Aza luteolin derivatives, processes for their preparation and uses thereof

Abstract

The application belongs to the technical field of biological medicine, and particularly relates to an azasessamin derivative, a preparation method thereof and application of the azasessamin derivative in preparation of an antitumor or antibacterial drug. 1 2 3 4 5 6 as described in the claims and specification. The application also provides application of the azasessamin derivative or the pharmaceutically acceptable salt, isomer, solvate thereof in preparation of an antitumor or antifungal drug.​​​​​

Description

Technical Field

[0001] This invention belongs to the field of biomedical technology, specifically relating to azasaicin derivatives, their preparation methods, and their application in the preparation of antitumor or antibacterial drugs. Background Technology

[0002] Cancer, also known as malignant tumors, has become one of the major diseases seriously threatening the physical and mental health of people around the world. According to GLOBOCAN 2020 estimates, there were approximately 19.3 million new cancer cases and 10 million cancer deaths globally in 2020. The number of new cancer cases is increasing year by year, and it is projected that by 2040, there will be 28.4 million new cancer cases globally, an increase of 47% compared to 2020. Due to the grim situation in cancer treatment, there is an urgent need to develop more effective and less toxic new anti-cancer drugs.

[0003] Invasive fungal disease (IFD) refers to the pathological changes and pathophysiological processes caused by fungi invading human tissues and blood, growing and multiplying within them, leading to tissue damage, organ dysfunction, and inflammatory responses. IFD is an opportunistic infection, prevalent in immunocompromised individuals, especially those with hematologic malignancies and organ transplant recipients. The main pathogens of hospital-acquired IFD include Candida, Cryptococcus neoformans, and Aspergillus. In ICU patients, Candida is the predominant cause of IFD, with Candida albicans being the most common pathogen (accounting for 40%–60%). Cryptococcus neoformans is a major cause of meningitis. However, the increasing prevalence of invasive fungal infections and resistance to antifungal drugs poses a growing threat to immunocompromised individuals, including cancer patients. The mortality rate of invasive fungal diseases caused by these drug-resistant bacteria can reach 88%–100%, posing significant challenges to clinical treatment. Therefore, there is an urgent need to find structurally novel antifungal drugs.

[0004] Sesamin is a lignan-based natural product with various biological activities isolated from sesame seeds. Its poor solubility severely hinders further research and development. Currently, over 80% of clinically used drugs contain nitrogen atoms, and the introduction of nitrogen can produce water-soluble hydrochlorides, sulfonates, etc. Furthermore, no nitrogen-containing sesamin derivatives have been reported in the literature. Summary of the Invention

[0005] To address the shortcomings of existing technologies, this invention designs and synthesizes a series of azasaicin derivatives, which have significantly improved solubility and exhibit certain antitumor and antibacterial activities.

[0006] The present invention adopts the following technical solution:

[0007] This invention provides azasaicin derivative of formula (I) or (II) or a pharmaceutically acceptable salt, isomer, or solvate thereof:

[0008]

[0009] The present invention preferably includes azasaicin derivatives of formula (III), (IV), (V) or (VI) or pharmaceutically acceptable salts, isomers or solvates thereof:

[0010]

[0011] in,

[0012] R 1 R 2 R 3 R 4 and R 5 Each group is independently selected from hydrogen, hydroxyl, amino, carboxyl, cyano, nitro, halogen, C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkyl, halo-C1-C6 alkoxy, substituted or unsubstituted 5-10 aryl or 5-10 heteroaryl groups, wherein the substituent is halogen, C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkyl;

[0013] R 6 Hydroxyl group, OAc;

[0014] Furthermore,

[0015] R 1 R 2 R 3 R 4 and R 5 Each group is independently selected from hydrogen, hydroxyl, amino, carboxyl, cyano, nitro, halogen, C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkyl, halo-C1-C6 alkoxy, substituted or unsubstituted 5-6 aryl or 5-10 heteroaryl, wherein the substituent is halogen, C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkyl;

[0016] R 6 Hydroxyl group, OAc;

[0017] Furthermore,

[0018] R 1 R 2 R 3 R 4 and R 5 Each group is independently selected from hydrogen, hydroxyl, amino, carboxyl, cyano, nitro, halogen, C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkyl, halo-C1-C6 alkoxy, substituted or unsubstituted phenyl groups. The substituents are halogens, C1-C6 alkyl groups, C1-C6 alkoxy groups, and halo-C1-C6 alkyl groups.

[0019] R 6 Hydroxyl group, OAc;

[0020] Furthermore,

[0021] R 1 R 2 R 4 and R 5 Each is independently selected from hydrogen;

[0022] R 3 The radicals are hydroxyl, amino, carboxyl, cyano, nitro, halogen, C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkyl, halo-C1-C6 alkoxy, substituted or unsubstituted phenyl. The substituents are halogens, C1-C6 alkyl groups, C1-C6 alkoxy groups, and halo-C1-C6 alkyl groups.

[0023] R 6 It consists of hydroxyl groups and OAc.

[0024] The present invention preferably includes azasaicin derivatives or pharmaceutically acceptable salts, isomers, and solvates thereof with the following structures:

[0025]

[0026]

[0027] The azasaicin derivatives of the present invention, or pharmaceutically acceptable salts thereof, are prepared by the following method:

[0028] Using sesamin as a raw material, new azasesaicin derivatives were synthesized via ether ring opening, mitsunobu, suzuki and other reactions according to synthetic route 1.

[0029]

[0030] Route 1: Synthetic route for azasaicin derivatives

[0031] Where Ar is R 3 The radicals are hydroxyl, amino, carboxyl, cyano, nitro, halogen, C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkyl, halo-C1-C6 alkoxy, substituted or unsubstituted phenyl. The substituents are halogens, C1-C6 alkyl groups, C1-C6 alkoxy groups, or halogenated C1-C6 alkyl groups.

[0032] The present invention provides a pharmaceutical composition comprising a zinebasein derivative of formula (I) or (II) or a pharmaceutically acceptable salt, isomer, solvate, and pharmaceutically acceptable carrier or excipient thereof.

[0033] The present invention provides a pharmaceutical composition comprising a zineb derivative of formula (III), (IV), (V) or (VI) or a pharmaceutically acceptable salt, isomer, solvate or a pharmaceutically acceptable carrier or excipient thereof.

[0034] Furthermore, the present invention provides the use of the azasazosenin derivatives of formula (I) or (II) or pharmaceutically acceptable salts, isomers, solvates or pharmaceutical compositions thereof in the preparation of antitumor drugs.

[0035] This invention provides the use of azasaicin derivatives of general formula (III), (IV), (V) or (VI) or pharmaceutically acceptable salts, isomers, solvates or pharmaceutical compositions thereof in the preparation of antitumor drugs.

[0036] The tumors mentioned are liver cancer and breast cancer.

[0037] The present invention also provides the use of the azasaicin derivatives shown in formula (I) or (II) or pharmaceutically acceptable salts, isomers, solvates or pharmaceutical compositions thereof in the preparation of antimicrobial drugs.

[0038] The present invention provides the use of azasaicin derivatives of formula (III), (IV), (V) or (VI) or pharmaceutically acceptable salts, isomers, solvates or pharmaceutical compositions thereof in the preparation of antimicrobial drugs.

[0039] The antibacterial drug mentioned is an antifungal drug.

[0040] The fungus mentioned is Candida albicans or Cryptococcus neoformans. Detailed Implementation

[0041] This invention uses sesamin as a raw material and synthesizes a new class of aza analogs via ether ring opening, mitsunobu, and suzuki reactions according to synthetic route 1. The target product was characterized by NMR. The cytotoxic activity of these compounds against liver cancer cells was screened by the MTT assay, and the antibacterial activity against drug-resistant Staphylococcus aureus, Escherichia coli, Candida albicans, and Cryptococcus neoformans was determined by the microbroth dilution method.

[0042] Example 1:

[0043] Sesamin (1.06 g, 3 mmol) and acetic anhydride (5 ml) were dissolved in dichloromethane (20 ml). Anhydrous aluminum trichloride (1.20 g, 9 mmol) was added in an ice-water bath with stirring. After 4 h of reaction, the reaction was quenched with hydrochloric acid (2 mol / L, 20 ml). The mixture was extracted with ethyl acetate, and the organic phase was washed with saturated sodium bicarbonate solution, water, and saturated brine, respectively. The mixture was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the crude product. Purification by silica gel column chromatography (eluent: petroleum ether:ethyl acetate = 2:1) yielded compound 1 (137.5 mg), with a yield of 11.1%.

[0044] 1 H NMR(400MHz,CDCl3,J in Hz)δ(ppm):6.84–6.70(m,6H),5.97–5.91(m,4H),4.86–4.77(m,2H),4.33(dd,J=11.11,6.33Hz,1H),4.23–4.13 (m,2H),4.07(t,J=8.20Hz,1H),2.86–2.75(m,1H),2.39–2.28(m,1H),2.16–2.10(m,1H),2.06–1.98(m,3H).13C NMR (100MHz, CDCl3) δ (ppm): 170.88, 148.06, 147.82, 147.31, 146.94, 137.07, 136.41, 119.54, 119.1 3,108.35,108.07,106.43,106.20,101.20,101.02,83.57,72.43,69.69,62.72,48.53,46.87,20.89.

[0045] Example 2:

[0046] Compound 1 (324.7 mg, 0.78 mmol), substituted aniline (2.35 mmol), and triphenylphosphine (411.3 mg, 1.57 mmol) were dissolved in dry dichloromethane (25 mL). Diisopropyl azodicarbonate (320 μl, 1.57 mmol) was slowly added to ice water with stirring. After the reactants had reacted completely, water (20 mL) was added and the mixture was extracted with dichloromethane. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain an oily substance. Purification by silica gel column chromatography yielded the target products 2a-2e.

[0047] 2a, Yield: 81.6%, 11H NMR (400 MHz, CDCl3, J in Hz) δ (ppm): 7.09–7.01 (m, 2H), 6.83–6.72 (m, 6H), 6.46–6.40 (m, 2H), 5.98–5.90 (m, 4H), 4.88 (d, J = 7.32 Hz, 1H), 4.85 (s, 1H), 4.55 (d, J = 4.21 Hz, 1H), 4.36 (dd, J = 11.18, 7.69 Hz, 1H), 4.29 (dd, J = 11.20, 6.70 Hz, 1H), 4.19–4.05 (m, 2H), 2.80–2.72 (m, 1H), 2.65–2.55 (m, 1H), 2.01 (s, 3H). 13 13C NMR (100 MHz, CDCl3) δ (ppm): 170.84, 148.36, 148.14, 147.24, 146.96, 144.92, 136.93, 135.65, 129.27, 122.38, 119.89, 119.08, 114.58, 108.68, 108.35, 106.88, 106.02, 101.29, 101.24, 83.36, 70.28, 62.31, 55.94, 49.82, 48.39, 20.96.

[0048] 2b, Yield: 82.9%, 1 1H NMR (400 MHz, CDCl3, J in Hz) δ (ppm): 7.21–7.15 (m, 2H), 6.82–6.65 (m, 6H), 6.47–6.33 (m, 2H), 5.98–5.90 (m, 4H), 4.87 (d, J = 7.07 Hz, 1H), 4.57–4.49 (m, 1H), 4.39–4.21 (m, 2H), 4.17–4.02 (m, 2H), 2.87–2.69 (m, 1H), 2.65–2.50 (m, 1H), 2.01 (s, 3H).

[0049] 2c, Yield: 68.9%, 1 1H NMR (400 MHz, CDCl3, J in Hz) δ (ppm): 6.84–6.72 (m, 8H), 6.51–6.37 (m, 2H), 5.99–5.90 (m, 4H), 4.90 (d, J = 7.00 Hz, 1H), 4.51 (d, J = 4.55 Hz, 1H), 4.41–4.32 (m, 1H), 4.32–4.23 (m, 1H), 4.17–4.08 (m, 2H), 2.84–2.70 (m, 1H), 2.60–2.52 (m, 1H), 2.01 (s, 3H).13 C NMR (100 MHz, CDCl3) δ (ppm): 170.86, 148.33, 148.11, 147.20, 146.94, 137.01, 119.99, 119.05, 115.99, 115.76, 114.42, 108.63, 108.32, 106.93, 106.04, 101.26, 101.22, 83.42, 70.42, 62.38, 56.49, 49.71, 48.29, 20.96.

[0050] 2d, yield: 91.7%, 1 H NMR (400 MHz, CDCl3, J in Hz) δ (ppm): 6.92 (d, J = 8.20 Hz, 2H), 6.81–6.71 (m, 6H), 6.52–6.40 (m, 2H), 5.95 (s, 2H), 5.93–5.89 (m, 2H), 4.91 (d, J = 6.85 Hz, 1H), 4.56 (d, J = 4.47 Hz, 1H), 4.41–4.32 (m, 1H), 4.31–4.22 (m, 1H), 4.18–4.09 (m, 2H), 2.88–2.73 (m, 1H), 2.59–2.48 (m, 1H), 2.20 (s, 3H), 2.01 (s, 3H). 13 C NMR (100 MHz, CDCl3) δ (ppm): 170.84, 148.24, 148.07, 147.15, 146.83, 137.12, 129.91, 120.02, 119.07, 113.68, 108.57, 108.30, 107.01, 106.08, 101.19, 83.50, 70.51, 62.46, 49.68, 48.23, 29.84, 20.98, 20.50.

[0051] 2e, yield: 82.3%, 1 H NMR (400 MHz, CDCl3, J in Hz) δ (ppm): 6.81–6.68 (m, 8H), 6.56–6.42 (m, 2H), 5.98–5.89 (m, 4H), 4.92 (d, J = 6.52 Hz, 1H), 4.52–4.45 (m, 1H), 4.38–4.30 (m, 1H), 4.29–4.22 (m, 1H), 4.20–4.08 (m, 2H), 3.70 (s, 3H), 2.89–2.69 (m, 1H), 2.57–2.43 (m, 1H), 2.01 (s, 3H). 13C NMR(100MHz, CDCl3)δ(ppm):170.89,148.24,148.06,147.13,137.11,119.03,115.00 ,108.56,108.30,106.07,101.22,101.19,83.48,70.66,62.48,55.83,49.55,21.00.

[0052] Example 3:

[0053] Compound 2 (0.65 mmol) and potassium carbonate (107.8 mg, 0.78 mmol) were dissolved in methanol-water (35 ml, methanol:water = 6:1). The mixture was stirred at room temperature for 2 h, then extracted with dichloromethane. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The target products 3a-3e were obtained by silica gel column purification.

[0054] 3a, Yield: 86.1%, 1 H NMR(400MHz,CDCl3,J in Hz)δ(ppm):7.09–7.01(m,2H),6.83–6.70(m,6H),6.50–6.43(m,2H),5.97–5.90(m,4H),4.86(d,J=7.24Hz,1H),4.69(d,J=4.07 Hz,1H),4.16(dd,J=9.55,3.55Hz,1H),4.07(dd,J=9.52,6.23Hz,1H),3.93–3.83(m,2H),2.85–2.75(m,1H),2.54–2.43(m,1H). 13 C NMR (100MHz, CDCl3) δ (ppm): 148.29, 148.12, 147.13, 146.87, 144.98, 137.42, 135.97, 129.24, 119.88, 11 8.88,114.83,108.62,108.34,107.03,106.00,101.25,101.21,83.13,70.19,60.89,56.04,53.00,48.39.

[0055] 3b, Yield: 60.1%, 11H NMR (400 MHz, CDCl3, J in Hz) δ (ppm): 7.20–7.15 (m, 2H), 6.82–6.72 (m, 6H), 6.46–6.36 (m, 2H), 5.96–5.92 (m, 4H), 4.85 (d, J = 7.27 Hz, 1H), 4.69 (d, J = 3.93 Hz, 1H), 4.19–4.12 (m, 1H), 4.10–4.02 (m, 1H), 3.92–3.84 (m, 2H), 2.84–2.74 (m, 1H), 2.53–2.46 (m, 1H). 13 13C NMR (100 MHz, CDCl3) δ (ppm): 148.30, 148.14, 147.14, 146.88, 137.42, 132.12, 119.86, 118.88, 115.27, 108.64, 108.35, 107.02, 106.00, 101.26, 101.22, 83.13, 70.18, 60.91, 53.02, 48.41, 31.74.

[0056] 3c, Yield: 80.1%, 1 1H NMR (400 MHz, CDCl3, J in Hz) δ (ppm): 6.85–6.71 (m, 8H), 6.51–6.44 (m, 2H), 5.97–5.89 (m, 4H), 4.91 (d, J = 7.08 Hz, 1H), 4.66 (d, J = 4.38 Hz, 1H), 4.20–4.05 (m, 2H), 3.96–3.84 (m, 2H), 2.85–2.75 (m, 1H), 2.51–2.40 (m, 1H). 13 13C NMR (100 MHz, CDCl3) δ (ppm): 154.96, 148.26, 148.10, 147.09, 146.82, 142.54, 137.49, 136.13, 119.96, 118.87, 115.96, 115.74, 114.79, 108.59, 108.33, 107.08, 106.01, 101.23, 101.19, 83.07, 70.22, 60.83, 56.68, 52.94, 48.43.

[0057] 3d, Yield: 94.5%, 11H NMR (400 MHz, CDCl3, J in Hz) δ (ppm): 6.97–6.86 (m, 2H), 6.84–6.70 (m, 6H), 6.53–6.43 (m, 2H), 5.98–5.85 (m, 4H), 4.96–4.87 (m, 1H), 4.75–4.68 (m, 1H), 4.18–4.02 (m, 2H), 3.95–3.80 (m, 2H), 2.85–2.73 (m, 1H), 2.56–2.37 (m, 1H), 2.23–2.14 (m, 3H). 13 13C NMR (100 MHz, CDCl3) δ (ppm): 148.15, 148.05, 147.02, 146.65, 144.03, 137.60, 136.65, 129.89, 127.07, 119.88, 118.89, 113.86, 108.52, 108.28, 107.10, 106.04, 101.14, 83.06, 70.20, 60.73, 55.97, 52.99, 48.46, 20.48.

[0058] 3e, Yield: 73.7%. 1 1H NMR (400 MHz, CDCl3, J in Hz) δ (ppm): 6.83–6.72 (m, 6H), 6.71–6.67 (m, 2H), 6.54–6.46 (m, 2H), 5.93 (s, 2H), 5.92–5.88 (m, 2H), 4.94 (d, J = 7.00 Hz, 1H), 4.65 (d, J = 4.50 Hz, 1H), 4.17–4.04 (m, 2H), 3.92–3.83 (m, 2H), 3.69 (s, 3H), 2.81–2.73 (m, 1H), 2.45–2.37 (m, 1H). 13 13C NMR (100 MHz, CDCl3) δ (ppm): 152.42, 148.15, 148.03, 147.00, 146.66, 140.33, 137.59, 136.57, 119.94, 118.86, 115.25, 114.98, 108.50, 108.28, 107.10, 106.03, 101.14, 82.96, 70.19, 60.64, 56.80, 55.80, 52.90, 48.47.

[0059] Example 4:

[0060] Compound 3 (0.39 mmol) and triphenylphosphine (204.9 mg, 0.78 mmol) were dissolved in anhydrous dichloromethane (15 mL). Diisopropyl azodicarbonate (155 μl, 0.781 mmol) was slowly added in an ice-water bath with stirring. The reaction was monitored by TLC. After the reactants were completely reacted, the reaction was quenched by adding water. The mixture was extracted with dichloromethane, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was then purified by silica gel column chromatography to obtain the target products 4a-4e.

[0061] 4a, Yield: 90.3%, 1 H NMR(400MHz,CDCl3,J in Hz)δ(ppm):7.13–7.04(m,2H),6.88–6.68(m,6H),6.56–6.49(m,2H),5.98–5.91(m,4H),4.75(d,J=5.82Hz,1H),4.67(d,J=8.28 Hz,1H),3.88(dd,J=9.90,3.68Hz,1H),3.82(dd,J=9.32,7.79Hz,1H),3.61–3.51(m,2H),3.47–3.36(m,1H),2.96–2.86(m,1H). 13 C NMR (100MHz, CDCl3) δ (ppm): 148.17, 148.10, 147.24, 146.82, 146.54, 136.13, 133.28, 128.75, 123.26, 119.99 ,119.29,116.74,108.61,108.30,107.31,106.37,101.21,101.20,86.67,70.20,65.72,55.26,51.21,50.15.

[0062] 4b, Yield: 92.1%, 1 H NMR(400MHz,CDCl3,J in Hz)δ(ppm):7.25–7.17(m,2H),6.87–6.72(m,4H),6.72–6.66(m,2H),6.49–6.41(m,2H),5.98–5.92(m,4H),4.73(d, J=5.76Hz,1H),4.67(d,J=8.29Hz,1H),3.90–3.77(m,2H),3.60–3.51(m,2H),3.47–3.36(m,1H),2.96–2.86(m,1H).

[0063] 1313C NMR (100 MHz, CDCl3) δ (ppm): 148.05, 147.98, 147.11, 146.95, 146.67, 136.04, 133.30, 131.48, 119.80, 119.14, 116.90, 110.12, 108.49, 108.18, 107.13, 106.23, 101.08, 86.53, 70.09, 65.34, 54.87, 51.13, 50.03.

[0064] 4c, Yield: 91.3%, 1 1H NMR (400 MHz, CDCl3, J in Hz) δ (ppm): 6.88–6.81 (m, 4H), 6.80–6.72 (m, 4H), 6.62–6.54 (m, 2H), 5.97–5.93 (m, 4H), 4.73 (d, J = 6.12 Hz, 1H), 4.60 (d, J = 8.17 Hz, 1H), 3.88 (dd, J = 9.77, 3.12 Hz, 1H), 3.80 (t, J = 8.55 Hz, 1H), 3.60–3.51 (m, 1H), 3.50–3.35 (m, 2H), 2.92–2.82 (m, 1H). 13 13C NMR (100 MHz, CDCl3) δ (ppm): 155.28, 148.10, 147.24, 146.74, 144.67, 136.11, 133.41, 120.10, 119.39, 117.14, 117.07, 115.48, 115.26, 108.56, 108.30, 107.47, 106.44, 101.19, 86.96, 70.32, 66.04, 56.19, 51.12, 50.25.

[0065] 4d, Yield: 86.8%, 1 1H NMR (400 MHz, CDCl3, J in Hz) δ (ppm): 6.98–6.92 (m, 2H), 6.88–6.72 (m, 6H), 6.57–6.50 (m, 2H), 5.97–5.90 (m, 4H), 4.72 (d, J = 6.07 Hz, 1H), 4.62 (d, J = 8.22 Hz, 1H), 3.90 (dd, J = 9.86, 3.22 Hz, 1H), 3.84–3.75 (m, 1H), 3.59–3.52 (m, 1H), 3.51–3.44 (m, 1H), 3.44–3.33 (m, 1H), 2.91–2.80 (m, 1H), 2.21 (s, 3H). 13C NMR (100MHz, CDCl3) δ (ppm): 148.02, 136.31, 129.44, 120.02, 119.38, 116.06, 108.4 9,108.29,107.51,106.47,101.18,86.97,70.41,65.61,55.73,51.19,50.24,20.47.

[0066] 4e, Yield: 80.1%, 1 H NMR(400MHz,CDCl3,J in Hz)δ(ppm):6.90–6.76(m,6H),6.76–6.72(m,4H),5.96–5.92(m,4H),4.82–4.73(m,1H),4.57(d,J=7.95Hz,1H ),3.94–3.87(m,1H),3.82–3.75(m,1H),3.72(s,3H),3.65–3.56(m,1H),3.43–3.33(m,2H),2.89–2.80(m,1H). 13 CNMR(100MHz, CDCl3)δ(ppm):148.08,147.97,147.22,146.55,136.19,120.16,119.47,117.77,114.4 0,108.45,108.28,107.65,106.53,101.17,101.09,87.23,70.47,65.90,55.71,53.57,51.05,50.29.

[0067] Example 5:

[0068] Compound 4b (91.2 mg, 0.18 mmol), boric acid (0.197 mmol), tetrakis(triphenylphosphine)palladium (20.8 mg, 0.018 mmol), and potassium carbonate (49.7 mg, 0.360 mmol) were dissolved in toluene (24 mL). The mixture was heated to 80 °C and stirred overnight under nitrogen protection. After the reaction was complete, water was added to quench the reaction. The mixture was extracted with dichloromethane, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the crude product. The crude product was purified by silica gel column chromatography to give product 5a-5h.

[0069] 5a, Yield: 85.3%, 11H NMR (400 MHz, CDCl3, J in Hz) δ (ppm): 7.53–7.47 (m, 2H), 7.44–7.34 (m, 4H), 7.28–7.22 (m, 1H), 6.89–6.73 (m, 8H), 5.98–5.92 (m, 4H), 4.85 (d, J = 5.87 Hz, 1H), 4.78 (d, J = 8.27 Hz, 1H), 3.99 (dd, J = 10.07, 3.63 Hz, 1H), 3.84 (dd, J = 9.33, 7.80 Hz, 1H), 3.71–3.61 (m, 2H), 3.50–3.41 (m, 1H), 2.99–2.90 (m, 1H). 13 13C NMR (100 MHz, CDCl3) δ (ppm): 148.18, 148.11, 147.24, 146.85, 141.01, 136.18, 128.80, 127.61, 126.56, 126.46, 120.16, 119.37, 116.19, 108.64, 108.32, 107.48, 106.41, 101.20, 86.60, 70.19, 66.27, 55.46, 51.24, 50.16.

[0070] 5b, yield: 81.3%. 1 1H NMR (400 MHz, CDCl3, J in Hz) δ (ppm): 7.44–7.40 (m, 2H), 7.39–7.30 (m, 4H), 6.88–6.82 (m, 2H), 6.80–6.76 (m, 4H), 6.70–6.63 (m, 2H), 5.97–5.94 (m, 4H), 4.83–4.73 (m, 2H), 3.95 (dd, J = 9.99, 3.84 Hz, 1H), 3.84 (dd, J = 9.29, 7.78 Hz, 1H), 3.70–3.56 (m, 2H), 3.49–3.39 (m, 1H), 2.98–2.89 (m, 1H). 13 13C NMR (100 MHz, CDCl3) δ (ppm): 148.15, 148.09, 147.62, 147.21, 146.75, 139.56, 136.24, 133.71, 132.23, 129.43, 128.93, 128.88, 127.65, 127.38, 119.96, 119.28, 115.71, 108.74, 108.62, 108.30, 107.34, 106.36, 101.20, 86.62, 70.25, 65.59, 54.95, 51.32, 50.15.

[0071] 5c, Yield: 63.1% 1 H NMR (400 MHz, CDCl3, J in Hz) δ (ppm): 8.15 (d, J = 5.35 Hz, 1H), 7.53–7.43 (m, 2H), 7.33–7.27 (m, 1H), 7.02 (s, 1H), 6.88–6.70 (m, 6H), 6.68–6.58 (m, 2H), 5.98–5.89 (m, 4H), 4.84 (d, J = 8.37 Hz, 1H), 4.80 (d, J = 5.46 Hz, 1H), 3.94 (dd, J = 10.04, 4.27 Hz, 1H), 3.86 (dd, J = 9.30, 7.76 Hz, 1H), 3.79–3.70 (m, 1H), 3.62 (dd, J = 9.40, 6.51 Hz, 1H), 3.51–3.43 (m, 1H), 3.03–2.94 (m, 1H). 13 C NMR (100 MHz, CDCl3) δ (ppm): 165.95, 153.94, 149.05, 148.25, 148.12, 147.75, 147.59, 147.25, 146.89, 136.14, 133.38, 127.98, 127.63, 125.49, 123.64, 119.89, 119.20, 118.41, 118.37, 115.27, 108.71, 108.33, 107.18, 106.29, 105.66, 105.29, 101.27, 101.23, 86.39, 70.11, 65.39, 54.39, 51.39, 50.06.

[0072] 5d, Yield: 49.0% 1 H NMR (400 MHz, CDCl3, J in Hz) δ (ppm): 7.42–7.39 (m, 1H), 7.39–7.36 (m, 1H), 7.33–7.28 (m, 2H), 7.26–7.24 (m, 1H), 6.89–6.71 (m, 6H), 6.64–6.62 (m, 1H), 6.62–6.59 (m, 1H), 5.98–5.91 (m, 4H), 4.75 (t, J = 7.49 Hz, 2H), 3.94 (dd, J = 9.91, 3.73 Hz, 1H), 3.83 (dd, J = 9.26, 7.80 Hz, 1H), 3.67–3.55 (m, 2H), 3.48–3.38 (m, 1H), 2.97–2.87 (m, 1H). 1313C NMR (100 MHz, CDCl3) δ (ppm): 148.00, 147.97, 147.22, 147.09, 146.58, 142.32, 136.18, 133.82, 126.87, 126.09, 125.81, 119.85, 119.17, 118.01, 115.54, 108.46, 108.18, 107.26, 106.27, 101.07, 86.58, 70.18, 65.37, 54.86, 51.20, 50.06.

[0073] 5e, Yield: 75.1%, 1 1H NMR (400 MHz, CDCl3, J in Hz) δ (ppm): 7.50 (d, J = 1.90 Hz, 1H), 7.19 (d, J = 8.71 Hz, 2H), 6.88–6.71 (m, 6H), 6.65–6.60 (m, 2H), 6.22 (d, J = 1.78 Hz, 1H), 5.99–5.64 (m, 4H), 4.80 (m, J = 4.4 Hz, 1H), 4.79–4.76 (m, 1H), 3.94 (dd, J = 9.93, 3.99 Hz, 1H), 3.89 (s, 3H), 3.85 (dd, J = 9.36, 7.74 Hz, 1H), 3.74–3.65 (m, 1H), 3.64–3.56 (m, 1H), 3.50–3.42 (m, 1H), 3.00–2.93 (m, 1H). 13 13C NMR (100 MHz, CDCl3) δ (ppm): 148.22, 148.13, 147.24, 146.84, 137.97, 136.19, 133.60, 129.39, 124.19, 123.63, 119.91, 119.23, 114.98, 113.18, 108.69, 108.32, 107.24, 106.31, 105.53, 101.22, 86.51, 70.19, 65.49, 54.56, 51.39, 50.14, 37.50.

[0074] 5f, Yield: 71.9%, 11H NMR (400 MHz, CDCl3, J in Hz) δ (ppm): 7.48–7.40 (m, 2H), 7.37–7.34 (m, 1H), 7.34–7.31 (m, 1H), 7.10–7.01 (m, 2H), 6.89–6.81 (m, 2H), 6.81–6.73 (m, 4H), 6.68–6.65 (m, 1H), 6.65–6.62 (m, 1H), 5.98–5.92 (m, 4H), 4.76 (t, J = 6.83 Hz, 2H), 3.95 (dd, J = 9.92, 3.77 Hz, 1H), 3.84 (dd, J = 9.29, 7.76 Hz, 1H), 3.68–3.55 (m, 2H), 3.48–3.40 (m, 1H), 2.96–2.90 (m, 1H). 13 13C NMR (100 MHz, CDCl3) δ (ppm): 160.61, 148.01, 147.97, 147.39, 147.09, 146.59, 137.18, 136.16, 133.78, 129.66, 127.82, 127.74, 127.26, 119.83, 119.15, 115.57, 115.53, 115.32, 108.47, 108.17, 107.24, 106.25, 101.06, 86.56, 70.16, 65.39, 54.86, 51.20, 50.07.

[0075] 5 g, yield: 88.7%, 1 1H NMR (400 MHz, CDCl3, J in Hz) δ (ppm): 7.42–7.36 (m, 4H), 7.21–7.16 (m, 2H), 6.88–6.82 (m, 2H), 6.81–6.76 (m, 4H), 6.68–6.63 (m, 2H), 5.97–5.94 (m, 4H), 4.76 (dd, J = 11.16, 7.10 Hz, 2H), 3.95 (dd, J = 9.91, 3.60 Hz, 1H), 3.84 (dd, J = 9.27, 7.79 Hz, 1H), 3.67–3.56 (m, 2H), 3.47–3.39 (m, 1H), 2.97–2.87 (m, 1H), 2.36 (s, 3H). 13C NMR (100MHz, CDCl3) δ (ppm): 148.12, 148.09, 147.40, 147.21, 146.69, 138.29, 136.32, 135.97, 134.02, 130.77, 129.50, 127.34, 12 6.38,126.30,119.98,119.31,115.71,108.59,108.30,107.41,106.40,101.19,86.73,70.33,65.56,55.04,51.35,50.21,21.17.

[0076] 5 hours, yield: 91.5%, 1 H NMR(400MHz,DMSO-d6,J in Hz)δ(ppm):8.89–8.83(m,1H),8.40–8.34(m,1H),7.90–7.84(m,1H),7.70–7.64(m,1H),7.63–7.57(m ,1H),7.52(dd,J=8.25,4.13Hz,1H),7.49–7.43(m,2H),6.99–6.94(m,1H),6.91–6.79(m,5H),6.67–6. 61(m,2H),6.04–5.97(m,4H),4.83(d,J=8.52Hz,1H),4.74(d,J=6.15Hz,1H),3.99(dd,J=10.00,3.02H z,1H),3.81–3.72(m,1H),3.65–3.55(m,1H),3.53–3.45(m,1H),3.43–3.39(m,1H),2.94–2.87(m,1H). 13 C NMR (100MHz, DMSO-d6) δ (ppm): 149.86, 147.45, 147.40, 146.99, 146.49, 145.98, 145.30, 139.91, 136.85, 136.44, 134.55, 130.98, 129.32, 128.50, 127.80, 126.76, 126.51, 121.24, 120.00, 119.14, 114.13, 108.30, 108.01, 107.29, 106.33, 100.91, 85.53, 69.39, 64.53, 53.82, 51.23, 49.43. Example 6: Evaluation of antitumor activity.

[0077] MTT assay:

[0078] The HepG2 (HB-8065) ​​liver cancer cell line and the MDA-MB-231 (HTB-26) breast cancer cell line used in the experiment were internationally recognized tumor cell lines purchased from ATCC. The tumor cells were cultured in Dulbecco's Modified Eagle Medium (DMEM) containing 10% fetal bovine serum, at a concentration of 3 × 10⁻⁶ cells / mL. 4 Cells were seeded at 100 μL / mL in 96-well plates, with 6 replicates per group. After 24 h of seeding, different concentrations of azasaicin compounds were added, and the cells were cultured for another 24 and 48 h. Then, 20 μL of 5 mg / mL MTT was added to each well, and the cells were cultured for another 5 h. The supernatant was then removed, and 150 μL of DMSO was added to each well. After shaking for 5 min, the absorbance at 570 nm was measured using an automated microplate reader. The growth inhibition rate (%) of the tested compounds on various tumor cells was calculated as follows: (mean OD value of blank control group - mean OD value of experimental group) / mean OD value of blank control group × 100%.

[0079] The results are shown in Table 1. The results indicate that compound 1 had no significant inhibitory activity against HepG2 and MDA-MB-231 in vitro; compounds 3b, 5b, and 5e all had significant in vitro antitumor activity against HepG2 and MDA-MB-231; compound 2b had significant antitumor activity against HepG2; and compound 4e had significant antitumor activity against MDA-MB-231.

[0080] Table 1. In vitro antitumor activity of sesamin derivatives (IC50) 50 , μM )

[0081]

[0082]

[0083] Example 7: Evaluation of the in vitro antibacterial activity of sesamin derivatives

[0084] (1) Antibacterial activity assay

[0085] Experimental strains: The antibacterial activity of the compounds was determined by the microdilution method in this invention. Antibacterial tests were conducted on two common bacteria, Staphylococcus aureus (ATCC 43300) and Escherichia coli (ATCC 25922).

[0086] Preparation of bacterial culture: The bacterial strain was cultured in liquid broth (BHI) at 37°C and 180 rpm for 12 h on a shaker, and then diluted with sterile BHI medium to an absorbance value (OD). 600 It should be between 0.03 and 0.06, then diluted 1:10 before use.

[0087] Drug solution preparation: The test compounds were dissolved in DMSO to prepare a concentration of 100 μg / mL; tetracycline (dissolved in DMSO to prepare a concentration of 0.4 mg / mL) served as a positive control.

[0088] Assay: The bacterial suspension diluted 1:10 was added to 150 μL / well of a 96-well plate, followed by 5 μL / well of the drug solution, with three replicates for each compound. A negative control was prepared using bacterial culture medium containing the same concentration of 2.5% DMSO, and a blank control was prepared using the same culture medium. After 24 hours of incubation, the OD... 600 The absorbance was measured. The experiment was independently repeated three times, and the data were processed using GraphPadPrism 5. Results: The experimental results are shown in Table 2. The results demonstrate that the azasaicin derivative has no inhibitory effect on either *S. aureus* or *E. coli*.

[0089] (2) Evaluation of antifungal activity

[0090] Experimental strains: The antifungal activity of the compounds was tested against the standard strain of Candida albicans (ATCC10231) and Cryptococcus neoformans (ATCC66031).

[0091] Activation of Candida albicans: Candida albicans was activated on YM agar (agar, 20.00 g / L; glucose, 10.00 g / L; malt extract, 3.00 g / L; animal tissue pepsin digest, 5.00 g / L; yeast extract, 3.00 g / L) solid medium and incubated overnight at 30°C.

[0092] Cryptococcus neoformans activation: Cryptococcus neoformans was activated on SDA agar (agar, 15.00 g / L; glucose, 40.00 g / L; casein trypsin digest, animal tissue pepsin digest 10.00 g / L) solid medium and incubated overnight at 30°C.

[0093] Preparation of bacterial culture: A single fresh Candida albicans clone was inoculated into YM broth medium (glucose, 10.00 g / L; malt extract, 3.00 g / L; animal tissue pepsin digest, 5.00 g / L; yeast extract, 3.00 g / L) and cultured overnight at 30°C with shaking at 200 rpm. The culture temperature was adjusted to OD using YM medium. 600=0.03-0.06, then dilute 10 times with YM broth medium to obtain a ready-to-use bacterial suspension.

[0094] Single clones of fresh Cryptococcus neoformans were inoculated into SDB broth (glucose, 20.00 g / L; a mixture of equal volumes of animal tissue pepsin hydrolysate and trypsin, 10.00 g / L) and cultured overnight at 30°C with shaking at 200 rpm; the OD was adjusted to YM medium. 600 =0.03-0.06 to obtain a ready-to-use bacterial suspension.

[0095] Determination of the antifungal activity of the compound against Candida albicans and Cryptococcus neoformans in liquid culture medium:

[0096] Add the prepared bacterial suspension to each well of a 96-well plate at a rate of 195 μL / well, followed by 5 μL of the compound solution dissolved in DMSO per well, for a total volume of 200 μL per well. Ketoconazole (20 μg / mL) was used as the positive control, and DMSO as the negative control. Each treatment was performed in triplicate, with a blank control group containing only culture medium and no bacteria. The plates were incubated at 30°C and 200 rpm for 24 h for *Candida albicans* and 48 h for *Cryptococcus neoformans*. The OD values ​​were then measured using an enzyme digester. 600 The experiment was independently repeated 3 times, and the data was processed using GraphPad Prism 5.

[0097] As shown in Table 2, compounds 1, 4d, and 5e exhibit certain inhibitory effects on C. albicans, with MIC... 50 The MICs were 176.3, 225.6, and 196.4 μM, respectively. Compounds 1, 4d, and 5e exhibited some inhibitory activity against *C. neoformans*, with MIC values ​​of 176.3, 225.6, and 196.4 μM. 50 The values ​​were 241.5, 201.4, and 196.4 μM.

[0098] Table 2. Antibacterial activity (MIC) of sesamin derivatives 50 , (μM)

[0099]

Claims

1. Azasazine derivatives of formula (I) or (II) or pharmaceutically acceptable salts thereof: in, R 1 R 2 R 4 and R 5 Each is independently selected from hydrogen, hydroxyl, amino, carboxyl, cyano, nitro, halogen, C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkyl, and halo-C1-C6 alkoxy. R 3 Selected from hydrogen, hydroxyl, amino, carboxyl, cyano, nitro, halogen, C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkyl, halo-C1-C6 alkoxy, substituted or unsubstituted phenyl, substituted or unsubstituted Replaced or not replaced Replaced or not replaced Replaced or not replaced The substituents are halogens, C1-C6 alkyl groups, C1-C6 alkoxy groups, or halo-C1-C6 alkyl groups; R 6 It consists of hydroxyl groups and OAc.

2. Azasazine derivatives or pharmaceutically acceptable salts thereof represented by formula (III), (IV), (V) or (VI): in, R 1 R 2 R 4 and R 5 Each is independently selected from hydrogen, hydroxyl, amino, carboxyl, cyano, nitro, halogen, C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkyl, and halo-C1-C6 alkoxy. R 3 Selected from hydrogen, hydroxyl, amino, carboxyl, cyano, nitro, halogen, C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkyl, halo-C1-C6 alkoxy, substituted or unsubstituted phenyl, substituted or unsubstituted Replaced or not replaced Replaced or not replaced Replaced or not replaced The substituents are halogens, C1-C6 alkyl groups, C1-C6 alkoxy groups, or halo-C1-C6 alkyl groups; R 6 It consists of hydroxyl groups and OAc.

3. The azasaicin derivative of claim 1 or 2, or a pharmaceutically acceptable salt thereof: in, R 1 R 2 R 4 and R 5 Each is independently selected from hydrogen, hydroxyl, amino, carboxyl, cyano, nitro, halogen, C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkyl, and halo-C1-C6 alkoxy. R 3 Selected from hydrogen, hydroxyl, amino, carboxyl, cyano, nitro, halogen, C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkyl, halo-C1-C6 alkoxy, substituted or unsubstituted phenyl, substituted or unsubstituted Replaced or not replaced Replaced or not replaced The substituent is halogen, C1-C6 alkyl, C1-C6 alkoxy, or halogenated C1-C6 alkyl.

4. The azasaicin derivative of claim 1 or 2, or a pharmaceutically acceptable salt thereof: in, R 1 R 2 R 4 and R 5 Each is independently selected from hydrogen; R 3 The radicals are hydroxyl, amino, carboxyl, cyano, nitro, halogen, C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkyl, halo-C1-C6 alkoxy, substituted or unsubstituted phenyl, substituted or unsubstituted. Replaced or not replaced Replaced or not replaced Replaced or not replaced The substituent is halogen, C1-C6 alkyl, C1-C6 alkoxy, or halogenated C1-C6 alkyl.

5. Azasaicin derivatives or pharmaceutically acceptable salts thereof with the following structures: 。 6. The method for preparing the azasaicin derivative or a pharmaceutically acceptable salt thereof according to claim 4, characterized in that, Its synthetic route is as follows: Ar for , This is the site where the group is attached to nitrogen; R 3 The radicals are hydroxyl, amino, carboxyl, cyano, nitro, halogen, C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkyl, halo-C1-C6 alkoxy, substituted or unsubstituted phenyl, substituted or unsubstituted. Replaced or not replaced Replaced or not replaced Replaced or not replaced The substituent is halogen, C1-C6 alkyl, C1-C6 alkoxy, or halogenated C1-C6 alkyl.

7. A pharmaceutical composition comprising a sesamin derivative of any one of claims 1-5 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or excipient.

8. The use of the azasaicin derivative of any one of claims 1-5 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition of claim 7 in the preparation of an antitumor drug, wherein the tumor is liver cancer or breast cancer.

9. The use of the azasaicin derivative of any one of claims 1-5 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition of claim 7 in the preparation of an antifungal drug.

10. The application according to claim 9, characterized in that, The fungus mentioned is Candida albicans or Cryptococcus neoformans.

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