Anthryl derivative triphenyl quaternary phosphonium salt compounds and uses thereof

Abstract

The application discloses an anthryl derivative triphenyl quaternary phosphonium salt compound and application thereof, in particular to a compound of formula I or a pharmaceutically acceptable salt thereof, wherein each variable is defined in the specification. The compound of the application shows good killing effect on various cancer cells. Moreover, the compound of the application has the advantages of cheap and easy-to-obtain raw materials, remarkable anticancer effect and suitability for large-scale preparation.

Description

Technical Field

[0001] This invention relates to the field of medicinal chemistry, specifically to anthracene-derived triphenyl quaternary phosphate compounds and their preparation methods, pharmaceutical compositions comprising the compounds, and the use of the compounds in the preparation of medicaments for treating or preventing cancer. Background Technology

[0002] Cancer, characterized by its high incidence, low cure rate, and difficulty in detection, has become a major threat to human life and health in the 21st century. Currently, the incidence and mortality rates of cancer in my country are showing an upward trend year by year. Therefore, the development of effective drugs for cancer treatment has become an urgent task in the field of drug synthesis (CA Cancer J Cli. 2021, 71(3):209-249.).

[0003] Mitochondria are unique organelles found in eukaryotic cells, possessing a specialized structure and their own set of genetic material. As crucial sites for the tricarboxylic acid cycle, fatty acid oxidation, and amino acid degradation, maintaining the integrity of mitochondrial structure and function is essential for normal cellular physiological activity. Cancer cell proliferation requires energy from mitochondria; therefore, mitochondria have become potential targets for the development of novel anti-tumor drugs. The design of small-molecule drugs targeting mitochondria aims to influence their physiological activities and ultimately kill cancer cells (Cell. 2006, 126(1):177-89.).

[0004] In previous studies, the inventors' research group discovered a class of anthracene-substituted small molecules, XI-011, with significant anticancer activity. Figure 1), which has significant inhibitory activity against a variety of cancer cells (Pharmacological Research, 2022, 177, 106-128). Recently, through in-depth research on anti-cancer mechanisms, it has been found that it has a strong activating effect on the P53 tumor suppressor gene and exhibits good anti-cancer activity (Int.J.Cancer, 2005, 115, 701–710.). In 2006, XI-011 was found to have the ability to bind to nucleic acids and inhibit DNA transcription (Antiviral Res. 2006, 69(1): 9-23.). The anti-cancer mechanism of XI-011 was initially elucidated in 2011, namely, by inhibiting the expression of MDMX, thereby increasing the level of P53 to induce apoptosis, showing significant inhibitory activity against a variety of cancer cells such as breast cancer and cervical cancer (Neoplasia. 2011, 13(7): 611-9.). Subsequent studies have shown that XI-011 does not directly act on MDMX or p53, but rather regulates MDMX expression to inhibit MDMX and upregulate p53 levels. In 2023, XI-011 was found to act as a ligand for hnRNPA2B1, binding to its nucleotide-binding domain and thus inhibiting MDMX transcription (Pharmacological Research, 2023, 189:106696.).

[0005] Based on previous research, the inventors have innovatively designed and synthesized a new class of compounds for cancer treatment through further in-depth research. These compounds have broad-spectrum anti-tumor activity and can effectively inhibit cervical cancer, gastric cancer, breast cancer, and glioma cells. They can inhibit MDMX transcription and target mitochondria, and have the advantages of simple preparation and low cost. Summary of the Invention

[0006] On the one hand, the present invention provides a compound of formula I or a pharmaceutically acceptable salt thereof.

[0007]

[0008] in:

[0009] R1 is selected from halogen and C. 1-6 alkyl;

[0010] Ring A is selected from naphthyl, anthracene, phenanthrene, and

[0011] L1 is selected from direct bonds and C 1-6 Alkylene;

[0012] X - Indicates halide ions;

[0013] n is 0, 1, 2, or 3;

[0014] m can be 1, 2, or 3.

[0015] In some implementations, R1 is selected from halogens and C. 1-3 alkyl;

[0016] L1 is selected from direct bond and methylene;

[0017] X - Cl - or Br - ;

[0018] n is 0 or 1;

[0019] m is 1.

[0020] In some embodiments, ring A is selected from naphthyl, anthracene, and

[0021] In some implementation schemes, Selected from:

[0022]

[0023] In some embodiments, the compound of formula I is selected from the following compounds:

[0024]

[0025] In another aspect, the present invention provides pharmaceutical compositions comprising a compound of formula I or a pharmaceutically acceptable salt thereof, and optionally a pharmaceutically acceptable excipient.

[0026] On the other hand, the present invention provides a compound of formula I or a pharmaceutically acceptable salt thereof for treatment or prevention, particularly for the treatment or prevention of cancer.

[0027] On the other hand, the present invention provides the use of a compound of formula I or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating or preventing cancer, preferably the cancer being selected from cervical cancer, gastric cancer, breast cancer and / or glioma.

[0028] In some implementations, the cell lines involved in the cancer are cervical cancer cell line Hela, gastric cancer cell line MKN45, breast cancer cell line MCF-7, or glioma cell line U87.

[0029] In another aspect, the present invention provides a method for synthesizing compounds of formula I, and the following examples illustrate general synthetic schemes for synthesizing compounds of the present invention.

[0030] In some embodiments, the present invention provides a method for preparing a compound of formula I, comprising the following steps:

[0031]

[0032] The compound of formula II reacts with triphenylphosphine to produce the compound of formula I.

[0033] Where X - Indicates a halide ion; X represents a halogen;

[0034] The other variables, such as R1, ring A, L1, and n, are defined as in Equation I above.

[0035] It should be understood that the specific type of X in Equation II is related to X. - The corresponding one.

[0036] For the reactions described, appropriate reaction conditions are known to those skilled in the art or can be conventionally determined, such as those shown in the examples. Unless otherwise specified, the starting materials and reagents used in the preparation of these compounds are generally commercially available or can be prepared by the methods described below, similar methods given below, or methods known in the art. If necessary, the starting materials and intermediates in the synthetic reaction process can be separated and purified using conventional techniques, including but not limited to filtration, distillation, crystallization, and chromatography.

[0037] In some embodiments, the reaction is carried out in an organic solvent, preferably acetonitrile.

[0038] In some embodiments, the reaction is carried out at -15°C to 100°C, preferably at 0°C to 50°C, and more preferably at room temperature.

[0039] definition:

[0040] Unless otherwise specified, the various terms used in this specification and claims have the meanings shown below. Where a particular term or phrase is not specifically defined, it should not be considered uncertain or unclear, but rather should be appropriately understood in accordance with the context of this document or its general meaning in the art.

[0041] As used herein, the term "alkyl" refers to a fully saturated straight-chain or branched aliphatic hydrocarbon group. Specifically, alkyl groups can have 1 to 6, 1 to 5, 1 to 4, 1 to 3, or 1 to 2 carbon atoms. A suitable C... 1-6 Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, and isopropyl.

[0042] When the alkyl groups defined above become divalent groups, that is, when they have two single bonds attached to two other groups, they are called "alkylene" groups. Alkylenes can have 1 to 6, 1 to 5, 1 to 4, 1 to 3, or 1 to 2 carbon atoms. Non-limiting examples of alkylenes include methylene, ethylene, methylmethylene, or propylene.

[0043] As used herein, the terms “halogen” or “halogenated” refer to fluorine (F), chlorine (Cl), bromine (Br) and / or iodine (I).

[0044] As used herein, the term "halogen ion" refers to the fluoride ion (F... - ), chloride ions (Cl) - ), bromide ions (Br) - ) and / or iodide ions (I - ).

[0045] As used herein, the term "direct bond" refers to a covalent bond that is directly connected to the relevant group. For example, when L1 is a direct bond, Formula I... It can also be expressed as That is, the triphenylphosphine moiety is directly connected to the A ring.

[0046] It should be understood that when a bond passes through a ring instead of being attached to an atom, it indicates that the bond can be attached to different positions on the ring, provided that the valence bond rules are followed. For example... It can represent wait.

[0047] It should be understood that those skilled in the art will know that "Ph" in Formula I and the compounds of the examples refers to phenyl; and "P" connected to L1 refers to phosphorus. Therefore, It can also be expressed as

[0048] As used herein, the term “pharmaceutical acceptable” means a molecular entity or composition that is approved or can be approved by the relevant authorities of each country, or is listed in a generally accepted pharmacopoeia for use in animals, preferably humans, or that will not produce adverse, allergic or other adverse reactions when administered appropriately to animals, such as humans.

[0049] As used herein, the term "pharmaceutically acceptable salt" means a salt of the compound of the present invention that is pharmaceutically acceptable and has the pharmacological activity required by the parent compound. Specifically, such salts are non-toxic and may be inorganic acid addition salts, organic acid addition salts, or base addition salts. Specifically, such salts include: (1) acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc.; or acid addition salts formed with organic acids such as acetic acid, propionic acid, hexanoic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid. Sulfonic acid, camphor sulfonic acid, glucohepanoic acid, 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid, lauryl sulfate, gluconic acid, glutamic acid, hydroxynaphthenic acid, salicylic acid, stearic acid, mucoconic acid, etc.; or (2) salts formed when acidic protons present in the parent compound are replaced by metal ions such as alkali metal ions, alkaline earth metal ions or aluminum ions, or when coordinated with organic bases such as ethanolamine, diethanolamine, triethanolamine, N-methylglucosamine, etc. Those skilled in the art understand the general principles and techniques for preparing pharmaceutical salts, such as those described in Berge et al., Pharm ScL, 66, 1-19. (1977).

[0050] As used herein, the term "pharmaceuticalally acceptable excipient" refers to an additive in a pharmaceutical composition other than the active ingredient, also known as an excipient, that is pharmacologically inactive, compatible with other components in the composition, and acceptable for administration to warm-blooded animals such as humans. It can be used as a carrier or medium for the compounds of this invention in the form of administration, examples including but not limited to cellulose and its derivatives (such as sodium carboxymethyl cellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as magnesium stearate), calcium sulfate, vegetable oils, polyols (such as propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (such as Tween derivatives), wetting agents (such as sodium dodecyl sulfate), colorants, flavoring agents, stabilizers, antioxidants, preservatives, etc.

[0051] As used herein, "compounds of the present invention" includes compounds of formula I of the present invention or pharmaceutically acceptable salts thereof.

[0052] application

[0053] The compounds and compositions of the present invention can be administered alone or in combination with one or more other therapeutic agents. Methods of administration of the compounds and compositions include, but are not limited to, oral, rectal, parenteral, or intravenous administration.

[0054] The effective therapeutic dose will depend in particular on the disease being treated, the severity of the disease, the age and relative health of the subject, the potency of the compound being administered, the mode of administration, and the desired treatment. In some embodiments, the compounds of the present invention may be administered at daily doses of 0.01 to 500 mg / kg body weight, 0.01 to 100 mg / kg body weight, for example, 0.1 to 10 mg / kg body weight.

[0055] Beneficial effects:

[0056] The compounds of this invention have broad-spectrum anticancer activity and show significant killing effects on a variety of cancers, such as human cervical cancer cell line HeLa, gastric cancer cell line MKN45, breast cancer cell line MCF-7, and glioma cell line U87.

[0057] The compounds of this invention can inhibit MDMX transcription and target mitochondria, thereby being effective against some drug-resistant tumors;

[0058] The compounds of this invention use commercially available compounds as substrates and can be synthesized through a simple synthetic route (even through one or two chemical reactions). They have the advantages of simple preparation conditions, easy separation, and suitability for industrial production. Attached Figure Description

[0059] The accompanying drawings are provided to further understand the technical solutions of the present invention and constitute a part of the specification. They are used together with the specific embodiments of this application to explain the technical solutions of the present invention and do not constitute a limitation on the technical solutions of the present invention.

[0060] Figure 1 Showing the structure of XI-011.

[0061] Figure 2 , Figure 3 The images show the proton and carbon NMR spectra of compound 4, respectively.

[0062] Figure 4 , Figure 5 The images show the 1H and 1C NMR spectra of compound 7, respectively.

[0063] Figure 6 , Figure 7 The images show the proton and carbon NMR spectra of compound 9, respectively.

[0064] Figure 8 , Figure 9 The images show the 1H and 1C NMR spectra of compound 11, respectively.

[0065] Figure 10 , Figure 11 The images show the proton and carbon NMR spectra of compound 13, respectively.

[0066] Figure 12 , Figure 13 The images show the proton and carbon NMR spectra of compound 15, respectively.

[0067] Figure 14 , Figure 15 The images show the 1H and 1C NMR spectra of compound 17, respectively.

[0068] Figure 16 The figure shows the half-maximal inhibition of compound 4 on the gastric cancer cell line MKN45.

[0069] Figure 17 The figure shows the half-maximal inhibitory effect of compound 7 on the human cervical cancer cell line HeLa.

[0070] Figure 18 The figure shows the half-maximal inhibitory effect of compound 13 on the breast cancer cell line MCF-7.

[0071] Figure 19 The figure shows the half-maximal inhibitory effect of compound 13 on glioma cells U87. Detailed Implementation

[0072] The technical solution of the present invention will be clearly and completely described below with reference to specific embodiments. However, it should be understood that the scope of protection of the present invention is not limited to these embodiments, and all changes or equivalent substitutions that do not depart from the concept of the present invention are included within the scope of protection of the present invention.

[0073] Unless otherwise specified, the experimental materials and reagents used in the following examples can be obtained from commercial sources, prepared according to existing methods, or prepared according to methods similar to those disclosed in this application.

[0074] It should be understood that, in the absence of specific definitions or descriptions, the abbreviations used herein have the meanings commonly understood by those skilled in the art.

[0075] Example 1: Preparation of compound 4:

[0076]

[0077] Step 1. Under argon protection, commercially available anthraquinone 1 (50 mmol) was dissolved in 350 mL of dry tetrahydrofuran. The resulting system was heated to 55°C, and a tetrahydrofuran solution of methyl magnesium bromide (100 mL, 1.5 M / L, 150 mmol) was slowly added dropwise to the reaction system. After the addition was complete, the reaction mixture was maintained at 55°C, stirred, and reacted for 3 hours. After the reaction was complete as monitored by TLC, 100 mL of water was added to the reaction system to quench the reaction. The organic phases were extracted with dichloromethane (3 × 80 mL), combined, dried over anhydrous sodium sulfate, and the solvent removed by rotary evaporation under vacuum. The resulting product required no further purification and was used directly in the next reaction step.

[0078] Step 2. Compound 2 (10 mmol) was dissolved in 250 ml of tetrahydrofuran. 50 ml of 48% hydrobromic acid aqueous solution was added to the reaction system, and the reaction was continued at room temperature for 1 hour. A large amount of pale yellow crystals appeared in the system. After filtration and drying, the target compound 3 was obtained, with a crude yield of 69%.

[0079] Step 3. Dissolve compound 3 (5 mmol) in 20 mL of acetonitrile, and add triphenylphosphine (7.5 mmol) to the solution. Continue the reaction at room temperature for 5 hours, then monitor the reaction by TLC. After the reaction is complete, remove the acetonitrile by rotary evaporation under vacuum. Dissolve the residue in V... 二氯甲烷 / V 甲醇 The solution was passed through a silica gel column at a ratio of 10:1 to obtain a yellow solid compound 4, with a yield of 81%.

[0080] Compound 4: 1 H NMR(500MHz, CDCl3)δ:7.88(d,J=8.5Hz,2H),7.56(d,J=8.5Hz,2H),7.51-7.48(m,3H),7.30-7 .28(m,12H),7.12(t,J=8.5Hz,2H),6.92(t,J=7.5Hz,2H),5.69(d,J=13.5Hz,2H),2.72(s,3H); 13 C NMR(125MHz, CDCl3)δ:134.67,134.65,134.20,134.12,132.40,132.34,130.21,130.17,129.69,129.59,129.19,12 9.16,125.53,124.93,124.63,124.43,124.41,117.70,117.03,116.31,116.23,25.32,24.95,14.32.ESI-HRMScalcd for C 34 H 28 P([M-Br - ] + )467.1924,found 467.1917.

[0081] Example 2: Preparation of compound 7:

[0082]

[0083] Step 1. Add triphenylphosphine (15 mmol) to a round-bottom flask containing 20 ml of acetonitrile and seal the flask. After it has completely dissolved, bubble the resulting solution with nitrogen for 2 minutes, and then use nitrogen protection. Add liquid bromine to the reaction system at room temperature. Quickly add commercially available 9-anthraquinone 5 (10 mmol) to the reaction system and react at room temperature for 1 hour. After the reaction is complete, filter the solution at 0 degrees Celsius. Dissolve the filtered solid in 1,4-dioxane and remove excess bromine by vacuum rotary evaporation. Then recrystallize the obtained solid twice in chloroform. The golden-yellow solid obtained is compound 6, with a yield of 76%.

[0084] Step 2. Dissolve compound 6 (5 mmol) in 20 mL of acetonitrile, and add 7.5 mmol of triphenylphosphine to the solution. Continue the reaction at room temperature for 5 hours, then monitor the reaction by TLC. After the reaction is complete, remove the acetonitrile by rotary evaporation under vacuum. Dissolve the residue in V... 二氯甲烷 / V 甲醇 The solution was passed through a silica gel column at a ratio of 10:1 to obtain a yellow solid compound 7, with a yield of 75%.

[0085] Compound 7: 1 H NMR(400MHz, Methanol-d4)δ:8.64(d,J=3.6Hz,1H),8.06(d,J=8.0Hz,2H),7.89(d,J=9.2Hz,2H),7.83-7.78(m,3H) ,7.60-7.54(m,8H),7.52-7.51(m,3H),7.49(m,1),7.39(t,J=6.4Hz,2H),7.22-7.17(m,2H),5.93(d,J=14.2Hz,2H). 13 C NMR(100MHz, CDCl3)δ=134.91,134.88,134.48,134.39,134.25,132.24,132.14,132.06,131.17,131.11,131.06,131.02, 129.98,129.85,129.00,128.68,128.56,127.33,126.57,125.10,124.08,124.05,118.24,117.40,25.82,25.35; ESI-HRMS calcd for C 33 H 25 BrP([M-Br - ] + )531.0872,found531.0862

[0086] Example 3: Preparation of compound 9:

[0087]

[0088] Step 1. Dissolve 5 mmol of commercially available 9-bromomethylanthracene in 20 mL of acetonitrile, and add 7.5 mmol of triphenylphosphine to the solution. Continue the reaction at room temperature for 5 hours, then monitor the reaction by TLC. After the reaction is complete, remove the acetonitrile by rotary evaporation under vacuum. Dissolve the residue in V... 二氯甲烷 / V 甲醇 The solution was passed through a silica gel column at a ratio of 10:1 to obtain a yellow solid compound 9, with a yield of 82%.

[0089] Compound 9: 1 H NMR(400MHz, DMSO-d6)δ:8.71(d,J=3.6Hz,1H),8.07(d,J=8.4Hz,2H),7.97(d,J=8.4Hz,2H),7.79(t,J=9.2Hz, 3H),7.58-7.53(m,7H),7.51-7.45(m,6H),7.39(t,J=6.5Hz,2H),7.13(t,J=6.5Hz,2H),6.11(d,J=14.6Hz,2H). 13 C NMR(100MHz,DMSO-d6)δ:134.95,134.33,134.23,130.82,130.78,129.81,129.69,128.95,125.92,125.13,124.24,117.97,117.04.ESI-HRMS calcd for C 33 H 26 P([M-Br - ] + )453.1767,found453.1758.

[0090] Example 4: Preparation of compound 11:

[0091]

[0092] Step 1. Dissolve 5 mmol of commercially available 4-methyl-1-bromomethylnaphthalene in 20 mL of acetonitrile, and add 7.5 mmol of triphenylphosphine to the solution. Continue the reaction at room temperature for 5 hours, then monitor the reaction by TLC. After the reaction is complete, remove the acetonitrile by rotary evaporation under vacuum. Dissolve the residue in V... 二氯甲烷 / V 甲醇 The mixture was passed through a silica gel column at a ratio of 10:1 to obtain a white solid compound 11, with a yield of 82%.

[0093] Compound 11: 1H NMR(500MHz, CDCl3)δ:7.72-7.61(m,10H),7.51(m,5H),7.47-7.45(m,1H),7.35(d,J=8.6Hz,1H),7.25 (t,J=7.7Hz,1H),7.21(t,J=7.7Hz,1H),7.01(t,J=7.7Hz,1H),5.72(s,1H),5.69(s,1H),3.46(s,2H). 13 C NMR(100MHz, CDCl3)δ:135.08,135.05,134.38,134.28,133.54,132.33,130.56,130.23,130.11, 129.42,129.37,128.66,126.44,125.81,125.42,123.14,118.11,117.2,27.85,27.38.ESI-HRMS calcd forC 30 H 26 P([M-Br - ] + )417.1767,found 417.1760.

[0094] Example 5: Preparation of compound 13:

[0095]

[0096] Step 1. Dissolve 5 mmol of commercially available 5-bromo-10,11-dihydro-5H-dibenzo[a,d][7]cycloheptene in 20 mL of acetonitrile, and add 7.5 mmol of triphenylphosphine to the solution. After reacting at room temperature for 5 hours, the reaction is detected by TLC.

[0097] After the reaction is complete, acetonitrile is removed by vacuum rotary evaporation. The residue is then treated with V... 二氯甲烷 / V 甲醇 The mixture was passed through a silica gel column at a ratio of 10:1 to obtain a white solid compound 13, with a yield of 78%.

[0098] Compound 13: 1 H NMR (500MHz, CDCl3) δ = 7.75 (t, J = 8.1Hz, 3H), 7.66–7.45 (m, 8H), 7.28 (d, J = 7.2Hz, 6H), 7.25 –7.20(m,3H),7.10(d,J=7.7Hz,2H),7.04–6.95(m,2H),3.47(s,1H),2.71(d,J=2.7Hz,4H). 13C NMR(125MHz, CDCl3)δ=141.71,141.66,135.22,135.19,135.07,134.98,133.91,133.85,131.08,131.06,130 .24,130.12,129.74,129.70,129.68,129.62,127.50,127.47,118.25,117.46,54.83,54.49,32.99;ESI-HRMS calcdfor C 33 H 28 P([M-Br - ] + )455.1923,found 455.1921.

[0099] Example 6: Preparation of compound 15:

[0100]

[0101] Step 1. Dissolve 5 mmol of commercially available 2-bromomethylnaphthalene in 20 mL of acetonitrile, and add 7.5 mmol of triphenylphosphine to the solution. Continue the reaction at room temperature for 5 hours, then monitor the reaction by TLC. After the reaction is complete, remove the acetonitrile by rotary evaporation under vacuum. Dissolve the residue in V... 二氯甲烷 / V 甲醇 The mixture was passed through a silica gel column at a ratio of 10:1 to obtain a white solid compound 15, with a yield of 71%.

[0102] Compound 15: 1 H NMR (500MHz, CDCl3) δ: 7.77-7.70 (m, 9H), 7.68 (d, J = 8.7Hz, 1H), 7.62-7.55 (m, 6H), 7. 52(d,J=8.0Hz,3H),7.44-7.35(m,2H),7.14(d,J=8.5Hz,1H),5.52(d,J=14.5Hz,2H). 13 C NMR (100MHz, CDCl3) δ: 135.07, 135.04, 134.59, 134.50, 131.35, 131.28, 130.28, 130.16, 128. 69,128.50,128.47,127.96,127.65,126.65,126.47,118.36,117.51,31.31,30.85.ESI-HRMS calcd for C 29 H 24 P([M-Br - ] + )403.1610,found 403.02.

[0103] Example 7: Preparation of compound 17:

[0104]

[0105] Step 1. Dissolve 5 mmol of commercially available 1-bromomethylnaphthalene in 20 mL of acetonitrile, and add 7.5 mmol of triphenylphosphine to the solution. Continue the reaction at room temperature for 5 hours, then monitor the reaction by TLC. After the reaction is complete, remove the acetonitrile by rotary evaporation under vacuum. Dissolve the residue in V... 二氯甲烷 / V 甲醇 The solution was passed through a silica gel column at a ratio of 10:1 to obtain a white solid compound 17, with a yield of 86%.

[0106] Compound 17: 1 H NMR(500MHz, CDCl3)δ:7.72-7.61(m,10H),7.51(m,5H),7.47-7.45(m,1H),7.35(d,J=8.6Hz,1H),7.25 (t,J=7.7Hz,1H),7.21(t,J=7.7Hz,1H),7.01(t,J=7.7Hz,1H),5.72(s,1H),5.69(s,1H),3.46(s,2H). 13 C NMR(100MHz, CDCl3)δ:135.08,135.05,134.38,134.28,133.54,132.33,130.56,130.23,130.11, 129.42,129.37,128.66,126.44,125.81,125.42,123.14,118.11,117.23,27.85,27.38.ESI-HRMS calcd forC 29 H 24 P([M-Br - ] + )403.1610,found403.04.

[0107] Example 8 Pharmacological Test

[0108] The inhibitory activities of compounds 4, 7, 9, 11, 13, 15, and 17 on human cervical cancer cell line HeLa, gastric cancer cell line MKN45, breast cancer cell line MCF-7, and glioma cell line U87 (all four cell lines were obtained from the cell bank of the Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences) were evaluated.

[0109] The half-maximal inhibitory concentration (IC50) of the compound against four human tumor cell lines (HeLa, MKN45, MCF-7, and U87) was determined using the MTT assay (3-(4,5-dimethylthiazol-2)-2,5-diphenyltetrazolium bromide). 50 ).

[0110] Detection principle: MTT can pass through the cell membrane and enter the cell. Succinate dehydrogenase in the mitochondria of living cells can reduce exogenous MTT to water-insoluble blue-purple needle-shaped formazan crystals, which are deposited in the cells. The crystals can be dissolved by dimethyl sulfoxide (DMSO), and the absorbance can be measured to reflect the cell viability.

[0111] Half-maximal inhibitory concentration (IC50) 50 The drug concentration is defined as the concentration at which 50% of tumor cells survive. A standard curve of cell growth inhibition rate is created based on the measured optical density (OD value), and the corresponding drug concentration is then obtained from the curve.

[0112] The determination method is as follows:

[0113] 1. Seed cells at a density of 2000 cells / well in 96-well plates and incubate in a CO2 incubator for 24 hours;

[0114] 2. Serially dilute the test compound (stock solution 10mM) to 10μM-5μM-2.5μM-1.25μM-0.625μM-0.3125μM-0.15625μM;

[0115] 3. Set up three parallel wells for each concentration, add the test compound to the seeded cells, and continue culturing for 72 hours;

[0116] 4. Remove the 96-well plate, add 20 μl of MTT solution to each well, and incubate in an incubator for 2 hours;

[0117] 5. Discard the supernatant, add 150 μl DMSO to each well, shake well for 15 min, and wait for the formazan to completely dissolve;

[0118] 6. Measure the absorbance at 570 nm.

[0119] Three parallel experiments were conducted, and the average value of the results was taken. The measured IC 50 The values ​​are shown in Table 1.

[0120] Table 1

[0121]

[0122] Pharmacological tests showed that the compounds of this invention exhibited significant antitumor activity against various cancer cell lines. Specifically, compound 13 showed an IC50 value against human cervical cancer cell line HeLa, gastric cancer cell line MKN45, breast cancer cell line MCF-7, and glioma cell line U87. 50 The values ​​reached IC respectively 50 The values ​​reached 3.498±0.567 μM, 4.568±0.464 μM, 0.900±0.137 μM, and 2.620±0.284 μM, respectively. Compound 13 altered the rigid planar core structure of the anthracene or naphthalene ring, replacing it with a flexible dibenzocycloheptane structure. Compared with other compounds, it showed significant inhibitory effects on the four cell lines, and its activity against the breast cancer MCF-7 cell line was increased by about 2 times.

[0123] Unconstrained by any theoretical framework, the anticancer mechanism of anthracene-derived triphenyl quaternary phosphate compounds is believed to involve the strong lipophilicity of triphenyl quaternary phosphates, which allows them to interact with the hydrophobic regions of the mitochondrial membrane, leading to their accumulation within the mitochondria. Mitochondria are vital organs for cellular metabolism and energy supply, and also a significant energy source for the malignant growth of cancer cells. While targeting mitochondria, anthracene-derived triphenyl quaternary phosphate compounds also possess the ability to inhibit DNA, ultimately suppressing mitochondrial DNA transcription, affecting normal mitochondrial physiological activities, and inducing apoptosis in cancer cells. This explains why compounds 4, 7, 9, 11, 13, 15, and 17 exhibited good inhibitory activity against human cervical cancer cell line HeLa, gastric cancer cell line MKN45, breast cancer cell line MCF-7, and glioma cell line U87.

[0124] The above embodiments describe in detail the preferred embodiments of the present invention, but the present invention is not limited to the above embodiments and implementation methods. Within the scope of the present invention, various equivalent modifications can be made to the technical solutions of the present invention, and all such modifications fall within the protection scope of the present invention. To avoid unnecessary repetition, the present invention will not describe the possible combinations of various features, steps, and / or elements separately; as long as they do not violate the spirit of the present invention, they should also be considered as the content disclosed by the present invention.

Claims

1. A pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient, characterized in that, The compound of formula I is selected from the following compounds: 。 2. Use of the pharmaceutical composition according to claim 1 in the preparation of a medicament for treating or preventing cancer, wherein the cancer is selected from cervical cancer, gastric cancer, breast cancer and / or glioma; wherein the cancer involves cell lines selected from: cervical cancer cell line HeLa, gastric cancer cell line MKN45, breast cancer cell line MCF-7 or glioma cell line U87.

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