Dehydroabietic acid-dithiocarbamate derivative as well as preparation method and application thereof

Abstract

The invention belongs to the technical field of biological medicines, and particularly discloses a dehydroabietic acid-dithiocarbamate derivative as well as a preparation method and application thereof. The dehydroabietic acid-dithiocarbamate derivative is a compound with a structural general formula as shown in a formula (I), or a pharmaceutically acceptable salt, a solvate or a hydrate of the dehydroabietic acid-dithiocarbamate derivative. The invention discloses a dehydroabietic acid-dithiocarbamate derivative as well as a preparation method and application thereof. The dehydroabietic acid-dithiocarbamate derivative is high in anti-tumor activity, excellent in selectivity and small in toxic and side effects. (I).

Description

Technical Field

[0001] This invention belongs to the field of biomedical technology, specifically relating to a dehydroabsic acid-dithiocarbamate derivative, its preparation method, and its application. Background Technology

[0002] Cancer is one of the leading diseases threatening human health worldwide, with its incidence and mortality rates continuing to rise. Currently, surgery, radiotherapy, and chemotherapy are the main clinical treatments for cancer. Chemotherapy works by non-selectively killing rapidly proliferating cells, but it is often accompanied by severe toxic side effects such as bone marrow suppression and gastrointestinal damage. Furthermore, tumor cells are prone to developing multidrug resistance, leading to treatment failure. Therefore, developing novel anti-tumor drugs with high efficacy, low toxicity, and clearly defined mechanisms of action has become an urgent need in the field of drug development.

[0003] Natural products, due to their diverse chemical structures, broad biological activities, and multiple targets, have always been a vital resource for the discovery of anti-tumor drugs. For example, paclitaxel and camptothecin derivatives have been successfully used clinically. However, the direct application of many natural active substances as drugs still faces numerous challenges, such as poor water solubility leading to low bioavailability, narrow therapeutic windows causing toxic reactions, or unclear targets hindering rational structural optimization. Therefore, rationally modifying promising natural product lead compounds to improve their physicochemical properties, enhance their activity, and reduce toxicity is a key strategy for promoting their translation into clinical drugs.

[0004] Dehydroabietic acid (DHA) is a diterpenoid natural product isolated from rosin, possessing a tricyclic phenanthrene skeleton. Studies have shown that DHA and its derivatives exhibit various biological activities, including anti-inflammatory, antibacterial, and antitumor effects. In terms of antitumor activity, DHA exerts its effects through inducing apoptosis and inhibiting proliferation and metastasis. However, its inherently weak antitumor activity limits its direct application. Summary of the Invention

[0005] The present invention aims to provide a dehydroabietic acid-dithiocarbamate derivative, its preparation method and application, which has high antitumor activity, excellent selectivity and low toxicity.

[0006] To solve the above-mentioned technical problems, the technical solution adopted by the present invention is as follows: A dehydroabietic acid-dithiocarbamate derivative, said dehydroabietic acid-dithiocarbamate derivative having a compound with the general structural formula shown in formula (I), or a pharmaceutically acceptable salt, solvate, or hydrate thereof. (I), Where R is selected from the following structures: .

[0007] Preferably, the dehydroabsic acid-dithiocarbamate derivative is selected from the following structures: .

[0008] The present invention also provides a method for preparing the aforementioned dehydroabietic acid-dithiocarbamate derivative, comprising the following steps: S1. Dehydroabietic acid, epichlorohydrin and base are added to a solvent and reacted. After the reaction is completed, the mixture is filtered and purified to obtain glycidyl dehydroabietic acid. S2. Add the secondary amine and base to the solvent, add carbon disulfide dropwise under ice bath, stir the reaction to obtain the reaction solution; S3. Dissolve the dehydroabietic glycidyl ester obtained in S1 in the solvent used in S2, add it to the reaction solution obtained in S2, stir and reflux, filter, concentrate, extract and purify to obtain dehydroabietic acid-dithiocarbamate derivative.

[0009] Preferably, in S1, the base is selected from one or more of triethylamine, N,N-diisopropylethylamine, pyridine, sodium carbonate, and potassium carbonate; and the solvent is selected from one or more of acetone, acetonitrile, tetrahydrofuran, and N,N-dimethylformamide.

[0010] Preferably, in S1, the reaction temperature is 50-60℃ and the reaction time is 1-5h.

[0011] Preferably, in S2, the base is selected from one or more of triethylamine, N,N-diisopropylethylamine, pyridine, sodium carbonate, and potassium carbonate; and the solvent is selected from one of anhydrous ethanol, methanol, and isopropanol.

[0012] Preferably, in S2, the stirring reaction temperature is 25°C and the reaction time is 0.5-1h.

[0013] Preferably, in S3, the stirring and reflux reaction temperature is 70-80℃, and the stirring and reflux reaction time is 1-12h.

[0014] The present invention also provides a pharmaceutical composition comprising, as an active ingredient, the aforementioned dehydroabietic acid-dithiocarbamate derivative or a pharmaceutically acceptable salt, solvate, or hydrate thereof, and one or more pharmaceutically acceptable carriers.

[0015] Preferably, pharmaceutically acceptable carriers are one or more of solvents, dispersants, suspending agents, surfactants, isotonic agents, thickeners, preservatives, solid binders, or lubricants.

[0016] The present invention also provides the use of the aforementioned dehydroabietic acid-dithiocarbamate derivatives in the preparation of medicaments for the prevention or treatment of tumors.

[0017] Preferably, the tumor includes one of colon cancer, liver cancer, breast cancer, stomach cancer, or lung cancer.

[0018] Compared with the prior art, the present invention has the following advantages and technical effects: This invention discloses a dehydroabietic acid-dithiocarbamate derivative, its preparation method, and its application. By combining dehydroabietic acid with the antitumor pharmacological group dithiocarbamate, a synergistic effect is achieved, enhancing the antitumor activity and targeting of the derivative. This dehydroabietic acid-dithiocarbamate derivative has potential antitumor activity and can inhibit the proliferation of tumor cells in vitro and in mice.

[0019] The technical solution of the present invention will be further described in detail below with reference to the accompanying drawings and embodiments. Attached Figure Description

[0020] Figure 1 This is the synthetic route for dehydroabscisic acid-dithiocarbamate derivatives in Example 1; Figure 2 The results show anti-tumor activity in vivo, among which... Figure 2 In the figure, A represents the weight change of tumor-bearing mice. Figure 2 In the graph, B represents the tumor volume growth curve in nude mice. Figure 2 C in the image represents a tumor photograph in a nude mouse. Figure 2 In the figure, D represents the tumor weight histogram of nude mice. Figure 3 Pathological sections (200X) of the heart, liver, spleen, lungs and kidneys of nude mice, scale bar 50μm. Detailed Implementation

[0021] The technical solution of the present invention will be further described below with reference to the accompanying drawings and embodiments.

[0022] Unless otherwise defined, the technical or scientific terms used in this invention shall have the ordinary meaning as understood by one of ordinary skill in the art to which this invention pertains.

[0023] Source of experimental materials: Human liver cancer (HepG2), breast cancer (MCF-7), gastric cancer cells (MGC-803), lung cancer (A549), and colon cancer (HCT116, SW480, HT29) cell lines were all obtained from the Cell Bank of the Chinese Academy of Sciences; the culture medium was a complete medium of DEME medium: fetal bovine serum: penicillin and streptomycin = 89:10:1.

[0024] In this invention, unless otherwise specified, all other test materials and instruments are conventional test materials in the field and can be purchased through commercial channels.

[0025] Example 1 of this invention describes the synthetic route for dehydroabietic acid-dithiocarbamate derivatives as follows: Figure 1 As shown.

[0026] Example 1 A dehydroabsic acid-dithiocarbamate derivative is prepared by the following steps: S1. Dehydroabietic acid (1.00 g, 3.3 mmol), epichlorohydrin (0.3 mL, 3.63 mmol), and anhydrous potassium carbonate (0.55 g, 3.96 mmol) were placed in a flask with acetone as the solvent. The mixture was reacted at 60 °C for 5 h. After the reaction was completed, the mixture was filtered, and the filtrate was concentrated and subjected to silica gel column chromatography (V). 石油醚 V 乙酸乙酯 The product was purified using a 12:1 mixed solvent to obtain glycidyl dehydroabietic acid ester, with a yield of 0.96 g and a yield of 82%. S2. Using anhydrous ethanol as the reaction solvent, carbon disulfide (0.14 mL, 2.3 mmol) was added dropwise to the reaction system of secondary amine (0.46 mmol) and anhydrous potassium carbonate (0.063 g, 0.46 mmol) under ice bath conditions. The mixture was stirred at 25 °C for 30 min to obtain the reaction solution. S3. Dissolve the glycidyl dehydroabietic acid ester (0.15 g, 0.42 mmol) obtained in S1 in 3 mL of anhydrous ethanol, and add it to the reaction solution obtained in S2. Stir and reflux at 70 °C for 12 h. After the reaction is complete, filter and concentrate the reaction mixture. Extract with ethyl acetate to remove water-soluble impurities generated in the reaction. Analyze by silica gel column chromatography (V... 石油醚 V 乙酸乙酯 Purification with a 10:1 mixed solvent yielded dehydroabscisic acid isopropanol-dithiocarbamate 3a-3s.

[0027] The dehydroabhidocyanine isopropanol-dithiocarbamate 3a-3s prepared in Example 1 was characterized and its purity was tested.

[0028] All compounds were analyzed by HRMS. 1 H NMR, 13Characterized by C NMR. Purity was determined by HPLC. Chromatographic conditions: gradient elution mode was used. Detection wavelength was 254 nm. Mobile phase: (1) 0 min, acetonitrile:water (0.1% ammonia) = 80:20 (%); 20 min, acetonitrile:water (0.1% ammonia) = 95:5 (%). (2) 0 min, acetonitrile:water (0.1% ammonia) = 85:15 (%); 20 min, 100% acetonitrile. Flow rate: 1.0 mL / min. Column temperature: 35℃.

[0029] Structural characterization of the target compound: 3-((4-ethylpiperazine-1-carbonothioyl)thio)-2-hydroxypropyl-(1 R ,4a S ,10a R 7-isopropyl-1,4a-dimethyl-1,2,3,4,4a,9,10,10a-octahydrophenanthrene-1-carboxylate (3a). White powder, yield: 57.37%, melting point: 91.2-92.1℃. 1 H NMR (400 MHz, CDCl3)δ 7.15 (d, J = 8.2 Hz, 1H), 6.99 (dd, J = 8.1, 2.0 Hz, 1H), 6.87 (d, J = 2.0Hz, 1H), 4.35 (s, 2H), 4.24 – 4.13 (m, 3H), 3.97 (s, 2H), 3.66 (m, 1H), 3.52(dd, J = 14.5, 6.6 Hz, 1H), 2.87 (dd, J = 8.0, 3.3 Hz, 2H), 2.83 – 2.75 (m, 1H), 2.53 (t, J = 5.0 Hz, 4H), 2.32 – 2.21 (m, 2H), 1.88 – 1.67 (m, 5H), 1.52 – 1.39(m, 3H), 1.29 (s, 3H), 1.24 (s, 2H), 1.21 (d, J = 6.8 Hz, 9H), 1.10 (t, J = 7.2Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 196.61, 178.61, 146.71, 145.67, 134.57,126.91, 124.11, 123.90, 69.28, 67.08, 52.03, 51.81, 47.83, HRMS(m / z): calcd for C 30 H 46 N₂O₃S₂[M+H] + : 547.3019; found:547.3028. HPLC purity 97.091%, t R = 14.507 min. 2-hydroxy-3-((4-methylpiperazine-1-carbonothioyl)thio)propyl(1 R ,4a S ,10a R )-7-isopropyl-1,4a-dimethyl-1,2,3,4,4a,9,10,10a-octahydrophenanthrene-1-carboxylate (3b). Pale yellow solid, yield: 61.54%, melting point: 86.5-87.5℃. 1 H NMR (400 MHz, CDCl3) δ7.17 (d, J = 8.2 Hz, 1H), 7.00 (dd, J = 8.2, 2.0 Hz, 1H), 6.88 (d, J = 2.0Hz, 1H), 4.36 (s, 1H), 4.24 – 4.13 (m, 3H), 3.99 (s, 1H), 3.67 (dt, J = 14.5, 4.5 Hz, 1H), 3.53 (dd, J = 14.5, 6.7 Hz, 1H), 2.88 (dq, J = 7.5, 3.7, 3.2 Hz,2H), 2.84 – 2.78 (m, 1H), 2.52 (t, J= 5.1 Hz, 3H), 2.34 (s, 3H), 2.30 – 2.27(m, 1H), 1.87 – 1.68 (m, 5H), 1.52 – 1.42 (m, 2H), 1.30 (s, 3H), 1.25 (s,3H), 1.22 (d, J = 6.8 Hz, 9H). 13 C NMR (100 MHz, CDCl3) δ 196.89, 178.63, 146.72,145.69, 134.58, 126.93, 124.12, 123.92, 69.29, 67.04, 54.21, 47.85, 45.44,44.85, 39.81, 37.87, 36.93, 36.69, 33.41, 31.89, 31.59, 30.08, 29.67, 25.21,23.94, 21.78, 18.53, 16.54. HRMS(m / z): calcd for C 29 H 44 N2O3S2[M+H] + : 533.2866;found: 533.2866. HPLC purity 96.274 %, t R = 13.186 min. 2-hydroxy-3-((4-(2-hydroxyethyl)piperazine-1-carbonothioyl)thio)propyl(1 R ,4a S ,10a R )-7-isopropyl-`1`,4a-dimethyl-1,2,3,4,4a,9,10,10a-octahydrophenanthrene-1-carboxylate (3c). White solid, yield: 42.46%, melting point: 118.1 - 119.8 °C. 1 H NMR (400 MHz, CDCl3) δ7.16 (d, J = 8.2 Hz, 1H), 7.00 (dd, J = 8.1, 1.5Hz, 1H), 6.89 – 6.86 (m, 1H), 4.36 (s, 1H), 4.18 (m, 3H), 3.99 (s, 1H), 3.69– 3.64 (m, 3H), 3.53 (dd,J = 14.9, 6.5 Hz, 1H), 2.90 – 2.85 (m, 2H), 2.84 –2.78 (m, 1H), 2.66 – 2.58 (m, 6H), 2.28 (dd, J = 20.3, 12.5 Hz, 3H), 1.77 (dq, J = 27.6, 13.3, 12.1 Hz, 5H), 1.47 (dd, J = 22.1, 8.5 Hz, 2H), 1.30 (s, 3H), 1.26(d, J = 9.5 Hz, 1H), 1.22 (d, J = 6.9 Hz, 9H). 13 C NMR (100 MHz, CDCl3) δ196.92,178.64, 146.70, 145.68, 134.55, 126.90, 124.10, 123.91, 69.23, 67.04, 58.99,57.86, 52.24, 47.83, 44.83, 39.80, 37.85, 36.90, 36.67, 33.39, 30.06, 29.64,25.18, 23.94, 23.92, 21.75, 18.50, 16.52. HRMS(m / z): calcd for C 30 H 45 N2O4S2[M+H] + : 563.2960; found: 563.2960. HPLC purity 97.684 %, t R = 8.967 min. 2-hydroxy-3-((4-methylpiperidine-1-carbonothioyl)thio)propyl-(1 R ,4a S ,10a R )-7-isopropyl-1,4a-dimethyl-1,2,3,4,4a,9,10,10a-octahydrophenanthrene-1-carboxylate (3d). Yellow oil, yield: 64.85%. 1 H NMR (400 MHz, CDCl3) δ7.17 (d, J= 8.1Hz, 1H), 7.00 (dd, J = 8.2, 2.1 Hz, 1H), 6.88 (d, J = 2.1 Hz, 1H), 5.47 (d, J =12.9 Hz, 1H), 4.62 (d, J = 13.5 Hz, 1H), 4.28 – 4.07 (m, 3H), 3.75 – 3.51 (m,2H), 3.16 (dd, J = 29.5, 12.8 Hz, 2H), 2.88 (dq, J = 7.3, 4.2, 3.3 Hz, 2H), 2.86– 2.76 (m, 1H), 2.28 (m, 2H), 1.91 – 1.69 (m, 8H), 1.55 – 1.40 (m, 3H), 1.30(s, 4H), 1.28 (s, 3H), 1.26 (d, J = 2.2 Hz, 4H), 1.23 (s, 10H), 1.21 (s, 10H),0.98 (d, J = 6.0 Hz, 3H). 13 C NMR (100 MHz, CDCl3) δ 195.55, 178.59, 146.75,145.68, 134.61, 126.94, 124.13, 123.91, 69.45, 67.04, 52.88, 50.73, 47.85,44.86, 39.79, 37.89, 36.94, 36.69, 34.00, 33.42, 30.86, 30.11, 25.22, 23.96,21.78, 21.20, 18.55, 16.55. HRMS(m / z): calcd for C 30 H 45 NO3S2[M+Na] + : 554.2733;found: 554.2708. HPLC purity 99.378 %, t R = 14.474 min. 2-hydroxy-3-((3-methylpiperidine-1-carbonothioyl)thio)propyl-(1 R ,4a S ,10aR )-7-isopropyl-1,4a-dimethyl-1,2,3,4,4a,9,10,10a-octahydrophenanthrene-1-carboxylate (3e). Yellow oil, yield: 59.32%. 1 1H NMR (500 MHz, CDCl3) δ7.17 (d, J J = 8.2Hz, 1H), 7.00 (d, J J = 7.8 Hz, 1H), 6.88 (s, 1H), 5.32 (d, J J = 12.3 Hz, 1H), 4.51(dd, J J = 52.5, 13.9 Hz, 1H), 4.20 – 4.15 (m, 1H), 3.87 – 3.71 (m, 1H), 3.67 (d, J J = 10.9 Hz, 1H), 3.60 – 3.42 (m, 1H), 3.18 (t, J J = 12.0 Hz, 1H), 2.91 – 2.86(m, 2H), 2.84 – 2.80 (m, 1H), 2.30 (d, J J = 12.6 Hz, 1H), 2.25 (m, 1H), 1.93 –1.67 (m, 10H), 1.66 – 1.56 (m, 2H), 1.52 (dd, J J = 9.1, 4.2 Hz, 1H), 1.42 (d, J J=7.0 Hz, 1H), 1.35 (d, J J = 13.0 Hz, 1H), 1.30 (d, J J = 5.4 Hz, 2H), 1.28 (d, J J = 2.5Hz, 2H), 1.25 (s, 1H), 1.23 (s, 3H), 1.21 (s, 6H). 1313C NMR (125 MHz, CDCl3) δ195.56, 178.58, 146.75, 145.67, 134.61, 126.93, 124.11, 123.90, 69.52, 67.07,47.85, 44.89, 44.58, 39.82, 37.92, 36.96, 36.72, 33.42, 32.77, 30.10, 29.67,25.21, 23.94, 21.78, 18.56, 16.56. HRMS(m / z): calcd for C 30 H 45 NO3S2[M+Na] + :554.2733; found: 554.2693. HPLC purity 98.794 %, t R = 14.137 min. 2-hydroxy-3-((2-methylpiperidine-1-carbonothioyl)thio)propyl-(1 R ,4a S ,10a R )-7-isopropyl-1,4a-dimethyl-1,2,3,4,4a,9,10,10a-octahydrophenanthrene-1-carboxylate (3f). Yellow oil, yield: 62.76%. 1 1H NMR (400 MHz, CDCl3) δ7.17 (d, J = 8.2Hz, 1H), 7.00 (d, J = 8.0 Hz, 1H), 6.88 (s, 1H), 4.22 – 4.12 (m, 3H), 3.67 (d, J = 7.5 Hz, 1H), 3.57 (s, 1H), 3.20 (s, 1H), 2.91 – 2.86 (m, 2H), 2.85 – 2.79(m, 1H), 2.33 – 2.24 (m, 2H), 1.88 – 1.63 (m, 12H), 1.58 – 1.45 (m, 3H), 1.31(s, 3H), 1.28 (s, 2H), 1.23 (s, 3H), 1.22 (s, 6H). 1313C NMR (125 MHz, CDCl3) δ195.62, 178.57, 146.75, 145.68, 134.61, 126.93, 124.11, 123.90, 69.50, 67.06,52.85, 50.70, 47.85, 44.90, 39.84, 37.92, 36.96, 36.72, 33.43, 30.85, 30.11,25.21, 23.95, 21.80, 21.18, 18.56, 16.56. HRMS(m / z): calcd for C 30 H 45 NO3S2[M+H] + : 532.2914; found: 532.2910. HPLC purity 99.111 %, t R = 14.157 min. 2-hydroxy-3-((3-hydroxypiperidine-1-carbonothioyl)thio)propyl-(1 R ,4a S ,10a R )-7-isopropyl-1,4a-dimethyl-1,2,3,4,4a,9,10,10a-octahydrophenanthrene-1- carboxylate (3g). Yellow oil, yield: 53.71%. 1 1H NMR (500MHz, DMSO- d 6 ) δ 7.16 (d, J = 8.2 Hz, 1H), 6.97 (dd, J = 8.1, 1.6 Hz, 1H), 6.84(s, 1H), 5.38 (dd, J = 5.6, 3.2 Hz, 1H), 4.89 (d, J = 4.1 Hz, 1H), 4.55 (s, 1H),4.15 – 4.05 (m, 1H), 4.02 (d, J = 5.2 Hz, 1H), 3.93 (m, 2H), 3.83 (td, J = 7.4,3.7 Hz, 1H), 3.69 (dd, J= 13.9, 3.8 Hz, 1H), 3.52 – 3.46 (m, 1H), 3.33 – 3.22(m, 1H), 2.86 – 2.73 (m, 3H), 2.30 (d, J = 12.4 Hz, 1H), 2.11 (dd, J = 13.2, 11.7Hz, 1H), 1.83 – 1.70 (m, 5H), 1.65 (s, 1H), 1.59 (d, J = 8.6 Hz, 1H), 1.42 (d, J = 8.1 Hz, 2H), 1.37 – 1.28 (m, 2H), 1.22 (s, 2H), 1.18 (s, 1H), 1.16 (d, J =6.9 Hz, 6H), 1.13 (s, 3H). 13 C NMR (125 MHz, DMSO- d 6 ) δ 194.55, 177.86, 147.06,145.51, 134.66, 126.95, 124.54, 124.19, 67.58, 64.93, 62.31, 47.61, 45.15,41.23, 38.09, 37.01, 36.59, 33.34, 30.07, 25.43, 24.39, 21.68, 18.59, 16.82.HRMS(m / z): calcd for C 29 H 43 NO4S2[M+H] + : 534.2712; found: 534.2683. HPLC purity 96.719 %, t R = 9.722 min. 2-hydroxy-3-((4-hydroxypiperidine-1-carbonothioyl)thio)propyl-(1 R ,4a S ,10a R )-7-isopropyl-1,4a-dimethyl-1,2,3,4,4a,9,10,10a-octahydrophenanthrene-1-carboxylate (3h). Yellow oil, yield: 50.26%. 11H NMR (500 MHz, CDCl3) δ 7.19 (d, J J = 8.1 Hz, 1H), 7.02 (dd, J J = 8.1, 2.1 Hz, 1H), 6.90 (d, J J = 2.1 Hz, 1H), 4.55 (s, 1H), 4.29 – 4.15 (m, 4H), 3.88 – 3.78 (m, 1H), 3.68 (m, 1H), 3.56 (m, 1H), 2.90 (dt, J J = 8.5, 4.5 Hz, 1H), 2.84 (p, J J = 7.0 Hz, 1H), 2.35 – 2.30 (m, 1H), 2.28 (dt, J J = 12.5, 2.4 Hz, 2H), 1.97 (d, J J = 8.2 Hz, 3H), 1.90 – 1.77 (m, 5H), 1.71 (m, 2H), 1.56 – 1.43 (m, 2H), 1.32 (s, 1H), 1.30 (s, 1H), 1.27 (s, 3H), 1.24 (d, J J = 7.1 Hz, 6H). 13 13C NMR (125 MHz, CDCl3) δ 196.14, 178.66, 146.77, 145.73, 134.62, 126.96, 124.14, 123.95, 69.48, 69.44, 67.12, 67.09, 65.89, 47.90, 44.92, 40.05, 37.95, 36.99, 36.76, 33.46, 30.12, 29.70, 25.23, 23.97, 21.82, 18.58, 16.59. HRMS (m / z): calcd for C 29 21 43 H31N1O4S2 [M + H] + : 534.2712; found: 534.2706. HPLC purity 100.000 %, t R R = 9.227 min. 2-hydroxy-3-((4-(2-hydroxyethyl)piperidine-1-carbonothioyl)thio)propyl (1 R,4a S ,10a R )-7-isopropyl-1,4a-dimethyl-1,2,3,4,4a,9,10,10a-octahydrophenanthrene-1-carboxylate (3i). Yellow oil, yield: 48.98%. 1 1H NMR (500MHz, CDCl3) δ7.16 (d, J J = 8.2 Hz, 1H), 6.99 (d, J J = 8.0 Hz, 1H), 6.88 (s, 1H),5.50 (s, 1H), 4.64 (s, 1H), 4.23 – 4.17 (m, 1H), 4.15 (d, J J = 7.9 Hz, 1H), 3.71(t, J J = 6.4 Hz, 2H), 3.62 – 3.49 (m, 1H), 3.23 – 3.06 (m, 2H), 2.90 – 2.86 (m,2H), 2.84 – 2.80 (m, 1H), 2.32 – 2.24 (m, 2H), 1.89 – 1.81 (m, 4H), 1.81 –1.73 (m, 3H), 1.73 – 1.66 (m, 2H), 1.53 (p, J J = 8.4, 7.4 Hz, 3H), 1.48 – 1.42(m, 1H), 1.29 (d, J J = 5.9 Hz, 3H), 1.27 (d, J J = 2.1 Hz, 2H), 1.25 (s, 1H), 1.23(s, 3H), 1.21 (d, J J = 2.1 Hz, 6H). 1313C NMR (125 MHz, CDCl3) δ 195.69, 178.66, 146.78, 145.70, 134.63, 126.96, 124.14, 123.94, 69.46, 67.09, 60.05, 47.89, 47.29, 44.93, 39.89, 38.51, 37.95, 36.99, 36.76, 33.46, 32.44, 30.13, 29.70, 25.24, 25.12, 23.99, 21.83, 18.59, 16.59, 16.36. HRMS(m / z): calcd for C 31 H 47 NO4S2[M+H] + : 584.2839; found: 584.2824. HPLC purity 99.014%, t R = 10.703 min. 2-hydroxy-3-((2-(2-hydroxyethyl)piperidine-1-carbonothioyl)thio)propyl(1 R ,4a S ,10a R )-7-isopropyl-1,4a-dimethyl-1,2,3,4,4a,9,10,10a-octahydrophenanthrene-1-carboxylate (3j). Yellow oil, yield: 44.13%. 1 1H NMR (400MHz, CDCl3) δ 7.17 (d, J = 8.2 Hz, 1H), 7.00 (dd, J = 8.2, 2.2 Hz, 1H), 6.88 (d, J = 2.1 Hz, 1H), 5.95 (s, 1H), 4.29 – 4.09 (m, 2H), 3.83 – 3.76 (m,1H), 3.65(m, 2H), 3.56 – 3.48 (m, 1H), 3.39 (td, J = 11.5, 3.0 Hz, 2H), 3.23 – 3.04 (m,2H), 2.88 (dd, J = 7.1, 3.5 Hz,2H), 2.81 (q, J= 6.9 Hz, 1H), 2.35 – 2.21 (m,2H), 2.13 (m, 1H), 1.94 – 1.74 (m, 6H), 1.74 – 1.68 (m,4H), 1.49 – 1.40 (m,2H), 1.30 (d, J = 5.5 Hz, 3H), 1.26 (d, J = 7.1 Hz, 3H), 1.23 (s, 3H), 1.21 (s,6H). 13 C NMR (100 MHz, CDCl3) δ 197.24, 178.69, 146.72, 145.69, 134.58, 126.93,124.11, 123.91, 69.27, 67.12, 64.02, 58.11, 56.45, 54.13, 47.86, 46.20,44.86, 37.87, 36.93, 36.70, 33.41, 32.98, 30.08, 29.33, 25.82, 25.20, 23.94,21.78, 19.09, 18.52, 16.54, 16.27. HRMS(m / z): calcd for C 31 H 47 NO4S2[M+H] + :584.2839; found: 584.2823. HPLC purity 99.899 %, t R = 11.988 min. 2-hydroxy-3-((4-(hydroxymethyl)piperidine-1-carbonothioyl)thio)propyl(1 R ,4a S ,10a R )-7-isopropyl-1,4a-dimethyl-1,2,3,4,4a,9,10,10a-octahydrophenanthrene-1-carboxylate (3k). Yellow oil, yield: 41.82%. 1 HNMR (400MHz, CDCl3) δ 7.12 – 7.08 (m, 1H), 6.93 (d, J= 8.0 Hz, 1H), 6.81 (s, 1H), 5.45(s, 1H), 4.60 (s, 1H), 4.17 – 4.06 (m, 2H), 3.71 – 3.58 (m, 1H), 3.45 (d, J =2.6 Hz, 3H), 3.09 (d, J = 33.7 Hz, 2H), 2.86 – 2.78 (m, 2H), 2.78 – 2.72 (m,1H), 2.27 – 2.15 (m, 2H), 1.87 – 1.59 (m, 9H), 1.49 – 1.32 (m, 3H), 1.23 (s,3H), 1.19 (d, J = 7.9 Hz, 3H), 1.15 (d, J = 6.9 Hz, 9H). 13 C NMR (100 MHz, CDCl3)δ195.84, 178.64, 146.72, 145.66, 134.58, 126.91, 124.11, 123.90, 69.42, 67.01,66.70, 62.53, 47.83, 47.23, 44.85, 39.79, 38.35, 37.86, 36.91, 36.68, 33.40,30.08, 29.65, 25.20, 23.94, 21.77, 18.52, 16.53. HRMS(m / z): calcd forC 30 H 45 NO4S2[M+Na] + : 570.2626; found: 570.2682. HPLC purity 99.049 %, t R = 9.599 min. 2-hydroxy-3-((piperidine-1-carbonothioyl)thio)propyl-(1 R ,4a S ,10a R )-7-isopropyl-1,4a-dimethyl-1,2,3,4,4a,9,10,10a-octahydrophenanthrene-1-carboxylate (3l). Yellow oil, yield: 67.86%. 11H NMR (500 MHz, CDCl3) δ 7.16 (d, J J = 8.2 Hz, 1H), 7.00 (dd, J J = 8.1, 2.1 Hz, 1H), 6.88 (d, J J = 2.2 Hz, 1H), 4.28 (s, 1H), 4.22 – 4.15 (m, 2H), 3.91 (s, 1H), 3.70 – 3.65 (m, 1H), 3.55 (m, 1H), 2.88 (dd, J J = 7.8, 3.2 Hz, 2H), 2.82 (td, J J = 6.9, 2.3 Hz, 1H), 2.32 – 2.24 (m, 2H), 1.86 – 1.76 (m, 3H), 1.74 – 1.65 (m, 9H), 1.56 – 1.39 (m, 3H), 1.30 (s, 2H), 1.28 (d, J J = 1.1 Hz, 1H), 1.23 (d, J J = 1.7 Hz, 3H), 1.21 (s, 6H). 13 13C NMR (125 MHz, CDCl3) δ 195.57, 178.61, 146.79, 145.71, 134.64, 126.96, 124.14, 123.93, 73.54, 69.55, 67.12, 62.56, 47.89, 44.92, 39.82, 37.95, 36.99, 36.75, 33.46, 30.14, 25.24, 24.21, 23.98, 21.82, 18.59, 16.59. HRMS (m / z): calcd for C 29 H 43 NO3S2 [M + H] + : 540.2577; found: 540.2557. HPLC purity 99.487%, t R R = 12.791 min. 2-hydroxy-3-((thiomorpholine-4-carbonothioyl)thio)propyl-(1 R ,4a S ,10a R)-7-isopropyl-1,4a-dimethyl-1,2,3,4,4a,9,10,10a-octahydrophenanthrene-1-carboxylate (3m). Yellow oil, yield: 38.29%. 1 H NMR (400 MHz, CDCl3) δ 7.17 (d, J =8.2 Hz, 1H), 7.00 (dd, J = 8.2, 2.1 Hz, 1H), 6.88 (d, J = 2.2 Hz,1H), 4.60 (s,1H), 4.26 – 4.12 (m, 3H), 3.89 – 3.71 (m, 1H), 3.71 – 3.62 (m, 1H), 3.54 (dd, J = 14.7, 6.9 Hz, 1H), 2.88 (dd, J = 8.4, 3.8 Hz, 2H), 2.85 – 2.78 (m,1H), 2.74(s, 3H), 2.35 – 2.21 (m, 2H), 1.91 – 1.63 (m,6H), 1.56 – 1.40 (m,3H), 1.30(s, 2H), 1.28 (s, 1H), 1.26 (d, J = 1.3 Hz, 1H), 1.23 (s, 3H), 1.21 (s, 6H). 13 CNMR (100 MHz, CDCl3) δ 196.76, 178.62, 146.72, 145.71, 134.56, 126.92,124.11, 123.93, 73.27, 69.31, 67.08, 62.85, 47.86, HRMS(m / z): calcd for C 28 H 41 NO3S3[M+H] + : 558.2141; found: 558.2101. HPLC purity 100.000%, tR = 15.149 min. ethyl 4-(((2-hydroxy-3-(((1 R ,4a S ,10a R )-7-isopropyl-1,4a-dimethyl-1,2,3,4,4a,9,10,10a-octahydrophenanthrene-1-carbonyl)oxy)propyl)thio)carbonothioyl)piperazine-1-carboxylate (3n). Yellow oil, yield: 35.26%. 1 1H NMR (400 MHz, CDCl3) δ 7.16 (d, J J = 8.2 Hz, 1H), 7.00 (dd, J J = 8.2, 2.0 Hz, 1H), 6.88 (d, J J = 2.0 Hz, 1H), 4.33 (s, 1H), 4.20 – 4.14 (m, 4H), 3.97 (s, 1H), 3.60 (t, J J = 5.4 Hz, 5H), 2.87 (dd, J J = 6.6, 2.8 Hz, 2H), 2.81 (q, J J = 6.9 Hz, 1H), 2.28 (ddt, J J = 19.8, 12.6, 2.7 Hz, 2H), 1.92 – 1.64 (m, 6H), 1.53 – 1.41 (m, 2H), 1.30 (s, 3H), 1.28 (s, 2H), 1.26 (s, 1H), 1.25 (d, J J = 2.4 Hz, 1H), 1.22 (s, 3H), 1.21 (s, 6H). 1313C NMR (100 MHz, CDCl3) δ197.54, 178.63, 155.22, 146.69, 145.69, 134.54, 126.91, 124.11, 69.23, 69.20, 67.06, 67.03, 61.91, 47.84, 44.83, 42.82, 39.85, 37.86, 36.91, 36.67, 33.39, 30.07, 25.19, 23.94, 23.93, 21.77, 18.51, 16.52, 16.50, 14.59. HRMS(m / z): calcd for C 31 H 46 N2O5S2[M+Na] + : 613.2740; found: 613.2742. HPLC purity 98.629%, t R = 13.253 min. 2-hydroxy-3-((pyrrolidine-1-carbonothioyl)thio)propyl-(1 R ,4a S ,10a R )-7-isopropyl-1,4a-dimethyl-1,2,3,4,4a,9,10,10a-octahydrophenanthrene-1-carboxylate (3o). Yellow oil, yield: 73.44%. 1 1H NMR (400 MHz, CDCl3) δ7.17 (d, J = 8.2Hz, 1H), 7.00 (dd, J = 8.1, 1.7 Hz, 1H), 6.88 (s, 1H), 4.21 – 4.15 (m, 2H),3.92 (t, J = 6.8 Hz, 2H), 3.66 (ddt, J = 12.4, 5.9, 3.0 Hz, 4H), 3.58 – 3.50 (m,1H), 2.88 (dd, J = 10.5, 5.3 Hz, 2H), 2.85 – 2.80 (m, 1H), 2.32 – 2.24 (m, 2H),2.11 – 2.06 (m, 2H), 1.99 (q, J= 6.6 Hz, 2H), 1.84 – 1.67 (m, 5H), 1.47 (td, J =13.3, 12.8, 5.8 Hz, 2H), 1.30 (s, 3H), 1.28 (s, 1H), 1.26 (s, 1H), 1.23 (s,3H), 1.21 (s, 6H). 13 C NMR (100 MHz, CDCl3) δ 192.81, 178.64, 146.80, 145.73,134.68, 126.99, 124.19, 123.97, 69.60, 67.02, 55.57, 50.95, 47.89, 44.90,39.16, 37.94, 36.99, 33.48, 30.15, 26.11, 25.29, 24.34, 24.03, 21.85, 18.61,16.61. HRMS(m / z): calcd for C 28 H 41 NO3S2[M+H] + : 526.2420; found: 526.2402. HPLC purity 97.061 %, t R = 14.782 min. 2-hydroxy-3-((indoline-1-carbonothioyl)thio)propyl-(1 R ,4a S ,10a R )-7-isopropyl-1,4a-dimethyl-1,2,3,4,4a,9,10,10a-octahydrophenanthrene-1-carboxylate (3p). Brown oil, yield: 32.46%. 1 H NMR (400 MHz, DMSO- d 6 ) δ 7.35 (d, J =7.4 Hz, 1H), 7.23 (t, J = 8.1 Hz, 1H), 7.16 (t, J = 7.6 Hz, 3H), 6.96 (dd, J = 8.2,2.0 Hz, 1H), 6.82 (d, J = 2.0 Hz, 1H), 5.48 (d,J = 5.4 Hz, 1H), 4.43 (t, J = 7.5Hz, 2H), 4.06 (d, J = 5.3 Hz, 1H), 4.03 – 3.94 (m, 2H), 3.18 (t, J = 8.2 Hz, 2H),2.83 – 2.72 (m, 3H), 2.29 (d, J = 12.6 Hz, 1H), 2.14 (d, J = 12.4 Hz, 1H), 1.75(t, J = 10.1 Hz, 4H), 1.65 – 1.57 (m, 3H), 1.38 – 1.31 (m, 2H), 1.22 (s, 3H),1.15 (s, 3H), 1.13 (s, 6H). 13 C NMR (100 MHz, DMSO- d 6 ) δ 191.51, 177.87,147.05, 145.51, 135.85, 134.67, 134.65, 126.96, 126.80, 126.03, 124.57,124.20, 118.43, 67.63, 67.11, 47.64, 45.13, 38.09, 37.00, 36.59, 33.35,30.09, 27.45, 25.46, 24.41, 21.72, 18.61, 16.83. HRMS(m / z): calcd forC 32 H 41 NO3S2[M+Na] + : 574.2406; found: 574.2420. HPLC purity 97.642 %, t R = 14.647 min. 3-((diethylcarbamothioyl)thio)-2-hydroxypropyl-(1 R ,4a S ,10a R )-7-isopropyl-1,4a-dimethyl-1,2,3,4,4a,9,10,10a-octahydrophenanthrene-1-carboxylate (3q). Yellow oil, yield 74.53%.1 1H NMR (400 MHz, CDCl3) δ 7.12 – 7.08 (m, 1H), 6.93 (dd, J J = 8.1, 1.9 Hz, 1H), 6.81 (s, 1H), 4.10 (m, 2H), 4.03 – 3.90 (m, 2H), 3.69 (dt, J J = 5.0, 4.3 Hz, 2H), 3.58 (m, 1H), 3.47 (m, 1H), 2.88 – 2.78 (m, 2H), 2.74 (dd, J J = 13.8, 6.9 Hz, 1H), 2.20 (m, 2H), 1.81 – 1.59 (m, 5H), 1.47 – 1.34 (m, 2H), 1.27 – 1.17 (m, 10H), 1.15 (d, J J = 6.8 Hz, 9H). 13 13C NMR(100 MHz, CDCl3) δ 195.70, 178.64, 146.80, 145.73, 134.67, 126.98, 124.18, 123.96, 69.57, 67.10, 50.22, 47.90, 47.12, 44.92, 39.77, 37.94, 37.00, 36.75, 33.48, 30.15, 25.28, 24.00, 21.84, 18.60, 16.60, 12.51, 11.57. HRMS(m / z): calcd for C 28 H 43 NO3S2[M+Na] + : 528.2577; found: 528.2559. HPLC purity 99.535 %, t R R = 16.111 min. 3-((dimethylcarbamothioyl)thio)-2-hydroxypropyl-(1 R ,4a S ,10a R )-7-isopropyl-1,4a-dimethyl-1,2,3,4,4a,9,10,10a-octahydrophenanthrene-1-carboxylate (3r). Yellow oil, yield: 76.21%. 1H NMR (500 MHz, CDCl3) δ 7.17 (d, J =8.2 Hz, 1H), 7.00 (dd, J = 8.1, 1.7 Hz, 1H), 6.89 – 6.87 (m, 1H), 4.25 – 4.13(m, 3H), 3.65 (m, 1H), 3.55 (s, 3H), 3.39 (s, 3H), 2.88 (dd, J 1.30 (s, 3H), 1.26 (s, 1H), 1.23 (s, 3H), 1.21 (s, 6H). 13 C NMR (125 MHz, CDCl3) δ 197.30, 178.62, 146.78, 145.72,134.63, 126.96, 124.14, 123.94, 69.51, 67.11, 47.89, 45.90, 44.91, 41.71,40.31, 37.95, 36.99, 36.75, 33.46, 30.12, 29.70, 25.24, 23.98, 21.82, 18.59,16.59. HRMS(m / z): calcd for C 26 H 39 NO3S2[M+H] + : 500.2264; found: 500.2260. HPLC purity 96.888%, t R = 12.469 min. 3-((4-acetylpiperazine-1-carbonothioyl)thio)-2-hydroxypropyl-(1 R ,4a S ,10a R )-7-isopropyl-1,4a-dimethyl-1,2,3,4,4a,9,10,10a-octahydrophenanthrene-1-carboxylate (3s). Yellow solid, yield: 65.26%, melting point: 105.6-106.4℃.1 H NMR (500 MHz,DMSO- d 6 ) δ 7.16 (d, J = 8.2 Hz, 1H), 6.97 (dd, J = 8.2, 2.0 Hz, 1H), 6.84 (s,1H), 5.40 (d, J = 3.4 Hz,1H), 4.22 (d, J = 33.3 Hz, 2H), 4.08 (dd, J = 11.0, 5.4Hz, 1H), 4.02 (dd, J = 5.3, 1.7 Hz, 1H), 3.97 (dd, J = 11.1, 5.0 Hz, 1H), 3.94 –3.90 (m, 1H), 3.57 (dt, J = 13.1, 5.3 Hz, 4H), 3.55 – 3.48 (m,2H), 2.79 (dt, J =13.6, 5.5 Hz, 3H), 2.30 (d, J = 12.6 Hz, 1H), 2.12 (dd, J = 12.5, 2.1 Hz, 1H),2.03 (d, J = 4.8 Hz, 3H), 1.75 (tt, J = 8.2, 4.2 Hz, 3H), 1.65 (t, J = 4.6 Hz,1H),1.59 (d, J = 8.6 Hz, 1H), 1.38 – 1.30 (m, 2H), 1.23 (d, J = 8.9 Hz, 3H), 1.19 (s,1H), 1.16 (d, J = 6.9 Hz, 6H), 1.14 (s, 3H). 13 C NMR (125 MHz, DMSO- d 6) δ 196.05,177.83, 169.14, 147.07, 145.53, 134.67, 126.96, 124.56, 124.21, 67.55, 67.32,62.26, 47.62, 45.15, 44.90, 41.06, 38.10, 37.02, 36.61, 33.33, 30.07, 25.43,24.39, 21.68, 18.59, 16.82. HRMS(m / z): calcd for C 30 H 44 N₂O₄S₂[M+Na] + : 583.2635; found: 583.2630. HPLC purity 98.094%, t R = 8.583 min. From the above target compounds 1 ¹H NMR analysis showed that the chemical shifts of hydrogen atoms on the benzene ring were in the range of δ 6.80–7.20 ppm; the chemical shifts of hydrogen atoms on the carbon atom of the nitrogen heterocycle shifted to the lower field to δ 2.80–4.00 ppm due to the electron-withdrawing effect of the nitrogen atom; the chemical shifts of the two hydrogen atoms on the carbon atom bonded to the ester bond were approximately δ 4.00 ppm; and the chemical shifts of the two hydrogen atoms on the carbon atom bonded to the sulfur atom shifted to the lower field to δ 4.00–4.30 ppm due to the deshielding effect of C=S. 13 CNMR spectra showed that the chemical shifts of the carbons on the benzene ring ranged from δ 120.00 to 160.00 ppm; the chemical shifts of the carbons in the ester group were around δ 170.00 ppm. A carbon adjacent to the ester bond had a chemical shift of around δ 70.00 ppm; the chemical shift of the carbons in the thioacryl carbonyl group was around δ 194.00 ppm. The chemical shifts of the methyl carbons ranged from δ 15.00 to 20.00 ppm. All target compounds were analyzed by HRMS, and the results were consistent with the designed target compounds. The purity of all compounds was >95%.

[0030] The in vitro and in vivo antitumor activity of the dehydroabscisic acid isopropanol-dithiocarbamate derivative prepared in Example 1 was evaluated.

[0031] Preparation of reagents for antitumor activity assay: Mix DMEM medium, fetal bovine serum and penicillin-streptomycin solution in a ratio of 89:10:1 to prepare a complete culture medium containing 10% fetal bovine serum. Store at 4°C for later use.

[0032] Preparation of drug solution: Dissolve 10 μmol of the target compound in 1 mL of cell culture grade dimethyl sulfoxide (DMSO), sonication may be used to aid dissolution. The final stock solution should have a concentration of 1 × 10⁻⁶. 4 Store at 4°C for μM concentration. Dilute the stock solution to the target concentration before use; prepare the solution fresh each time.

[0033] Preparation of MTT solution: Dissolve 250 mg MTT powder in 50 mL PBS, sonicate to aid dissolution, to a final concentration of 5 mg / mL, and filter through a sterile microporous membrane with a pore size of 0.22 μm.

[0034] In vitro antitumor activity screening: Cell seeding: MCF-7, HepG2, HCT-116, MGC-803, A549, HT29, SW480, and HK2 cells in logarithmic growth phase and in good growth condition were washed with PBS, trypsinized, and centrifuged. A single-cell suspension was then prepared using culture medium, and 5000-8000 cells were seeded per well (the actual number of cells can be adjusted according to differences in growth rate and volume). The cell suspension was seeded into 96-well plates at 180 μL / well, ensuring even distribution. 150 μL of PBS was added around each well for sealing. Cells were cultured at 37°C and 5% CO2.

[0035] Cell culture: When the cell adhesion density reaches 60-70%, remove the original culture medium and add drug-containing culture medium. Six concentration gradients of the drug solution were prepared (80, 40, 20, 10, 5, 2.5 μM; for HK2 cells, 100, 50, 25, 12.5, 6.25, 3.125 μM), with four replicates for each concentration. 180 μL of drug solution was added to each well. 5-Fluorouracil (5-FU) was used as a positive control, while the blank control group was treated with an equal volume of 1% cell culture-grade DMSO in complete culture medium. The drug treatment lasted for 48 hours.

[0036] Colorimetric assay: After 48 h of drug treatment, add 20 μL of MTT solution (5 mg / mL) to each well, incubate at 37 °C for 4 h, remove the original culture medium and retain the formazan crystals, add 150 μL of DMSO and place in a microplate reader and shake well for 2 min to fully dissolve the formed formazan crystals, and read the absorbance (OD) at a wavelength of 490 nm.

[0037] Statistical analysis: The cell growth inhibition rate was calculated, and the IC50 of the test drug was calculated using SPSS Statistics 25.0 software. 50 Values. Experimental results are expressed as the mean ± standard deviation (SD) of three parallel experiments. The growth inhibition rate is calculated using the following formula: .

[0038] In vitro antitumor activity results: The antiproliferative activity of 19 target compounds against MCF-7, HepG2, HCT-116, MGC-803, A549, HT29, and SW480 cells, as well as their toxicity to normal HK2 cells, was evaluated using the MTT assay. 5-FU was used as a positive control. The experimental results are shown in Table 1.

[0039] Table 1. In vitro antiproliferative activity of compounds 3a-3s

[0040] Note: a: half-maximal inhibitory concentration.

[0041] Table 1 shows that most of the synthesized compounds exhibited antitumor cell proliferation activity superior to that of the parent DHA to some extent. For MCF-7, HepG2, MGC-803, and A549 cell lines, some compounds showed moderate activity and some selectivity against colon cancer cells. For HCT116 cells, compounds 3h, 3j, and 3s had IC50 values ​​ranging from 11.06 to 15.71 μM, with antitumor activity comparable to the positive control drug 5-FU. In HT-29 cells, most compounds showed some antitumor activity. Compounds 3c, 3g, 3h, 3i, 3j, and 3s showed better activity, indicating that the toxicity of these compounds to tumor cells is enhanced when electron-rich groups such as hydroxyl groups are introduced into nitrogen-containing heterocycles. Furthermore, the electron-rich substituents at the para position showed stronger activity than those at the ortho and meta positions. Compounds 3h and 3s showed good activity against all three colon cancer cell lines, comparable to the positive control drug 5-FU, and exhibited less toxicity to normal HK2 cells. Compounds 3h and 3s will be selected for further mechanistic studies.

[0042] In vivo antitumor activity assessment: To verify the antitumor activity and low toxicity of compounds 3h and 3s in tumor-bearing mice, the mice were treated every two days, with the specific experimental protocol as follows: BALB / c nude mice (half male and half female) aged 4-5 weeks were purchased and housed in an SPF-grade environment for one week of acclimatization before the experiment. The cultured HCT116 colon cancer cells were diluted with a serum-free mixture of Methylprednisolone and Maternal gel and inoculated into the armpits of the nude mice (0.1 mL), at a cell mass of 5 × 10⁶ cells / mL. 5 Each / each

[0043] After the model is established, the patient's weight and tumor volume are measured the following day. The tumor volume is maintained until it reaches 100-150 mm. 3Nude mice were divided into three groups: a control group, a positive control group (5-FU, DHA), and an experimental group, with six mice in each group. 20g / 0.1mL of the drug solution was administered intraperitoneally. The control group received the same volume of 2% DMSO + 43% saline + 55% PEG-300. The mice were administered the drug twice daily, and their weight, volume, and tumor volume were recorded. Seventeen days after administration, the mice were euthanized by cervical dislocation, and their heart, liver, spleen, lungs, and kidneys were harvested for histopathological analysis. Intact tumor tissue was removed, and the tumor weight was recorded, and the tumor inhibition rate was calculated.

[0044] ; in, Indicates the major axis, Indicates the minor axis.

[0045] .

[0046] The results were analyzed using GraphPad Prism 9.4, and one-way ANOVA was used for statistical analysis of the data. Results are expressed as mean ± standard deviation (SD). p This indicates that compared with the control group, p <0.05, p <0.01, p <0.001, p <0.0001, p <0.05 indicates that the data analysis results are statistically significant. The results are as follows... Figures 2-3 As shown.

[0047] Depend on Figure 2 It was found that the mice maintained a stable weight during treatment, with no significant weight loss. In the 3h and 3s treatment groups at a dose of 35 mg / kg, tumor growth began to slow after 5 days of treatment, and by 17 days, the tumor volume in the mice was significantly lower than that in the control group.

[0048] Mice were sacrificed 17 days after treatment, and tumor weight was measured. Antitumor activity was assessed by calculating the tumor growth inhibition rate (TIR); a TIR > 40% indicated effective antitumor activity. Compounds 3h and 3s showed TIRs of 40.1% and 44.9% at a high dose of 35 mg / kg, respectively, demonstrating effective antitumor effects, both superior to their parent nucleus DHA (12.0%) and slightly inferior to the positive control drug 5-FU (53.1%). (Slices are shown below.) Figure 3 As shown.

[0049] Depend on Figure 3 It was found that the myocardial cells had normal morphology and arrangement. The liver cords had normal shape and arrangement, with no obvious lesions. The white and red pulp of the spleen had normal structure and proportion. In the 3h and 3s treatment groups, there was uneven alveolar expansion and alveolar septal rupture, while the kidneys showed no obvious lesions.

[0050] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention and not to limit them. Although the present invention has been described in detail with reference to preferred embodiments, those skilled in the art should understand that modifications or equivalent substitutions can still be made to the technical solutions of the present invention, and these modifications or equivalent substitutions cannot cause the modified technical solutions to deviate from the spirit and scope of the technical solutions of the present invention.

Claims

1. A dehydroabietic acid-dithiocarbamate derivative, characterized in that, The dehydroabietic acid-dithiocarbamate derivatives have compounds with the general structural formula shown in formula (I), or pharmaceutically acceptable salts, solvates, or hydrates thereof. （I）， Where R is selected from the following structures: 。 2. The dehydroabietic acid-dithiocarbamate derivative according to claim 1, characterized in that, The dehydroabsic acid-dithiocarbamate derivatives are selected from the following structures: 。 3. A method for preparing a dehydroabietic acid-dithiocarbamate derivative as described in any one of claims 1 or 2, characterized in that, Includes the following steps: S1. Dehydroabietic acid, epichlorohydrin and base are added to a solvent and reacted. After the reaction is completed, the mixture is filtered and purified to obtain glycidyl dehydroabietic acid. S2. Add the secondary amine and base to the solvent, add carbon disulfide dropwise under ice bath, stir the reaction to obtain the reaction solution; S3. Dissolve the dehydroabietic glycidyl ester obtained in S1 in the solvent used in S2, add it to the reaction solution obtained in S2, stir and reflux, filter, concentrate, extract and purify to obtain dehydroabietic acid-dithiocarbamate derivative.

4. The method according to claim 3, characterized in that, In S1, the reaction temperature is 50-60℃ and the reaction time is 1-5h.

5. The method according to claim 3, characterized in that, In S2, the stirring reaction temperature is 25°C and the reaction time is 0.5-1h.

6. The method according to claim 3, characterized in that, In S3, the stirring and reflux reaction temperature is 70-80℃, and the stirring and reflux reaction time is 1-12h.

7. A pharmaceutical composition, characterized in that, The active ingredient is a dehydroabietic acid-dithiocarbamate derivative or a pharmaceutically acceptable salt, solvate, or hydrate thereof as described in any one of claims 1-2, and one or more pharmaceutically acceptable carriers.

8. The pharmaceutical composition according to claim 7, characterized in that, Pharmaceutically acceptable carriers are one or more of the following: solvents, dispersants, suspending agents, surfactants, isotonic agents, thickeners, preservatives, solid binders, or lubricants.

9. The use of the dehydroabietic acid-dithiocarbamate derivative as described in any one of claims 1-2 in the preparation of a medicament for the prevention or treatment of tumors.

10. The application according to claim 9, characterized in that, The tumor includes one of the following: colon cancer, liver cancer, breast cancer, stomach cancer, or lung cancer.

Images