Bibenzyl polycyclic compound, preparation method thereof and application of bibenzyl polycyclic compound in preparation of anti-tumor disease drugs
By optimizing the structure and synthesis route of bibenzyl polycyclic compounds, the problems of poor cancer cell inhibition and insufficient selectivity in the existing technology were solved, and efficient inhibition of various cancer cells was achieved, especially the selective killing of drug-resistant cells.
Patent Information
- Application Number
- CN202510937857.4
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-07-08
- Publication Date
- 2025-10-10
AI Technical Summary
Existing technologies are difficult to effectively inhibit the growth of various cancer cells, especially drug-resistant cells, and are highly toxic to normal cells and lack selectivity.
A series of bibenzyl polycyclic compounds were designed and synthesized. By optimizing their structures, especially the length of the connecting bonds and substituents, their inhibitory activity against cancer cells was improved, and these compounds were prepared through multiple synthetic routes.
It achieves effective inhibition of multiple cancer cells, especially the selective killing of drug-resistant cells, has low toxicity to normal cells, and has broad-spectrum anti-cancer activity.
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Figure CN120757494A_ABST
Abstract
Description
Technical Field
[0001] The present invention belongs to the field of medical technology and relates to a bibenzyl polycyclic compound, a preparation method thereof and an application thereof in the preparation of an anti-tumor drug. Background Art
[0002] The information disclosed in this background technology section is only intended to enhance understanding of the overall background of the invention and should not necessarily be regarded as an admission or any form of suggestion that the information constitutes the prior art already known to those skilled in the art.
[0003] Macrocyclic Bisbibenzyls are a class of natural products with unique structures, mainly found in mosses (such as Marchantia Marchantia ) and certain fungi. Its core structure consists of two bibenzyl units connected by ether or carbon-carbon bonds, forming a rigid three-dimensional conformation that imparts significant biological activity. Studies have shown that this class of compounds can inhibit tumor growth through multiple mechanisms, including inhibiting tubulin polymerization, arresting the cell cycle (such as the G1 / S or G2 / M phases), inducing tumor cell apoptosis, and inhibiting angiogenesis and metastasis-related pathways, thereby exerting anti-tumor effects.
[0004] The antitumor activity of macrocyclic bisbibenzyl compounds is closely related to their structural characteristics. Substituents on the bibenzyl backbone (e.g., hydroxyl, methoxy) and their spatial arrangement significantly influence their targeting ability. For example, Marchantin C binds to DNA topoisomerase II via the hydroxyl group on the benzyl ring, interfering with DNA replication. Furthermore, the size and flexibility of the macrocyclic ring determine its transmembrane permeability and target affinity. Structural modifications can further optimize their pharmacokinetic properties, reduce toxicity, and enhance antitumor specificity, providing important insights for drug design. Summary of the Invention
[0005] Research has revealed that tricyclic compounds containing a bibenzyl structure exhibit strong inhibitory activity against A549, MDA-MB-231, and MCF-7 tumor cells. These compounds have been optimized to prepare a series of compounds with similar activity. Based on these findings, the present invention provides bibenzyl polycyclic compounds, methods for their preparation, and their use in the preparation of anti-tumor drugs. The compounds provided by the present invention exhibit strong inhibitory effects against various cancer cells, are selective for drug-resistant cells, and exhibit minimal toxicity to normal cells, making them promising novel potential anti-tumor drugs.
[0006] In order to achieve the above object, the technical solution of the present invention is: In the first aspect, a bibenzyl polycyclic compound has a chemical structure as shown in Formula A.
[0007] wherein X and Y are independently selected from C or N; R1 is absent, -H, -CH3, -C2H5, -OCH3, -OBn, -F, -Br, -NH2, -OH, -NHCH3, -CN or -CONH2; R2, R3, R4, R5, and R6 are each independently selected from -H, -CH3, -C2H5, -OCH3, -OBn, -F, -Br, -NH2, -OH, -NHCH3, -CN, and -CONH2; R7 is -H or , n is 1 or 2.
[0008] When X is N, R1 does not exist, that is, its chemical structure is: .
[0009] In some embodiments, its chemical structure is as shown in Formula I or Formula II, .
[0010] In the compound represented by formula I, when X is N, R1 is absent, that is, its chemical structure is: .
[0011] In the compounds represented by Formula II, studies have shown that the value of n affects the anti-tumor activity of the compounds. Compared with n=2, when n=1, the anti-tumor activity is higher.
[0012] In some embodiments, the compound is selected from the following compounds: .
[0013] In a second aspect, a method for preparing a bibenzyl polycyclic compound comprises the steps of reacting according to any one of the following reaction schemes 1-5; Reaction Scheme 1 is: ; Reaction Scheme 2 is: ; Reaction Scheme 3 is: ; Reaction Scheme 4 is: ; Reaction Scheme 5 is:
[0014] In Reaction Scheme 1, X and Y are C or N, R1 is -H or -OCH3, R2 is -H or -OCH3, R3 is -H, -CH3 or -OCH3, and R4 is -H or -OCH3. In Reaction Scheme 2, R1 is -H or -Br, and R2 is -H or -Br. In Reaction Scheme 5, X is C or N.
[0015] In a third aspect, a pharmaceutical composition comprises the above-mentioned bibenzyl polycyclic compound or a pharmaceutically acceptable salt thereof.
[0016] The pharmaceutically acceptable salt according to the present application can be a salt formed with an inorganic acid (e.g., hydrochloric acid, sulfuric acid, nitric acid, or hydrobromic acid, etc.), a salt formed with an organic acid (e.g., methanesulfonic acid, toluenesulfonic acid, or trifluoroacetic acid), or a salt formed with a base, such as an alkali metal salt (sodium, potassium, etc.), an alkaline earth metal salt (calcium, magnesium, etc.), or an organic base salt (trimethylamine, triethylamine, ethanolamine, etc.).
[0017] In some embodiments, one or more pharmaceutically or food-acceptable excipients are further included. The excipient can be a carrier and / or an excipient. The excipient can be in solid or liquid form. The pharmaceutical composition according to the present application can be in solid or liquid form by adding the excipient. The solid form of the pharmaceutical composition includes powder, tablet, dispersed granule, capsule, pill, and suppository. The powder and tablet can contain about 5% to about 95% of the active ingredient. Suitable solid excipients can be magnesium carbonate, magnesium stearate, talc, sugar, or lactose. The tablet, powder, pill, and capsule are solid dosage forms suitable for oral administration. The liquid form of the pharmaceutical composition includes solution, suspension, and emulsion, examples of which are aqueous solution or water-propylene glycol solution for parenteral injection, or sweetened oral solution. In addition, a small water injection for injection, a freeze-dried powder injection, a large infusion (large volume injection), or a small infusion (small volume injection) can be prepared.
[0018] In a fourth aspect, a pharmaceutical preparation comprises the above-mentioned bibenzyl polycyclic compound or a pharmaceutically acceptable salt thereof as an active ingredient, and is in the form of a solid oral preparation, a liquid oral preparation, or an injection.
[0019] In some embodiments, the dosage form is a tablet, a dispersible tablet, an enteric-coated tablet, a chewable tablet, an orally disintegrating tablet, a capsule, a sugar-coated tablet, a granule, a dry powder, an oral solution, a small aqueous injection, a lyophilized powder injection, a large infusion, or a small infusion.
[0020] A fifth aspect is the use of the above-mentioned bibenzyl polycyclic compound, pharmaceutical composition or pharmaceutical preparation in the preparation of anti-tumor drugs.
[0021] In some embodiments, the tumor disease is a sensitive and resistant tumor disease.
[0022] In some embodiments, the tumor disease includes one or more of lung cancer, breast cancer, gastric cancer, esophageal cancer, liver cancer, colorectal cancer, thyroid cancer, prostate cancer, cervical cancer, ovarian cancer and leukemia.
[0023] The beneficial effects of the present invention are: The bibenzyl polycyclic compound provided by the present invention has the advantages of novel structure, outstanding activity effect, low preparation cost, etc., and has good application prospects in the preparation of drugs for treating tumor diseases.
[0024] The present invention conducted in vitro pharmacological experiments, using paclitaxel and doxorubicin as positive control drugs, to test the cytotoxic effects of the compounds on sensitive tumor cells A549, MDA-231, MCF-7 and drug-resistant tumor cells A549 / Tax, MCF-7 / ADR, as well as human normal cells MCF-10A. The experimental results showed that (1) the lead compound QSJ-F44 had good inhibitory activity against A549, MDA-MB-231, and MCF-7 tumor cells. At the same time, the tricyclic compounds obtained by optimizing the main ring structure of the lead compound QSJ-F44, such bibenzyl polycyclic compounds, showed excellent inhibitory activity against breast cancer cell lines. Among them, the inhibitory activity of compound I8 on MCF-7 cells reached the nanomolar level, and IC 50 Compared with the positive control drug DOX (IC 50 = 0.05 μM) is smaller; compound I9 has stronger inhibitory activity than the lead compound QSJ-F44. (2) The tetracyclic compound has a broad spectrum of anticancer activity. By comparing the compound structures, the present invention found that the length of the connecting bond between the tricyclic and tetracyclic rings has a certain effect on the anti-tumor activity, that is, the activity of the single-carbon connecting chain is better than that of the double-carbon connecting chain. At the same time, the activity results show that the target compound has a stronger killing effect on drug-resistant tumor cells than on sensitive tumor cells, especially compound I 23 , I 25 It has selective inhibitory activity against MCF-7 / ADR. DETAILED DESCRIPTION
[0025] In order to enable those skilled in the art to more clearly understand the technical solution of the present invention, the technical solution of the present invention will be described in detail below with reference to specific embodiments.
[0026] Example 1: Compound 10-1 11 Preparation
[0027] 1. Preparation of Compounds 5a-5b Step a: Potassium carbonate (2.5 eq) and benzyl bromide (1.75 eq) were added to a solution of compound 1a-1b (1.0 eq) in acetonitrile. The reaction mixture was heated at reflux at 82°C for 6 hours. After completion of the reaction (monitored by TLC), the mixture was filtered, and the solvent was evaporated under reduced pressure. Target compounds 2a-2b were isolated and purified by column chromatography.
[0028] Step b: Compound 2a-2b (1.0 eq) was dissolved in ethanol and stirred in an ice-water bath at 0°C. Sodium borohydride (2.5 eq) was slowly added, followed by stirring at room temperature for 8 hours. After completion of the reaction (monitored by TLC), water was added to quench the reaction at 0°C. The reaction mixture was evaporated under reduced pressure to remove ethanol, then extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure. Target compounds 3a-3b were isolated and purified by column chromatography.
[0029] Step c: Dissolve compound 3a-3b (1.0 eq) in dichloromethane and stir in an ice-water bath at 0°C. Slowly add thionyl chloride (2.0 eq) and a catalytic amount of triethylamine, then stir at room temperature for 11 hours. After completion of the reaction (monitored by TLC), evaporate the reaction mixture under reduced pressure and purify by column chromatography to obtain the target compounds 4a-4b.
[0030] Step d: Compounds 4a-4b (1.0 eq) and triphenylphosphine (1.5 eq) were dissolved in acetonitrile. The reaction mixture was heated to reflux at 82°C. After completion of the reaction (monitored by TLC), the reaction mixture was cooled to room temperature. The residue was collected by filtration and dried to afford the target compounds 5a-5b (white solid, 62% yield; orange solid, 73% yield).
[0031]
[0032] 2. Preparation of Compounds 8a-8f Step e: Compounds 6a-6f (1.0 eq), compound 7 (1.2 eq), and potassium carbonate (1.25 eq) were dissolved in a 2:1:1 mixture of toluene:ethanol:water under anhydrous and oxygen-free conditions. Tetrakistriphenylphosphine palladium (1% eq) was added under nitrogen, and the reaction mixture was heated to reflux at 90°C. After completion of the reaction (monitored by TLC), the insoluble material was filtered off, and the reaction mixture was evaporated under reduced pressure to remove the ethanol. Dichloromethane was added to the mixture, and the mixture was washed three times with saturated brine. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure. The target compounds 8a-8f were isolated and purified by column chromatography (white solids, yields 54%-85%).
[0033] 3. Compound 10-1 11 Preparation Step f: Potassium carbonate (2.0 eq) and a catalytic amount of 18-crown-6 were added to a dichloromethane solution of compounds 5a-5b (1.1 eq) and compounds 8a-8f (1.0 eq). The reaction mixture was heated to reflux at 40°C. After completion of the reaction (monitored by TLC), the mixture was filtered and the solvent evaporated under reduced pressure to afford crude products, compounds 9a-9l, which were directly used in the next reaction.
[0034] Step g: Pd / C (20 wt%) was added to a solution of compound 9a-9l (1.0 eq) in ethyl acetate, hydrogen was introduced, and the mixture was stirred at room temperature. After the reaction was complete (monitored by TLC), the mixture was filtered and the solvent was evaporated under reduced pressure. Target compound I0-I was isolated and purified by column chromatography. 11 (white solid, yield 49%-95%).
[0035] I0: 1 H NMR (600 MHz, Chloroform-d) δ 8.31 (s, 1H), 7.82 – 7.79 (m, 2H),7.22 (d, J = 8.0 Hz, 2H), 7.11 (s, 1H), 7.00 – 6.97 (m, 2H), 6.73 – 6.68 (m,2H), 3.95 (s, 3H), 2.94 – 2.82 (m, 4H), 2.20 (s, 3H). I1: HRMS: 321.1592 [M+H] + . 1 H NMR (600 MHz, Chloroform- d ) δ 8.27 (s,1H), 8.13 (d, J = 2.9 Hz, 1H), 7.76 (d,J = 7.9 Hz, 2H), 7.19 (d, J = 7.9 Hz, 2H),7.08 (s, 1H), 7.02 (dd, J = 8.4, 2.9 Hz, 1H), 6.87 (d, J = 8.4 Hz, 1H), 3.93 (s,3H), 3.02 (s, 4H), 2.19 (s, 3H). I2:HRMS: 320.1641 [M+H] + . 1 H NMR (600 MHz, DMSO-d6) δ 9.62 (s, 1H),8.06 (s, 1H), 7.55 (d, J = 7.8 Hz, 2H), 7.26 (d, J = 7.8 Hz, 2H), 7.18 (d, J= 7.6 Hz, 1H), 7.13 (s, 1H), 7.09 (d, J = 7.6 Hz, 1H), 7.06 (s, 2H), 3.86 (s,3H), 2.99 – 2.92 (m, 4H), 2.16 (s, 3H). I3:HRMS: 317.1540 [M-H] - . 1 H NMR (600 MHz, Chloroform- d ) δ 7.52 – 7.48(m, 2H), 7.23 (d, J = 8.1 Hz, 2H), 7.19 (d, J = 7.6 Hz, 1H), 7.10 – 7.06 (m, 3H),7.04 (d, J = 1.4 Hz, 1H), 6.78 – 6.74 (m, 2H), 3.90 (s, 3H), 2.95 – 2.87 (m,4H), 2.26 (s, 3H). I4:HRMS: 307.1437 [M+H] + . 1 H NMR (600 MHz, Chloroform- d ) δ 8.46 (d, J =5.8 Hz, 1H), 8.14 (d, J= 2.9 Hz, 1H), 7.79 – 7.75 (m, 2H), 7.21 – 7.18 (m,2H), 7.16 (d, J = 2.4 Hz, 1H), 7.05 (dd, J = 8.4, 2.8 Hz, 1H), 6.89 (d, J = 8.4 Hz,1H), 6.76 (dd, J = 5.8, 2.4 Hz, 1H), 3.88 (s, 3H), 3.01 (td, J = 6.2, 2.3 Hz,4H). I5:HRMS: 306.1486 [M+H] + . 1 H NMR (600 MHz, Chloroform- d ) δ 8.49 (d, J =5.7 Hz, 1H), 7.86 – 7.81 (m, 2H), 7.23 (d, J = 8.1 Hz, 2H), 7.20 (d, J = 2.4 Hz,1H), 7.01 – 6.97 (m, 2H), 6.77 (dd, J = 5.8, 2.5 Hz, 1H), 6.73 – 6.69 (m, 2H),3.91 (s, 3H), 2.96 – 2.83 (m, 4H). I6:HRMS: 277.1334 [M+H] + . 1 H NMR (600 MHz, Methanol-d4) δ 8.57 (ddd, J= 4.9, 1.7, 0.9 Hz, 1H), 8.01 (d, J = 2.8 Hz, 1H), 7.88 (td, J = 7.7, 1.8 Hz,1H), 7.82 (t, J = 7.7 Hz, 3H), 7.34 (ddd, J = 7.4, 4.9, 1.1 Hz, 1H), 7.29 (d,J = 8.3 Hz, 2H), 7.13 (dd, J = 8.4, 2.9 Hz, 1H), 7.06 (d, J = 8.4 Hz, 1H),3.03 (s, 4H). I7:HRMS: 276.1382 [M+H]+ . 1 H NMR (600 MHz, Chloroform- d ) δ 8.68 (ddd, J =4.9, 1.8, 1.0 Hz, 1H), 7.92 – 7.86 (m, 2H), 7.74 (ddd, J = 7.6, 1.8, 1.8 Hz,1H), 7.71 (ddd, J = 8.0, 1.2, 1.2 Hz, 1H), 7.25 (d, J = 8.1 Hz, 3H), 7.21 (ddd, J =7.3, 4.8, 1.3 Hz, 1H), 7.05 – 7.00 (m, 2H), 6.76 – 6.71 (m, 2H), 2.98 – 2.85(m, 4H). I8:HRMS: 366.1696 [M+H] + . 1 H NMR (600 MHz, Chloroform- d ) δ 8.29 (d, J =2.9 Hz, 1H), 7.47 – 7.43 (m, 2H), 7.26 – 7.21 (m, 3H), 7.06 (d, J = 8.5 Hz,1H), 6.75 (s, 2H), 3.91 (s, 6H), 3.88 (s, 3H), 3.11 – 2.99 (m, 4H). I9:HRMS: 363.1597 [M-H] - . 1 H NMR (600 MHz, Chloroform- d ) δ 7.49 – 7.45(m, 2H), 7.24 – 7.21 (m, 2H), 7.08 – 7.04 (m, 2H), 6.79 – 6.75 (m, 4H), 3.93(s, 6H), 3.90 (s, 3H), 2.95 – 2.87 (m, 4H). I 10 :HRMS: 350.1747 [M+H] + . 1 H NMR (600 MHz, Chloroform-d ) δ 8.30 (d, J =2.9 Hz, 1H), 7.48 – 7.44 (m, 2H), 7.28 (dd, J = 8.4, 2.8 Hz, 1H), 7.26 – 7.24(m, 2H), 7.11 (d, J = 8.4 Hz, 1H), 6.84 – 6.80 (m, 2H), 3.82 (s, 3H), 3.74 (s,3H), 3.10 (dd, J = 8.3, 4.1 Hz, 2H), 3.03 (dd, J = 10.1, 6.1 Hz, 2H), 2.28 (s,3H). I 11 :HRMS: 347.1643 [MH] - . 1 H NMR (600 MHz, Chloroform- d ) δ 7.47 – 7.44(m, 2H), 7.24 – 7.22 (m, 2H), 7.11 – 7.08 (m, 2H), 6.83 – 6.80 (m, 2H), 6.78– 6.75 (m, 2H), 3.82 (s, 3H), 3.75 (s, 3H), 2.90 (d, J = 2.7 Hz, 4H), 2.27 (s,3H). Example 2: Compound I 12 -I 13 Preparation
[0036] Step b: Same as Example 1, to obtain target compounds 11a-11b (white solid, yields of 71.1% and 77.4%, respectively).
[0037] Step h: Compounds 11a-11b (1.0 eq) were dissolved in acetonitrile with stirring. Triphenylphosphine hydrobromide (1.0 eq) was added and refluxed at 82°C for 12 hours. After completion of the reaction (monitored by TLC), the mixture was filtered and the solvent evaporated under reduced pressure. Target compounds 12a-12b were isolated and purified by column chromatography (pale yellow solids, yields of 80.7% and 57.5%, respectively).
[0038] Step f: Same as Example 1 to obtain the target compound 13.
[0039] Step g: Same as Example 1 to obtain target compound I 12 , I 13 (white solid, yields are 12.7% and 27.3% respectively).
[0040] I 12 :HRMS: 382.0804 [M+H] + . 1 H NMR (600 MHz, Chloroform-d) δ 8.31 (s,1H), 7.85 (d, J = 8.2 Hz, 2H), 7.40 – 7.36 (m, 2H), 7.22 (d, J = 8.2 Hz, 2H),7.12 (s, 1H), 7.03 (d, J = 8.3 Hz, 2H), 3.95 (s, 3H), 2.96 – 2.89 (m, 4H), 2.20 (s, 3H). I 13 :HRMS: 461.9875 [M+H] + . 1 H NMR (600 MHz, Chloroform-d) δ 8.31 (s,1H), 7.86 (d, J = 8.1 Hz, 2H), 7.48 (d, J = 8.1 Hz, 1H), 7.46 (d, J = 1.9 Hz,1H), 7.22 (d, J = 8.1 Hz, 2H), 7.12 (s, 1H), 6.94 (dd, J = 8.2, 1.9 Hz, 1H), 3.95 (s, 3H), 2.96 – 2.92 (m, 2H), 2.91 – 2.87 (m, 2H), 2.20 (s, 3H). Example 3: Compound I 14 -I 15 Preparation
[0041] Step c: The same reaction as in Example 1 was performed to obtain the target compound 15 (white solid, yield 99.6%).
[0042] Step d: The same reaction as in Example 1 was carried out to obtain the target compound 16 (white solid, yield 87.6%).
[0043] Step f: Same as Example 1 to obtain target compound 17.
[0044] Step g: Same as Example 1 to obtain target compound I 14(Yellow solid, 85.4% yield).
[0045] Step i: Sodium methoxide (6.0 eq) was dissolved in methanol and compound I was added. 14 (1.0 eq), stirred for 30 minutes, paraformaldehyde (2.0 eq) was added, and stirred at room temperature for 17.5 hours. Sodium borohydride (1.0 eq) was weighed and added, and the mixture was heated under reflux at 65°C for 5 hours. After the reaction was completed (monitored by TLC), saturated sodium bicarbonate solution was added to quench the reaction, and the mixture was extracted three times with dichloromethane and washed once with saturated brine. The organic phase was collected, dehydrated with anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. The target compound I was isolated and purified by column chromatography. 15 (Yellow solid, 51.2% yield).
[0046] I 14 :HRMS: 319.1802 [M+H] + . 1 H NMR (600 MHz, DMSO-d6) δ 8.26 (s, 1H), 7.98 (d, J = 8.2 Hz, 2H), 7.43 (s, 1H), 7.28 (d, J = 8.2 Hz, 2H), 6.88 (d, J= 8.3 Hz, 2H), 6.47 (d, J = 8.3 Hz, 2H), 4.81 (s, 2H), 3.96 (s, 3H), 2.84 (dd, J = 9.2, 6.6 Hz, 2H), 2.73 (dd, J = 9.3, 6.6 Hz, 2H), 2.13 (s, 3H). I 15 :HRMS: 333.1948 [M+H] + . 1 H NMR (600 MHz, Chloroform-d) δ 8.33 (s,1H), 7.86 (d, J = 8.2 Hz, 2H), 7.28 (d, J = 8.1 Hz, 2H), 7.13 (s, 1H), 7.02(d, J = 8.3 Hz, 2H), 6.56 (d, J = 8.4 Hz, 2H), 3.96 (s, 3H), 2.93 (dd, J =9.5, 6.2 Hz, 2H), 2.85 (dd, J = 9.6, 6.3 Hz, 2H), 2.82 (s, 3H), 2.21 (s, 3H). Example 4: Compound I 16 -I19 Preparation
[0047] Step d: Same as Example 1 to obtain target compound 24.
[0048] Step e: Same as Example 1, to obtain target compounds 19 and 1 16 (white solid, yields 95% and 41% respectively).
[0049] Step f: Same as Example 1 to obtain target compounds 20 and 25.
[0050] Step g: Same as Example 1, to obtain target compound 21 (white solid, yield 97%), I 17 -I 19 (white solid, yields are 92%, 24%, and 88% respectively).
[0051] Step j: Under anhydrous and oxygen-free conditions, lithium aluminum tetrahydride (4.0 eq) was added to a solution of compound 21 (1.0 eq) in ultra-dry tetrahydrofuran. The mixture was stirred at room temperature for 6 hours. After completion of the reaction (monitored by TLC), water was added at a ratio of 1 ml per gram of lithium aluminum tetrahydride, followed by an equal volume of 15% sodium hydroxide solution. After stirring for a period of time, the mixture was filtered, and the solvent was evaporated under reduced pressure. The target compound 22 was isolated and purified by column chromatography to obtain a white solid in a 98% yield.
[0052] Step k: Phosphorus tribromide (0.4 eq) was added to a dichloromethane solution of compound 22 (1.0 eq) at 0°C in an anhydrous, oxygen-free environment. The reaction system was stirred at 0°C for 6 hours and then returned to room temperature. After completion of the reaction (monitored by TLC), the reaction system was washed three times with saturated brine. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the solvent evaporated under reduced pressure. Column chromatography was used to isolate and purify the target compound 23 (white solid, 38% yield).
[0053] I 16 : 1H NMR (600 MHz, Chloroform-d) δ 8.41 – 8.38 (m, 1H), 7.43 (d, J =7.4 Hz, 2H), 7.40 – 7.36 (m, 4H), 7.34 – 7.30 (m, 2H), 7.22 (d, J = 8.0 Hz,2H), 7.10 (d, J = 8.5 Hz, 2H), 6.89 (d, J = 8.5 Hz, 2H), 6.20 (s, 2H), 5.04(s, 2H), 3.95 (s, 2H), 3.81 (s, 3H), 3.75 (s, 6H), 2.93 (m, 2H), 2.88 (m,2H), 2.34 (s, 3H). I 17 : 1 H NMR (600 MHz, Chloroform- d ) δ 8.42 (d, J = 2.1 Hz, 1H), 7.41 (d, J = 2.1 Hz, 1H), 7.40 – 7.35 (m, 2H), 7.21 – 7.17 (m, 2H), 6.98 – 6.94 (m, 2H),6.67 – 6.61 (m, 2H), 6.19 (s, 2H), 3.96 (s, 2H), 3.82 (s, 3H), 3.74 (s, 6H),2.92 – 2.76 (m, 4H), 2.35 (s, 3H). I 18 : 1 H NMR (600 MHz, Chloroform- d ) δ 8.41 – 8.39 (m, 1H), 7.45 – 7.41(m, 3H), 7.40 – 7.36 (m, 2H), 7.36 – 7.34 (m, 2H), 7.34 – 7.30 (m, 1H), 7.25(d, J= 8.0 Hz, 2H), 7.12 – 7.08 (m, 2H), 6.91 – 6.88 (m, 2H), 6.13 (s, 2H),5.04 (s, 2H), 3.80 (s, 3H), 3.74 (s, 6H), 2.98 – 2.91 (m, 4H), 2.91 – 2.86(m, 2H), 2.72 – 2.64 (m, 2H), 2.37 (s, 3H). I 19 : 1 H NMR (600 MHz, Chloroform- d ) δ 8.38 (d, J = 2.6 Hz, 1H), 7.45 (d, J = 2.2 Hz, 1H), 7.32 (d, J = 7.7 Hz, 2H), 7.26 (s, 2H), 7.18 (d, J = 7.8 Hz, 2H),6.93 (d, J = 8.3 Hz, 2H), 6.63 – 6.59 (m, 2H), 6.13 (s, 2H), 3.80 (s, 3H), 3.74(d, J = 1.0 Hz, 6H), 2.96 – 2.91 (m, 2H), 2.91 – 2.85 (m, 2H), 2.84 – 2.79 (m,2H), 2.70 – 2.65 (m, 2H), 2.37 (s, 3H). Example 3: Preparation of compound I 20 -I 31
[0054] I. Preparation of compounds 5a-5c Step a: Same as Example 1 to give the target compounds 2a-2c.
[0055] Step b: Same as Example 1 to give the target compounds 3a-3c.
[0056] Step c: Same as Example 1 to give the target compounds 4a-4c.
[0057] Step d: Same as Example 1 to give the target compounds 5a-5c.
[0058]
[0059] 2. Preparation of Compounds 32 and 36 Step d: Same as Example 1 to obtain the target compound 33.
[0060] Step e: The same reaction as in Example 1 was carried out to obtain target compounds 27 (white solid, yield 96%) and 31 (white solid, yield 58%).
[0061] Step f: Same as Example 1 to obtain target compound 34.
[0062] Step g: Same as Example 1 to obtain target compound 35.
[0063] Step j: Same as Example 1 to obtain target compound 29 (yield 90%).
[0064] Step k: Same as Example 1 to obtain target compound 30 (yield 69%).
[0065] Step m: Concentrated hydrochloric acid (0.6 ml / mol) was added to an ethanol solution of compound 31 / 35 (1.0 eq). The reaction system was allowed to react at room temperature for 6 hours, then returned to room temperature. After completion of the reaction (monitored by TLC), the reaction system was washed three times with saturated brine. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the solvent evaporated under reduced pressure. Column chromatography was used to separate and purify the target compounds 32 / 36 (white solids, yields of 82% and 86%, respectively).
[0066]
[0067] Step 2: Compound I 20 -I 31 Preparation Step f: Same as Example 1 to obtain target compounds 37a-37c and 38a-38c.
[0068] Step g: Same as Example 1 to obtain target compound I 20 -I 31 (white solid, yield 12%-49%).
[0069] I 21 :HRMS: 485.2327 [M+H] + . 1 H NMR (400 MHz, Chloroform- d ) δ 7.20 – 7.13(m, 6H), 6.83 (dd, J = 8.4, 2.6 Hz, 1H), 6.81 – 6.76 (m, 2H), 6.68 (dd,J = 10.8,2.8 Hz, 2H), 6.19 (s, 2H), 3.90 (s, 2H), 3.81 (s, 3H), 3.81 (s, 3H), 3.73 (s,6H), 2.94 – 2.87 (m, 4H). I 23 :HRMS: 486.2278 [M+H] + . 1 H NMR (400 MHz, Chloroform- d ) δ 8.30 (d, J =2.9 Hz, 1H), 7.23 (d, J = 2.8 Hz, 1H), 7.22 – 7.15 (m, 5H), 7.07 (d, J = 8.5 Hz,1H), 6.82 (dd, J = 8.4, 2.6 Hz, 1H), 6.76 (d, J = 2.7 Hz, 1H), 6.18 (s, 2H), 3.87(s, 2H), 3.82 – 3.78 (m, 6H), 3.72 (s, 6H), 3.12 – 2.99 (m, 4H). I 25 :HRMS: 485.2327 [M+H] + . 1 H NMR (400 MHz, Chloroform- d ) δ 7.19 – 7.12(m, 5H), 7.00 (d, J = 8.0 Hz, 2H), 6.82 – 6.73 (m, 4H), 6.16 (s, 2H), 3.85 (s,2H), 3.77 (s, 3H), 3.76 (s, 3H), 3.70 (s, 6H), 2.90 – 2.79 (m, 4H). I 27 :HRMS: 499.2486 [M+H]+. 1H NMR (400 MHz, Chloroform-d) δ 7.20 – 7.11 (m, 5H), 7.02 – 6.96 (m, 2H), 6.84 (d, J = 2.7 Hz, 1H), 6.81 (dd, J = 2.8 Hz, 1H), 6.70 (d, J = 8.4 Hz, 2H), 6.14 (s, 2H), 3.84 (s, 3H), 3.80 (s, 3H), 3.74 (s, 6H), 2.92 – 2.81 (m, 6H), 2.69 – 2.63 (m, 2H). I 29 : HRMS: 500.2435 [M+H] + . 1 H NMR (400 MHz, Methanol- d 4) δ 8.02 (d, J = 2.8 Hz, 1H), 7.18 (d, J = 7.8 Hz, 2H), 7.11 (dd, J = 8.4, 2.8 Hz, 1H), 7.08 – 7.00 (m, 4H), 6.82 – 6.75 (m, 2H), 6.11 (s, 2H), 3.78 (s, 3H), 3.69 (s, 3H), 3.67 (s, 6H), 2.99 (s, 4H), 2.83 (t, J = 7.6 Hz, 2H), 2.59 (t, J = 7.7 Hz, 2H). I 31 : 1 H NMR (400 MHz, Chloroform-d) δ 7.20 (d, J = 7.8 Hz, 2H), 7.18 – 7.12 (m, 4H), 6.84 – 6.77 (m, 3H), 6.70 – 6.65 (m, 2H), 6.12 (s, 2H), 3.84 (s, 3H), 3.80 (s, 3H), 3.74 (s, 6H), 2.96 – 2.89 (m, 4H), 2.86 (dd, J = 10.0, 6.3 Hz, 2H), 2.65 (dd, J = 9.7, 6.4 Hz, 2H). Example 4: In vitro anti-proliferation experiment The MTT method was used to detect the activity of the bibenzyl polycyclic compounds of the present invention in inhibiting tumor cell proliferation. Cancer cells growing in the logarithmic phase were inoculated into 96-well plates and divided into blank control group, negative control group, positive control group and experimental group with different concentrations of target compounds. After the cells adhered overnight, the drugs were administered and incubated for 48 hours. 20 μl of freshly prepared MTT solution (5 mg / ml, PBS as solvent) filtered through a 0.22 μm microporous membrane was added to each well. After addition, the cells were placed in an incubator and incubated for another 4 hours. The solution in the wells was discarded, 150 μl of DMSO was added to each well, and the absorbance was detected at a wavelength of 490 nm using an enzyme reader after shaking at 37°C for 15 minutes. The IC value of the compound on the cells was calculated based on the absorbance. 50 .
[0070] Table 1 Inhibitory activity of target compounds against five cancer cell lines and one normal cell line
[0071] a human non-small cell lung cancer cells; b Paclitaxel-resistant human non-small cell lung cancer cells; c human breast cancer cells; d human breast cancer doxorubicin-resistant cells; e human normal mammary epithelial cells; f Data not measured.
[0072] The experimental results in Table 1 show that (1) the lead compound QSJ-F44 has good inhibitory activity against A549, MDA-MB-231, and MCF-7 tumor cells. At the same time, the tricyclic compounds obtained by optimizing the main ring structure of the lead compound QSJ-F44 show excellent inhibitory activity against breast cancer cell lines. Among them, the inhibitory activity of compound I8 against MCF-7 cells reaches the nanomolar level, and IC 50 Compared with the positive control drug DOX (IC 50 = 0.05 μM) is smaller; compound I8 has better inhibitory activity against MDA-MB-231 cells (IC 50 Compound I9 has stronger inhibitory activity against MCF-7 cells than the lead compound QSJ-F44; Compound I3 has the best inhibitory activity against doxorubicin-resistant MCF-7 cells (IC 50Less than 0.5 μM). (2) The tetracyclic compound has a broad spectrum of anticancer activity. By comparing the structures of the compounds, the present invention found that the length of the connecting bond between the tricyclic and tetracyclic rings has a certain effect on the anti-tumor activity, that is, the activity of the single-carbon connecting chain is better than that of the double-carbon connecting chain. At the same time, the activity results show that the target compound has a stronger killing effect on drug-resistant tumor cells than on sensitive tumor cells, especially compound I. 23 , I 25 It has selective inhibitory activity against MCF-7 / ADR.
[0073] The foregoing description is merely a preferred embodiment of the present invention and is not intended to limit the present invention. Those skilled in the art will readily appreciate that various modifications and variations of the present invention are possible. Any modifications, equivalent substitutions, or improvements made within the spirit and principles of the present invention are intended to be within the scope of protection of the present invention.
Claims
1. A bibenzyl polycyclic compound, characterized in that: Its chemical structure is shown in formula A. wherein X and Y are independently selected from C or N; R1 is absent, -H, -CH3, -C2H5, -OCH3, -OBn, -F, -Br, -NH2, -OH, -NHCH3, -CN or -CONH2; R2, R3, R4, R5, and R6 are each independently selected from -H, -CH3, -C2H5, -OCH3, -OBn, -F, -Br, -NH2, -OH, -NHCH3, -CN, and -CONH2; R7 is -H or , n is 1 or 2.
2. The bibenzyl polycyclic compound according to claim 1, wherein Its chemical structure is shown in Formula I or Formula II, 。 3. The bibenzyl polycyclic compound according to claim 1, wherein: The compound is selected from the following compounds: 。 4. A method for preparing a bibenzyl polycyclic compound, characterized in that: The method comprises the steps of performing a reaction according to any one of the following reaction schemes 1-5; Reaction Scheme 1 is: ； Reaction Scheme 2 is: ； Reaction Scheme 3 is: ； Reaction Scheme 4 is: ； Reaction Scheme 5 is: Wherein, in reaction scheme 1, X and Y are C or N, R1 is -H or -OCH3, R2 is -H or -OCH3, R3 is -H, -CH3 or -OCH3, and R4 is -H or -OCH3; In reaction scheme 2, R1 is -H or -Br, and R2 is -H or -Br; In Reaction Scheme 5, X is C or N.
5. A pharmaceutical composition, characterized in that: The invention comprises the bibenzyl polycyclic compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3.
6. The pharmaceutical composition according to claim 5, characterized in that It also includes one or more pharmaceutically or food-acceptable excipients.
7. A pharmaceutical preparation, characterized in that: The active ingredient is the bibenzyl polycyclic compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, and the dosage form is a solid oral preparation, a liquid oral preparation or an injection.
8. The pharmaceutical preparation according to claim 7, characterized in that The dosage form is tablets, dispersible tablets, enteric-coated tablets, chewable tablets, orally disintegrating tablets, capsules, sugar-coated tablets, granules, dry powders, oral solutions, small water injections for injection, freeze-dried powder injections for injection, large infusions or small infusions.
9. Use of the bibenzyl polycyclic compound according to any one of claims 1 to 3, the pharmaceutical composition according to claim 5 or 6, or the pharmaceutical preparation according to claim 7 or 8 in the preparation of an anti-tumor drug.
10. The use according to claim 9, characterized in that: The tumor disease includes one or more of lung cancer, breast cancer, gastric cancer, esophageal cancer, liver cancer, colorectal cancer, thyroid cancer, prostate cancer, cervical cancer, ovarian cancer and leukemia.