, the reaction system was placed at room temperature for 3.5 h. The reaction was monitored by TLC until it was complete. Under ice bath conditions, 15 mL of saturated ammonium chloride aqueous solution was added dropwise to the system. After the addition was complete, the mixture was stirred for 15 min to ensure complete quenching. The reaction system was then extracted with ethyl acetate and saturated brine. The extraction was repeated 2-3 times and dried with Na2SO4. The sixth intermediate was obtained by column chromatography using petroleum ether:ethyl acetate at a volume ratio of 5:1 as the eluent. B5: Take 3.09 mmol of the sixth intermediate obtained from B4 and 20 mL of acetonitrile and add them to a double-necked flask. Under nitrogen protection, add 0.14 mL of 2 mol / L hydrochloric acid dropwise. Stir at room temperature for 40 h. After the reaction is completed by TLC monitoring, cool the system to room temperature, concentrate under reduced pressure, and purify by column chromatography using dichloromethane:methanol at a volume ratio of 20:1 as the eluent to obtain the seventh intermediate. B6: Take 0.38 mmol of the seventh intermediate obtained from B5, 10 mL of tetrahydrofuran, 15.2 mg of 0.5 mol / L sodium hydroxide aqueous solution, and 1.9 mmol of sodium borohydride, and add them to a double-necked flask. Under nitrogen protection, react at 40 °C for 1.5 h. Then, add 15.2 mg of 1 mol / L sodium hydroxide aqueous solution and 0.76 mmol of benzyl bromide to the reaction system in sequence, and continue to react at 40 °C for 3 h. After the reaction is completed, adjust the pH to weakly acidic with saturated ammonium chloride aqueous solution. Then, extract the reaction system with ethyl acetate and saturated brine, repeat the extraction 2-3 times, and dry with anhydrous Na2SO4. Use petroleum ether:ethyl acetate at a volume ratio of 5:1 as the eluent for column chromatography to obtain the eighth intermediate. B7: Take 1.97 mmol of the eighth intermediate obtained from B6, 2.96 mmol of carbon tetrabromide, and 10 mL of redistilled tetrahydrofuran and add them to a double-necked flask. Under nitrogen protection, place the flask in an ice bath and stir. After the reaction system cools to 0°C, slowly add 2.96 mmol of triphenylphosphine and stir overnight at room temperature. After the reaction is completed by TLC monitoring, concentrate under reduced pressure to remove the solvent, and use petroleum ether:ethyl acetate at a volume ratio of 80:1 as the eluent for column chromatography to obtain 7-bromo-1,3-bis(benzylthio)heptane, 9-bromo-1,3-bis(benzylthio)nonane, 10-bromo-1,3-bis(benzylthio)decane, 11-bromo-1,3-bis(benzylthio)undecane, 12-bromo-1,3-bis(benzylthio)dodecane, or 13-bromo-1,3-bis(benzylthio)tridecane.

8. The use of the triphenylphosphine derivative according to claim 1 in the preparation of antitumor drugs.

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