A tripterine derivative targeting prdx3 and a preparation method and application thereof

Abstract

This invention discloses a triptolide derivative targeting PRDX3, its preparation method, and its application. The derivative has the structure shown in general formula (I) or (II). This invention also relates to the preparation method of this type of compound and its application in the preparation of antitumor drugs.

Description

Technical Field

[0001] This invention relates to the fields of medicinal chemistry and biomedicine, specifically to a triptolide derivative targeting PRDX3, its preparation method, and its application. Background Technology

[0002] Malignant tumors are a major disease that seriously threatens human health worldwide, and clinical treatment mainly relies on surgery, radiotherapy, chemotherapy, and targeted therapy. Among these, targeted therapy has made significant progress, but it still faces challenges such as drug resistance, off-target toxicity, and a narrow therapeutic window, making it urgent to develop novel anti-tumor drugs that are highly effective and have low toxicity.

[0003] Peroxidase 3 (PRDX3) is a key antioxidant enzyme located in mitochondria, primarily responsible for scavenging reactive oxygen species (ROS) and maintaining redox homeostasis. Studies have found that PRDX3 is significantly overexpressed in various tumor tissues, including breast cancer, liver cancer, and lung cancer. By scavenging excess ROS, it blocks the oxidative stress-induced apoptosis pathway, thereby promoting tumor cell proliferation and invasion. Given the central role of mitochondria in tumorigenesis and development, and the crucial role of PRDX3 in maintaining redox homeostasis in tumor cells, targeted inhibition of PRDX3 activity has become a novel strategy for anti-tumor drug development. However, PRDX3 also plays an important physiological role in maintaining mitochondrial redox homeostasis in normal tissues and cells. Traditional small-molecule inhibitors struggle to distinguish between tumor and normal cells, resulting in poor selectivity and significant toxic side effects, thus hindering the development of highly effective and low-toxicity PRDX3 inhibitors.

[0004] Tripterygium wilfordii, a pentacyclic triterpenoid natural product isolated from the traditional Chinese medicine Tripterygium wilfordii, has been proven to be an effective small molecule inhibitor of PRDX3 and has broad-spectrum in vitro antitumor activity. However, it has inherent drawbacks such as multi-organ toxicity, poor targeting, and narrow therapeutic window, which seriously hinder its clinical translation.

[0005] In recent years, leveraging the biological characteristic that tumor cells have a significantly higher mitochondrial membrane potential than normal cells, small molecule drug delivery technologies using lipophilic cations (such as triphenylphosphine, TPP) as mitochondrial targeting carriers have provided a new approach to addressing the aforementioned problems. This technology, by covalently linking drugs to groups such as TPP, can achieve selective enrichment of drugs in tumor cell mitochondria, thereby enhancing anti-tumor effects and reducing toxicity to normal cells. As of the date of this application, there are no reports on triptolide derivatives targeting mitochondrial PRDX3, indicating a significant technological gap in this field.

[0006] Therefore, developing a novel triptolide derivative based on mitochondrial targeted modification that can efficiently and selectively inhibit PRDX3 activity is of great scientific and clinical significance for breaking through the technical bottlenecks of existing anti-tumor drugs and opening up new avenues for targeted tumor therapy. Summary of the Invention

[0007] The primary objective of this invention is to provide a triptolide derivative that targets PRDX3.

[0008] Another object of the present invention is to provide a method for preparing the above-mentioned derivatives.

[0009] Another object of the present invention is to elucidate the bioactivity of the above-mentioned derivatives in inhibiting PRDX3 and in antitumor activity, and to provide their use in the preparation of antitumor drugs.

[0010] This invention provides the structure and preparation method of a PRDX3 inhibitor based on mitochondrial targeting technology. This invention also provides partial activity screening results of the above compound and its uses.

[0011] To achieve the above objectives, the present invention adopts the following technical solution:

[0012] I. Tripterygium wilfordii derivatives targeting PRDX3

[0013] This invention provides a triptolide derivative targeting PRDX3 having the structure shown in general formula (I) or (II).

[0014]

[0015] In general formulas (I) and (II):

[0016] n1 = 1, 2, 4, 5, 7;

[0017] n2 = 3, 4, 5;

[0018] The R1 group represents a mitochondrial targeting group, selected from one of the following groups:

[0019]

[0020] R2 is selected from one of the following groups:

[0021]

[0022] R3 is selected from one of the following groups:

[0023]

[0024] According to a preferred embodiment of the present invention, the compounds are compounds 2a-2c, 5a-5e, 7a, 10a-10d, and 13a-13f having specific structural formulas, as shown below:

[0025]

[0026] II. Preparation method of triptolide derivatives targeting PRDX3

[0027] A method for preparing a triptolide derivative targeting PRDX3, the synthetic route is as follows:

[0028] (1) The synthetic route for the target compounds 2a-2c is as follows:

[0029]

[0030] Reagents and conditions: (i) Cl–C(=O)–(CH2) with different structures n –Br, triethylamine, dichloromethane, 0℃, 30min; (ii) acetonitrile, 90℃, reflux, 48h.

[0031] Where n = 3, 4, 5;

[0032] (2) The synthetic route for the synthesis of target compounds 5a-5e and compound 7a is as follows:

[0033]

[0034] Reagents and conditions: (i) 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride, 1-hydroxybenzotriazole, N,N-dimethylacetamide, rt, 2h; (ii) trifluoroacetic acid, dichloromethane, 0℃, 30min; (iii) Carter's condensing agent, N,N-diisopropylethylamine, dichloromethane, rt, 2h; (iv) acetonitrile, 90℃, reflux, 48h;

[0035] Where n = 1, 2, 4, 5, 7;

[0036] (3) The synthesis of target compounds 10a-10d and 13a-13f, the synthetic route is as follows:

[0037]

[0038] Reagents and conditions: (i) Triethylamine, dichloromethane, 0℃, 30 min; (ii) Carter's condensing agent, N,N-diisopropylethylamine, dichloromethane, rt, 2 h; (iii) Acetonitrile, 90℃, reflux, 48 h;

[0039] Among them, R3 is , , , ;

[0040] R2 is , , , , , , .

[0041] III. Application of triptolide derivatives targeting PRDX3

[0042] This invention provides the use of the aforementioned triptolide derivative targeting PRDX3 in the preparation of antitumor drugs. Experiments have demonstrated that the triptolide derivative based on mitochondrial targeting technology of this invention can be used to prepare antitumor drugs targeting PRDX3.

[0043] As shown in Table 1, paclitaxel (PTX) and the lead compound tripterygium oleoresin were selected as positive controls. The in vitro antitumor activity of the synthesized first-round modified target compounds 2a-2c, 5a-5e and 7a was evaluated, and the in vitro cytotoxicity of the drugs was determined by the CCK-8 assay.

[0044] As shown in Table 2, the lead compound tripterygium wilfordii was selected as a positive control. The in vitro antitumor activity of the synthesized target compounds 2c and 7a was evaluated, and the in vitro cytotoxicity of the drugs was determined by the CCK-8 assay.

[0045] As shown in Table 3, the in vitro selectivity index (SI; SI = CC) was performed on the synthesized target compounds 2c and 7a, as well as the lead compound tripterycin. 50 / IC 50 )evaluate.

[0046] As shown in Table 4, the in vitro antitumor activity of the two-round modified compounds 10a-10d and 13a-13f was evaluated, and the in vitro cytotoxicity of the drugs was determined by the CCK-8 assay.

[0047] like Figure 1 As shown, the in vitro antitumor mechanism of the representative compound 10d was evaluated.

[0048] This invention discloses a triptolide derivative targeting PRDX3, its preparation method, antitumor activity test results, and its first application as a PRDX3 inhibitor. Experiments demonstrate that the triptolide derivative based on mitochondrial targeting technology can be used as an antitumor drug targeting PRDX3. Attached Figure Description

[0049] Figure 1 This is a diagram illustrating the ability of compound 10d of the present invention to bind to PRDX3 and target mitochondria.

[0050] Among them, (A) is the thermal stability experiment, (B) is the surface plasmon resonance experiment, (C) is the mitochondrial membrane potential detection, and (D) is the reactive oxygen species detection.

[0051] The technical solution of the present invention will be further described in detail below through embodiments. Detailed Implementation

[0052] The technical solution of the present invention will be described below through embodiments. To make the objectives, technical solutions, and advantages of this application clearer, the present invention will be described clearly and completely below in conjunction with embodiments. The following description is intended to further elaborate on the content of the present invention; unless otherwise specified, the meanings of the technical terms used are consistent with the common understanding of those skilled in the art.

[0053] The compounds of this invention can be synthesized using commercially available reagents according to the methods described below, or prepared using conventional methods and other reagents in the art. Compounds of formulas 2a-2c, 5a-5e, 7a, 10a-10d, or 13a-13f can be prepared by a variety of methods, including standard chemical synthetic routes. Representative general synthetic strategies are listed below, and the relevant compounds can be obtained using known organic synthesis techniques. When referring to the examples below, those skilled in the art can obtain similar derivatives by incorporating conventional group substitutions without departing from the spirit of the invention. For sensitive or reactive groups, protecting groups can be used according to conventional chemical principles, and their operation and deprotection follow standard organic synthesis methods (TW Greene & PGM Wuts, Protective Groups in Organic Synthesis, 3rd ed., Wiley, 1999), and removed at appropriate stages in a manner well known in the art. The selection of synthetic methods, reaction conditions, and the sequence of steps should be adapted to the preparation of the target compound.

[0054] Those skilled in the art can identify the stereocenters that may be present in compounds of formulas 2a-2c, 5a-5e, 7a, 10a-10d, or 13a-13f. Therefore, this invention covers all possible stereoisomers, including racemic mixtures and single enantiomers. If the target compound is a single enantiomer, it can be obtained through stereospecific synthesis or by resolving the final product or intermediate. The resolving of the starting material, intermediate, or final product can be performed using methods known in the art (see EL Eliel, SHWilen & LN Mander, Stereochemistry of Organic Compounds, Wiley-Interscience, 1994).

[0055] Example 1. Preparation of the compound

[0056] The synthetic method of triptolide derivatives targeting PRDX3 includes:

[0057] (1) The synthetic route for the target compounds 2a-2c is as follows:

[0058]

[0059] Celastrol (1.0 eq.) and triethylamine (2 eq.) were added to 12 mL of anhydrous dichloromethane, and then Cl–C(=O)–(CH2) with different structures were added dropwise. n –Br (4 eq.), 0℃, stirred for 30 min. After the reaction was completed by TLC monitoring, water was added to quench the reaction, and the mixture was extracted with dichloromethane (15 mL × 4). The upper organic phases were combined and collected, and then washed with saturated sodium chloride solution (15 mL × 3). The mixture was dried over anhydrous magnesium sulfate, filtered, and dichloromethane was removed by rotary evaporation under reduced pressure. The crude product was mixed with 100-200 mesh silica gel and separated by column chromatography to obtain intermediates 1a-1c.

[0060] Intermediates 1a-1c (1 eq.) were dissolved in 15 mL of acetonitrile, and triphenylphosphine (3 eq.) was added. The mixture was heated at 110 °C for 48 h. After the reaction was completed as monitored by TLC, the reaction was quenched with water, and the mixture was extracted with dichloromethane (15 mL × 3). The organic phases were combined and collected. The organic phases were then washed with saturated sodium chloride solution (15 mL × 3), dried over anhydrous magnesium sulfate, filtered, and the dichloromethane was removed by rotary evaporation under reduced pressure. The crude product was mixed with 100-200 mesh silica gel and column chromatography was used to separate the target compounds 2a-2c.

[0061] The spectral data of compounds 2a-2c are as follows:

[0062] 2a: Yellow solid, yield 25%, Mp: 125-136 ℃. 1H NMR (600 MHz, DMSO) δ 7.93 –7.90 (m, 3H), 7.84 – 7.78 (m, 12H), 7.13 (dd,J = 5.4, 3.6 Hz, 1H), 7.07 (dd,J = 5.5, 3.4 Hz, 1H), 6.84 (s, 1H), 6.02 (s, 1H), 2.56 (t, J = 7.0 Hz, 2H), 2.35 (s, 1H), 2.22 (s, 2H), 2.12 (s, 1H), 2.04 (s, 1H), 1.98 (s, 1H), 1.77(t, J = 8.0 Hz, 2H), 1.72 (s, 3H), 1.64 (dd, J = 15.4, 8.5 Hz, 3H), 1.56 (d,J = 7.5 Hz, 3H), 1.44 (d, J = 18.9 Hz, 5H), 1.26 – 1.24 (m, 5H), 1.12 (s,3H), 1.08 (s, 3H), 0.65 (d, J = 8.4 Hz, 3H). ESI-MS: m / z 781.4022 (M)+.C 51 H 58 O5P + [781.4016].

[0063] 2b Yellow solid, yield 28%, Mp: 120-138 ℃. 1H NMR (600 MHz, DMSO) δ 7.91 –7.90 (m, 3H), 7.81 – 7.78 (m, 13H), 7.33 (d, J = 7.1 Hz, 1H), 6.43 (d, J =7.2 Hz, 1H), 6.38 (d, J = 4.7 Hz, 1H), 2.69 (t, J = 7.2 Hz, 2H), 2.39 (s,1H), 2.33 (s, 1H), 2.07 (s, 2H), 1.87 – 1.84 (m, 3H), 1.74 – 1.69 (m, 5H),1.58 (d, J = 8.2 Hz, 3H), 1.47 (d, J = 11.2 Hz, 3H), 1.43 (s, 3H), 1.40 (d, J= 5.3 Hz, 2H), 1.26 – 1.23 (m, 7H), 1.12 (d, J = 3.2 Hz, 3H), 1.09 (s, 3H), 0.66 (d, J = 6.4 Hz, 3H). ESI-MS: m / z 795.4180 (M)+. C 52 H 60 O5P + [795.4173].

[0064] 2c: Yellow solid, yield 21%, Mp: 113-129 ℃. 1 H NMR (600 MHz, DMSO) δ 7.90(s, 3H), 7.80 (d, J = 7.8 Hz, 12H), 6.88 (s, 1H), 6.42 (d, J = 7.0 Hz, 1H), 6.37 (s, 1H), 5.99 (s, 1H), 2.55 (d, J = 8.3 Hz, 2H), 2.26 (s, 2H), 2.09 (d,J = 2.8 Hz, 2H), 1.84 (d, J = 15.4 Hz, 3H), 1.75 – 1.71 (m, 5H), 1.67 (s,3H), 1.60 (s, 3H), 1.55 (s, 3H), 1.43 (s, 5H), 1.24 (s, 9H), 0.65 (s, 3H).ESI-MS: m / z 809.4333 (M)+. C 53 H 62 O5P + [809.4329].

[0065] (2) The synthetic route for the target compounds 5a-5e and 7a is as follows:

[0066]

[0067] Celastrol (1.0 eq.), EDCI (2 eq.), Hobt (1.2 eq.), and H2N–(CH2) with different structures were compared. n –NH-Boc (1.2 eq.) was dissolved in 4 mL of N,N-dimethylformamide and reacted at room temperature for 2 h. After the reaction was completed as monitored by TLC, an equal volume of 1 mol / L hydrochloric acid was added, and the mixture was extracted with ethyl acetate (15 mL × 4). The upper organic phases were combined and collected, and then washed with saturated sodium chloride solution (15 mL × 3). The mixture was dried over anhydrous magnesium sulfate, filtered, and the ethyl acetate was removed by rotary evaporation under reduced pressure. The crude product was separated by column chromatography with 100-200 mesh silica gel to obtain intermediates 3a-3e.

[0068] Intermediate 3a-3e (1.0 eq.) was added to a 25 mL round-bottom flask, followed by 5 mL of dichloromethane. Trifluoroacetic acid was added dropwise at 0 °C, and the reaction was carried out at 0 °C for 30 min. After the reaction was completed by TLC monitoring, the solvent was removed by rotary evaporation under reduced pressure. The pH of the reaction solution was adjusted to approximately 7 with saturated sodium bicarbonate solution, and then extracted with dichloromethane (10 mL × 3). The upper organic phases were combined, dried over anhydrous magnesium sulfate, filtered, and the dichloromethane was removed by rotary evaporation under reduced pressure to obtain intermediate 4a-4e.

[0069] Intermediates 4a-4e (1.0 eq.), EDCI (2 eq.), Hobt (1.2 eq.), and 7-(diethylamino)coumarin-3-carboxylic acid (1.2 eq.) were dissolved in 4 mL of N,N-dimethylformamide and reacted at room temperature for 2 h. After the reaction was completed as monitored by TLC, an equal volume of 1 mol / L hydrochloric acid was added, and the mixture was extracted with ethyl acetate (15 mL × 4). The upper organic phases were combined and collected, then washed with saturated sodium chloride solution (15 mL × 3), dried over anhydrous magnesium sulfate, filtered, and the ethyl acetate was removed by rotary evaporation under reduced pressure. The crude product was separated by column chromatography with 100-200 mesh silica gel to obtain the target compounds 5a-5e.

[0070] Celastrol (1.0 eq.), DIPEA (2 eq.), Carter's condensing agent (1.2 eq.), and 6-bromohexylamine hydrochloride (1.2 eq.) were dissolved in 4 mL of N,N-dimethylformamide and reacted at room temperature for 2 h. After the reaction was completed as monitored by TLC, an equal volume of 1 mol / L hydrochloric acid was added, and the mixture was extracted with dichloromethane (15 mL × 4). The upper organic phases were combined and collected, then washed with saturated sodium chloride solution (15 mL × 3), dried over anhydrous magnesium sulfate, filtered, and dichloromethane was removed by rotary evaporation under reduced pressure. The crude product was separated by column chromatography with 100-200 mesh silica gel to obtain intermediate 6a.

[0071] Intermediate 6a (1 eq.) was dissolved in 15 mL of acetonitrile, and triphenylphosphine (3 eq.) was added. The mixture was heated at 110 °C for 48 h. After the reaction was completed as monitored by TLC, the reaction was quenched with water, extracted with dichloromethane (15 mL × 3), and the organic phases were combined and collected. The organic phase was then washed with saturated sodium chloride solution (15 mL × 3), dried over anhydrous magnesium sulfate, filtered, and dichloromethane was removed by rotary evaporation under reduced pressure. The crude product was mixed with 100-200 mesh silica gel and separated from target compound 7a by column chromatography.

[0072] The spectral data of compounds 5a-5e and 7a are as follows:

[0073] 5a: Reddish-brown solid, yield 36%, Mp: 135-137 ℃. 1H NMR (600 MHz, DMSO) δ 8.77(t, J = 6.0 Hz, 1H), 8.70 (s, 1H), 8.63 (s, 1H), 7.70 (d, J = 9.0 Hz, 1H), 7.60 (t, J = 4.8 Hz, 1H), 6.84 (ddd, J = 11.5, 8.0, 1.9 Hz, 2H), 6.67 (d, J =2.4 Hz, 1H), 6.34 (d, J = 1.5 Hz, 1H), 6.10 (d, J = 7.2 Hz, 1H), 3.50 (q, J =7.2 Hz, 4H), 3.39 (q, J = 6.7 Hz, 2H), 3.22 – 3.15 (m, 1H), 2.96 (dq, J =11.6, 3.9 Hz, 1H), 2.39 (d, J = 15.3 Hz, 1H), 2.18 – 2.03 (m, 5H), 2.02 –1.95 (m, 1H), 1.75 (ddd, J = 33.6, 16.6, 7.1 Hz, 2H), 1.57 (d, J = 8.8 Hz,2H), 1.52 (dd, J = 15.6, 8.2 Hz, 1H), 1.48 – 1.41 (m, 2H), 1.40 – 1.35 (m,3H), 1.31 (s, 3H), 1.19 – 1.11 (m, 9H), 1.05 (d, J = 12.8 Hz, 6H), 0.88 (d, J= 14.1 Hz, 1H), 0.46 (s, 3H). ESI-MS: m / z 736.4327 (M + H)+. C 45 H 57 N3O6[735.4247].

[0074] 5b: Reddish-brown solid, yield 43%, Mp: 130-137 ℃. 1H NMR (600 MHz, DMSO) δ 8.67(d, J = 5.9 Hz, 1H), 8.65 (s, 1H), 8.63 (s, 1H), 7.68 (d, J = 9.0 Hz, 1H), 7.65 (t, J = 5.7 Hz, 1H), 7.03 (d, J = 6.6 Hz, 1H), 6.80 (dd, J = 9.0, 2.4Hz, 1H), 6.61 (d, J = 2.4 Hz, 1H), 6.36 (d, J = 1.4 Hz, 1H), 6.32 (d, J = 7.2Hz, 1H), 3.48 (q, J = 7.0 Hz, 4H), 3.25 (h, J = 6.5 Hz, 2H), 3.06 (dq, J =12.7, 6.3 Hz, 1H), 2.91 (dq, J = 13.0, 6.6 Hz, 1H), 2.42 (d, J = 15.4 Hz,1H), 2.18 – 2.13 (m, 1H), 2.12 – 2.09 (m, 1H), 2.06 (s, 3H), 2.01 – 1.96 (m,1H), 1.85 – 1.76 (m, 2H), 1.63 (d, J = 8.8 Hz, 2H), 1.54 (ddd, J = 28.9,13.3, 6.3 Hz, 6H), 1.45 – 1.40 (m, 1H), 1.36 (s, 3H), 1.31 (dd, J = 13.9, 4.4Hz, 1H), 1.20 (s, 3H), 1.14 (t, J = 7.0 Hz, 6H), 1.06 (d, J = 10.2 Hz, 6H), 0.87 (d, J = 14.0 Hz, 1H), 0.54 (s, 3H). ESI-MS: m / z 750.4479 (M + H)+.C 46 H 59 N3O6 [749.4404].

[0075] 5c: Reddish-brown solid, yield 33%, Mp: 120-127 ℃. 1H NMR (600 MHz, DMSO) δ 8.67(s, 1H), 8.64 (s, 1H), 8.60 (t, J = 5.8 Hz, 1H), 7.68 (d, J = 8.9 Hz, 1H), 7.51 (t, J = 5.6 Hz, 1H), 7.05 (d, J = 6.9 Hz, 1H), 6.80 (dd, J = 9.1, 2.4Hz, 1H), 6.62 (d, J = 2.4 Hz, 1H), 6.39 (d, J = 1.4 Hz, 1H), 6.32 (d, J = 7.1Hz, 1H), 3.48 (q, J = 7.1 Hz, 4H), 3.25 (q, J = 6.6 Hz, 2H), 2.97 (dt, J =12.9, 6.5 Hz, 1H), 2.87 (dt, J = 13.0, 6.4 Hz, 1H), 2.40 (d, J = 15.4 Hz,1H), 2.20 – 2.16 (m, 1H), 2.08 (s, 4H), 2.00 – 1.93 (m, 1H), 1.83 – 1.76 (m,2H), 1.63 (q, J = 5.9 Hz, 2H), 1.57 – 1.50 (m, 3H), 1.49 – 1.44 (m, 3H), 1.41(d, J = 11.7 Hz, 2H), 1.37 (s, 3H), 1.34 – 1.21 (m, 4H), 1.19 (s, 3H), 1.14(t, J = 7.0 Hz, 6H), 1.04 (d, J = 14.4 Hz, 6H), 0.86 – 0.83 (m, 1H), 0.53 (s,3H). ESI-MS: m / z 778.4798 (M + H)+. C 48 H 63 N3O6 [777.4717].

[0076] 5d: Reddish-brown solid, yield 56%, Mp: 134-147 ℃. 11H NMR (600 MHz, DMSO) δ 8.69 (s, 1H), 8.64 (s, 1H), 8.60 (t, J = 5.7 Hz, 1H), 7.68 (d, J = 9.0 Hz, 1H), 7.53 (t, J = 5.4 Hz, 1H), 7.07 (dd, J = 7.2, 1.4 Hz, 1H), 6.81 (dd, J = 9.0, 2.5 Hz, 1H), 6.62 (d, J = 2.3 Hz, 1H), 6.40 (d, J = 1.5 Hz, 1H), 6.35 (d, J = 7.2 Hz, 1H), 3.49 (q, J = 7.0 Hz, 4H), 3.24 (t, J = 6.8 Hz, 2H), 2.96 – 2.93 (m, 1H), 2.90 – 2.87 (m, 1H), 2.4 (s, 1H), 2.19 (d, J = 8.1 Hz, 1H), 2.08 (s, 4H), 1.97 (s, 1H), 1.80 (t, J = 10.0 Hz, 2H), 1.65 (d, J = 8.8 Hz, 2H), 1.57 (d, J = 15.5 Hz, 3H), 1.51 (d, J = 8.0 Hz, 1H), 1.48 – 1.43 (m, 3H), 1.39 (s, 3H), 1.34 (t, J = 6.8 Hz, 2H), 1.31 – 1.24 (m, 4H), 1.22 (s, 3H), 1.15 (t, J = 7.0 Hz, 6H), 1.06 (d, J = 19.4 Hz, 6H), 0.85 (d, J = 7.0 Hz, 2H), 0.54 (s, 3H). ESI-MS: m / z 792.4949 (M + H)+. C 49 H 65 N3O6 [791.4873].

[0077] 5e: Reddish-brown solid, yield 62%, M.p.: 134 - 147 °C. 1¹H NMR (600 MHz, DMSO) δ 8.68 (s, 1H), 8.65 (s, 1H), 8.61 (t, J = 5.7 Hz, 1H), 7.68 (d, J = 9.0 Hz, 1H), 7.51 (t, J = 5.5 Hz, 1H), 7.07 – 7.04 (m, 1H), 6.80 (dd, J = 9.0, 2.4 Hz, 1H), 6.61 (d, J = 2.5 Hz, 1H), 6.38 (d, J = 1.5 Hz, 1H), 6.32 (d, J = 7.2 Hz, 1H), 3.48 (q, J = 7.0 Hz, 4H), 3.25 (q, J = 6.7 Hz, 2H), 2.91 (tt, J = 12.5, 6.7 Hz, 2H), 2.39 (d, J = 15.5 Hz, 1H), 2.17 (dd, J = 11.4, 3.8 Hz, 1H), 2.08 (s, 4H), 1.95 (dt, J = 13.8, 7.0 Hz, 1H), 1.78 (dd, J = 12.2, 7.4 Hz, 2H), 1.68 – 1.61 (m, 2H), 1.57 – 1.51 (m, 3H), 1.45 (dd, J = 20.4, 7.5 Hz, 3H), 1.42 – 1.38 (m, 2H), 1.37 (s, 3H), 1.32 (t, J = 6.6 Hz, 3H), 1.26 – 1.20 (m, 6H), 1.18 (s, 4H), 1.13 (d, J = 7.1 Hz, 6H), 1.03 (d, J = 10.8 Hz, 6H), 0.83 (dd, J = 11.5, 3.2 Hz, 1H), 0.53 (s, 3H). ESI-MS: m / z 820.5266 (M + H)+. C 51 H 69 N3O6 [819.5186].

[0078] 7a: Reddish-brown solid, yield 52%, M.p.: 127 - 138 °C. 1H NMR (600 MHz, DMSO) δ 8.70(s, 1H), 7.89 (ddt, J = 6.9, 4.8, 1.5 Hz, 3H), 7.80 – 7.75 (m, 12H), 7.55 (t,J = 5.5 Hz, 1H), 7.08 (dd, J = 7.1, 1.4 Hz, 1H), 6.36 – 6.33 (m, 2H), 3.54 –3.49 (m, 2H), 2.92 – 2.85 (m, 2H), 2.40 (d, J = 15.5 Hz, 1H), 2.16 – 2.12 (m,1H), 2.09 (s, 4H), 1.94 (dd, J = 13.8, 4.0 Hz, 1H), 1.85 – 1.76 (m, 2H), 1.67 – 1.54 (m, 5H), 1.53 – 1.42 (m, 5H), 1.39 (d, J = 14.1 Hz, 7H), 1.29 – 1.25(m, 4H), 1.22 (s, 3H), 1.07 (s, 3H), 1.02 (s, 3H), 0.87 – 0.83 (m, 2H), 0.51(s, 3H). ESI-MS: m / z 794.4703 (M)+. C 53 H 65 NO3P + [794.4697].

[0079] (3) Synthesis of the target products 10a-10d and 13a-13f after two rounds of modification. The synthetic route is as follows:

[0080]

[0081] The synthesis of intermediates 1c and 6a is as described above.

[0082] Intermediate 1c (1.0 eq.), DIPEA (2 eq.), Carter's condensing agent (1.2 eq.), and various amino compounds (1.2 eq.) were dissolved in 4 mL of N,N-dimethylformamide and reacted at room temperature for 2 h. After the reaction was completed as monitored by TLC, an equal volume of 1 mol / L hydrochloric acid was added, and the mixture was extracted with dichloromethane (15 mL × 4). The upper organic phases were combined and collected, then washed with saturated sodium chloride solution (15 mL × 3), dried over anhydrous magnesium sulfate, filtered, and dichloromethane was removed by rotary evaporation under reduced pressure. The crude product was separated by column chromatography with 100-200 mesh silica gel to obtain intermediates 9a-9d.

[0083] Intermediate 6a (1.0 eq.) and triethylamine (2 eq.) were added to 12 mL of anhydrous dichloromethane, followed by dropwise addition of acyl chloride compounds with different structures (4 eq.). The mixture was stirred at 0 °C for 30 min. After the reaction was completed as monitored by TLC, the reaction was quenched with water, extracted with dichloromethane (15 mL × 4), and the upper organic phases were combined and collected. The organic phases were then washed with saturated sodium chloride solution (15 mL × 3), dried over anhydrous magnesium sulfate, filtered, and the dichloromethane was removed by rotary evaporation under reduced pressure. The crude product was separated by column chromatography with 100-200 mesh silica gel to obtain intermediates 12a-12f.

[0084] Intermediates 9a-9d or 12a-12f (1 eq.) were dissolved in 15 mL of acetonitrile, and triphenylphosphine (3 eq.) was added. The mixture was heated at 110 °C for 48 h. After the reaction was completed as monitored by TLC, the reaction was quenched with water, extracted with dichloromethane (15 mL × 3), and the organic phases were combined and collected. The organic phase was then washed with saturated sodium chloride solution (15 mL × 3), dried over anhydrous magnesium sulfate, filtered, and dichloromethane was removed by rotary evaporation under reduced pressure. The crude product was mixed with 100-200 mesh silica gel and column chromatography was used to separate the target compounds 10a-10d and 13a-13f.

[0085] The spectral data for compounds 10a-10d and 13a-13f are as follows:

[0086] 10a: Yellow solid, yield 21%, Mp: 120-136 ℃. 1H NMR (600 MHz, DMSO) δ 7.90(d, J = 1.8 Hz, 3H), 7.82 – 7.78 (m, 12H), 7.32 (dd, J = 12.3, 7.4 Hz, 2H), 6.42 (d, J = 7.2 Hz, 1H), 6.37 (s, 1H), 3.74 – 3.72 (m, 1H), 3.61 (s, 2H), 2.56 (d, J = 7.1 Hz, 2H), 2.41 (s, 1H), 2.24 (d, J = 12.1 Hz, 1H), 2.08 (d, J= 8.4 Hz, 4H), 1.96 (s, 1H), 1.82 (d, J = 11.3 Hz, 2H), 1.66 (d, J = 6.4 Hz,2H), 1.61 – 1.58 (m, 6H), 1.53 (s, 1H), 1.49 (s, 1H), 1.42 (s, 3H), 1.24 (s,5H), 1.08 (s, 3H), C 56 H 69 NO4P + [850.4959].

[0087] 10b: Yellow solid, yield 22%, Mp: 117-123 ℃. 1H NMR (600 MHz, DMSO) δ 7.91 –7.89 (m, 3H), 7.82 – 7.77 (m, 13H), 7.32 (d, J = 7.1 Hz, 1H), 6.41 (d, J =7.2 Hz, 1H), 6.37 (s, 1H), 4.17 – 4.13 (m, 1H), 3.61 (s, 2H), 2.56 (t, J =7.0 Hz, 2H), 2.40 (s, 1H), 2.23 (d, J = 12.5 Hz, 1H), 2.08 (d, J = 8.3 Hz,4H), 1.95 (q, J = 12.9 Hz, 6H), 1.82 (d, J = 9.9 Hz, 2H), 1.67 (s, 2H), 1.61– 1.58 (m, 6H), 1.52 (s, 1H), 1.49 (s, 1H), 1.46 (s, 1H), 1.42 (s, 3H), 1.23(d, J = 3.5 Hz, 5H), 1.08 – 1.07 (m, 3H), 1.04 (s, 3H), 0.88 – 0.82 (m, 3H), 0.53 (d, J = 7.3 Hz, 3H). ESI-MS: m / z 862.4966 (M)+. C 57 H 69 NO4P + [862.4959].

[0088] 10c: Yellow solid, yield 27%, Mp: 117-123 ℃. 1H NMR (600 MHz, DMSO) δ 7.90(d, J = 1.9 Hz, 3H), 7.82 – 7.78 (m, 12H), 7.32 (d, J = 6.9 Hz, 1H), 7.07 (s,1H), 6.44 – 6.34 (m, 2H), 3.61 (s, 2H), 3.07 – 3.02 (m, 2H), 2.76 (d, J = 3.0Hz, 1H), 2.61 (s, 1H), 2.56 (s, 1H), 2.40 (d, J = 8.7 Hz, 1H), 2.08 (d, J =8.5 Hz, 4H), 1.97 (s, 1H), 1.82 (s, 2H), 1.68 (s, 2H), 1.60 (t, J = 4.0 Hz, 6H), 1.53 (s, 1H), 1.49 (s, 3H), 1.42 (s, 3H), 1.24 (d, J = 3.9 Hz, 5H), 1.08(d, J = 2.5 Hz, 3H), 1.05 (s, 3H), 0.86 (d, J = 5.9 Hz, 2H), 0.57 (d, J = 6.6Hz, 3H). ESI-MS: m / z 846.4640 (M)+. C 56 H 65 NO4P + [846.4646].

[0089] 10d: Yellow solid, yield 20%, Mp: 120-136 ℃. 1H NMR (600 MHz, DMSO) δ 7.91(d, J = 6.9 Hz, 3H), 7.82 – 7.77 (m, 12H), 7.57 (t, J = 5.5 Hz, 1H), 7.32 (d,J = 6.9 Hz, 1H), 6.42 (d, J = 7.2 Hz, 1H), 6.38 (s, 1H), 3.60 (s, 2H), 2.96(dd, J = 14.8, 7.2 Hz, 2H), 2.56 (t, J = 7.3 Hz, 2H), 2.43 – 2.40 (m, 1H),2.23 (d, J = 8.3 Hz, 1H), 2.08 (d, J = 8.5 Hz, 4H), 1.97 (s, 1H), 1.84 – 1.79 (m, 2H), 1.66 (d, J = 8.0 Hz, 2H), 1.60 (d, J = 8.2 Hz, 6H), 1.53 (s, 1H), 1.49 (s, 1H), 1.47 (s, 1H), 1.42 (s, 3H), 1.24 (s, 5H), 1.08 (s, 3H), 1.04(s, 3H), 0.92 (s, 2H), 0.86 (dq, J = 7.3, 3.9 Hz, 3H), 0.58 (d, J = 5.1 Hz,3H). ESI-MS: m / z 836.4808 (M)+. C 55 H 67 NO4P + [836.4802].

[0090] 13a: Yellow solid, yield 19%, Mp: 112-125 ℃. 1H NMR (600 MHz, DMSO) δ 7.89(d, J = 7.2 Hz, 3H), 7.77 (dd, J = 7.4, 4.0 Hz, 12H), 7.56 (t, J = 5.5 Hz,1H), 7.33 (d, J = 7.0 Hz, 1H), 6.40 (d, J = 7.2 Hz, 1H), 6.34 (s, 1H), 3.51(s, 2H), 2.88 (d, J = 6.6 Hz, 2H), 2.24 (d, J = 5.9 Hz, 5H), 2.12 (s, 3H),1.95 (s, 1H), 1.81 (d, J = 17.2 Hz, 2H), 1.57 (d, J 0.87 – 0.84 (m, 2H), 0.54 (d, J = 5.9 Hz, 3H). ESI-MS: m / z836.4810 (M)+. C 55 H 67 NO4P + [836.4802].

[0091] 13b: Yellow solid, yield 21%, Mp: 113-126 ℃. 1H NMR (600 MHz, DMSO) δ 7.90 –7.88 (m, 3H), 7.79 – 7.76 (m, 12H), 7.59 (t, J = 5.5 Hz, 1H), 7.34 – 7.30 (m,1H), 6.40 (d, J = 7.2 Hz, 1H), 6.33 (d, J = 1.4 Hz, 1H), 3.54 – 3.51 (m, 2H), 2.90 – 2.86 (m, 2H), 2.57 (d, J = 7.7 Hz, 2H), 2.42 (s, 1H), 2.22 (d, J = 6.0Hz, 1H), 2.10 (d, J = 11.6 Hz, 7H), 1.95 (d, J = 4.0 Hz, 1H), 1.80 (dd, J =13.5, 6.5 Hz, 2H), 1.64 (q, J = 5.7 Hz, 2H), 1.57 (s, 2H), 1.53 – 1.48 (m,4H), 1.41 (d, J = 8.5 Hz, 6H), 1.23 (s, 7H), 1.07 (s, 3H), 1.02 (s, 3H), 0.85(dd, J = 6.7, 3.6 Hz, 2H), 0.54 (s, 3H). ESI-MS: m / z 850.4965 (M)+. C 56 H 69 NO4P + [850.4959].

[0092] 13c: Yellow solid, yield 20%, Mp: 115-130 ℃. 1H NMR (600 MHz, DMSO) δ 7.90 –7.88 (m, 3H), 7.77 (q, J = 5.9 Hz, 12H), 7.57 (t, J = 5.5 Hz, 1H), 7.33 (d, J= 7.0 Hz, 1H), 6.40 (d, J = 7.2 Hz, 1H), 6.33 (s, 1H), 3.53 (d, J = 12.5 Hz, 2H), 2.88 (q, J = 7.3 Hz, 2H), 2.53 (d, J = 10.6 Hz, 2H), 2.39 (s, 1H), 2.17– 2.14 (m, 1H), 2.10 (d, J = 8.4 Hz, 6H), 1.99 – 1.92 (m, 2H), 1.80 (dd, J =14.9, 7.5 Hz, 2H), 1.62 (dd, J = 14.2, 7.3 Hz, 4H), 1.48 (d, J = 7.6 Hz, 4H), 1.41 (d, J = 8.2 Hz, 7H), 1.23 (s, 7H), 1.07 (s, 3H), 1.02 (s, 3H), 0.95 (s,2H), 0.87 – 0.83 (m, 2H), 0.54 (s, 3H). ESI-MS: m / z 864.5120 (M)+. C 57 H 71 NO4P + [864.5115].

[0093] 13d: Yellow solid, yield 24%, Mp: 119-131 ℃. 1H NMR (600 MHz, DMSO) δ 7.90 –7.88 (m, 3H), 7.79 – 7.76 (m, 12H), 7.56 (t, J = 5.4 Hz, 1H), 7.32 (d, J =7.0 Hz, 1H), 6.40 (d, J = 7.2 Hz, 1H), 6.32 (s, 1H), 3.51 (s, 2H), 2.88 (t, J= 6.6 Hz, 2H), 2.39 (d, J = 14.3 Hz, 2H), 2.09 (d, J = 7.0 Hz, 7H), 1.95 (s,1H), 1.85 – 1.81 (m, 2H), 1.57 (d, J = 7.3 Hz, 4H), 1.49 (s, 4H), 1.41 (d, J= 3.9 Hz, 6H), 1.24 (d, J = 4.9 Hz, 7H), 1.07 (s, 3H), 1.02 (s, 3H), 0.94 (s,2H), 0.85 (d, J = 7.2 Hz, 2H), 0.54 (d, J = 6.3 Hz, 3H). ESI-MS: m / z 862.4963(M)+. C 57 H 69 NO4P + [862.4959].

[0094] 13e: Yellow solid, yield 22%, Mp: 116-133 ℃. 1H NMR (600 MHz, DMSO) δ 7.90 –7.88 (m, 3H), 7.80 – 7.76 (m, 12H), 7.57 (t, J = 5.5 Hz, 1H), 7.33 (dd, J =7.1, 1.4 Hz, 1H), 6.40 (d, J = 7.2 Hz, 1H), 6.32 (d, J = 1.5 Hz, 1H), 3.52 (dt, J = 12.7, 6.5 Hz, 2H), 2.92 – 2.85 (m, 2H), 2.39 (d, J = 4.0 Hz, 1H), 2.31 – 2.20 (m, 6H), 2.10 (s, 3H), 1.98 – 1.95 (m, 2H), 1.85 – 1.80 (m, 2H),1.65 (d, J = 8.8 Hz, 2H), 1.57 (q, J = 9.5 Hz, 4H), 1.48 (q, J = 7.5 Hz, 4H),1.40 (d, J = 15.3 Hz, 7H), 1.23 (s, 7H), 1.07 (d, J = 6.9 Hz, 4H), 1.02 (d, J= 9.5 Hz, 4H), 0.87 – 0.83 (m, 2H), 0.54 (s, 3H). ESI-MS: m / z 876.5118 (M)+.C 58 H 71 NO4P + [876.5115].

[0095] 13f: Yellow solid, yield 18%, Mp: 110-125 ℃. 1H NMR (600 MHz, DMSO) δ 7.88(d, J = 1.9 Hz, 3H), 7.79 – 7.76 (m, 13H), 7.57 (d, J = 5.9 Hz, 1H), 7.48 (q,J = 2.3 Hz, 4H), 7.36 (d, J = 7.1 Hz, 1H), 6.87 (s, 1H), 6.84 (d, J = 2.1 Hz,1H), 6.43 (d, J = 7.2 Hz, 1H), 6.38 (s, 1H), 3.52 (s, 2H), 2.90 – 2.87 (m,2H), 2.41 (s, 2H), 2.18 (d, J = 19.1 Hz, 4H), 2.09 (d, J = 5.9 Hz, 3H), 1.58 (d, J = 7.9 Hz, 4H), 1.51 (d, J = 15.0 Hz, 4H), 1.44 (s, 6H), 1.24 (d, J =4.3 Hz, 7H), 1.08 (s, 3H), 1.02 (d, J = 3.9 Hz, 3H), 0.86 (s, 2H), 0.56 (d, J= 7.1 Hz, 3H). ESI-MS: m / z 924.5118 (M)+. C 62 H 71 NO4P + [924.5115].

[0096] Example 2. Screening and evaluation of the in vitro antitumor activity of the target compound

[0097] To evaluate the antiproliferative activity of the synthesized PRDX3 inhibitors, their inhibitory rates on breast cancer cells Cal-51, liver cancer cells HepG2, lung cancer cells H1975 and A549, and their cytotoxicity against normal human embryonic kidney cells HEK-293T were determined. After treating cells with the compounds at a concentration of 1 μM for 48 h, the proliferation inhibition rate was detected using the CCK-8 assay, with paclitaxel (PTX) and the lead compound celastrol as controls. Table 1 summarizes the antiproliferative activity and cytotoxicity data of each compound at 1 μM. The results showed that compounds 2c and 7a, compared to the lead compound celastrol, exhibited significantly reduced cytotoxicity against normal HEK-293T cells, while simultaneously demonstrating increased inhibitory activity against tumor cells H1975 and A549.

[0098] Table 1. Antitumor cell proliferation inhibition rate of the modified compounds. 1 (%)

[0099]

[0100] 1 The experimental results are expressed as mean ± SD (n ≥ 3).

[0101] To synthesize the preliminary screening results, compounds 2c and 7a were selected for further IC50 analysis. 50 Test results (Table 2) showed that 2c and 7a had significantly better anti-proliferative activity against H1975 cells than triptolide, with IC50 values ​​significantly higher. 50 The values ​​were 0.37 ± 0.94 μM and 0.93 ± 0.48 μM, respectively. To investigate the toxicity of the compound to normal cells, the selectivity index (SI; SI = CC) was further calculated. 50 / IC 50 The data (Table 3) show that the selectivity indices of compounds 2c and 7a were 1.02 and 0.61, respectively, both exceeding the selectivity of the lead compound, thus verifying the feasibility of the mitochondrial targeted modification strategy in improving the therapeutic window of the compound.

[0102] Table 2. Antitumor cell proliferation activity of the modified compounds

[0103]

[0104] 1 IC 50 / 1 CC 50 values ​​are expressed as the mean ± SD (n ≥ 3)

[0105] Table 3 SI Index of Compounds with One Round of Modification 1

[0106]

[0107] 1 SI = CC 50 / IC 50

[0108] To further enhance antitumor activity, reduce systemic toxicity, and improve the binding affinity to the target protein PRDX3, we selected the dominant compounds 2c and 7a from the first round of modification for a second round of structural modification. Different substituents were used to derivatize the C-20 carboxyl group and C-3 hydroxyl group, yielding a series of derivatives, 10a–10d and 13a–13f, etc. The IC50 of the second-round modified derivatives against H1975 cells was then determined. 50 Values ​​and CC values ​​of normal 293T cells 50Evaluation of the value and corresponding selectivity index. The results revealed (Table 4) that compound 10d had an IC50 value for H1975 cells. 50 The value was 0.64 ± 0.15 µM, the selectivity index (SI) was 1.28, and the preferred compound 10d showed the best inhibitory activity against H1975 cells compared to triptolide (IC50). 50 It is 3 times more potent than 1.72±0.15μM, while its toxicity to normal cells is reduced by 3 times and its selectivity index is increased by 6 times.

[0109] Table 4. Antitumor cell proliferation activity of the two-round modified compounds

[0110]

[0111]

[0112]

[0113] 1 IC 50 / 1 CC 50 values ​​are expressed as the mean ± SD (n ≥ 3)

[0114] 2 SI = CC 50 / IC 50

[0115] Example 3. Evaluation of the in vitro antitumor mechanism of the target compound

[0116] Based on the screening results of the antiproliferative activity of the target compounds, representative compounds were selected for thermal stability and surface plasmon resonance experiments to evaluate their binding to PRDX3 and further investigate their effects on mitochondrial function in tumor cells. Since H1975 cells are sensitive to the target compounds, this cell line was used to detect the binding ability of the compounds to PRDX3. Using β-actin as an internal control, the protein expression level was quantitatively analyzed using ImageJ software.

[0117] To clarify the direct interaction between 10d and PRDX3, thermal stability experiments confirmed that the 10d treatment significantly improved the thermal stability of PRDX3. Figure 1 A). Surface plasmon resonance analysis showed a significant binding affinity between 10d and PRDX3 protein, with a dissociation constant (Kd) of 0.514 μM ( Figure 1B), compared to the lead compound tripterygium (Kd = 8.56 μM), showed improved binding affinity to PRDX3. In summary, these findings consistently indicate that 10d binds directly to the PRDX3 protein.

[0118] To verify whether compound 10d exerts its antitumor effect by influencing mitochondrial function, this invention investigated its effects on mitochondrial membrane potential and intracellular reactive oxygen species (ROS) levels in H1975 cells. Changes in mitochondrial membrane potential were detected using the JC-1 fluorescent probe, and ROS levels were assessed using the DCFH-DA probe. The results are as follows: Figure 1 C and Figure 1 As shown in Figure D, compared with the control group, H1975 cells treated with compound 10d exhibited a significant decrease in mitochondrial membrane potential, manifested by a significantly reduced JC-1 polymer / monomer fluorescence ratio. Simultaneously, the DCFH-DA fluorescence intensity of cells treated with compound 10d was significantly enhanced, indicating a marked increase in intracellular reactive oxygen species (ROS) levels. These results suggest that compound 10d can induce mitochondrial dysfunction in H1975 cells, including mitochondrial membrane potential depolarization and an increase in oxidative stress levels.

[0119] Although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art can still modify the technical solutions described in the foregoing embodiments or make equivalent substitutions for some of the technical features. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the protection scope of the present invention.

Claims

1. A triptolide derivative targeting PRDX3, characterized in that, It has the structure shown in general formula (I) or (II): In general formulas (I) and (II): n1= 1，2，4，5，7； n2= 3，4，5； The R1 group represents a mitochondrial targeting group, selected from one of the following groups: R2 is selected from one of the following groups: R3 is selected from one of the following groups: 。 2. The triptolide derivative targeting PRDX3 as described in claim 1, characterized in that, It is one of the following compounds: 。 3. The method for preparing the triptolide derivative targeting PRDX3 as described in claim 2, characterized in that, The synthesis route is as follows: (1) The synthetic route for the target compounds 2a-2c is as follows: Reagents and conditions: (i) Cl–C(=O)–(CH2) with different structures n –Br, triethylamine, dichloromethane, 0℃, 30min; (ii) acetonitrile, 90℃, reflux, 48h; Where n = 3, 4, 5; (2) The synthetic route for the target compounds 5a-5e and 7a is as follows: Reagents and conditions: (i) 1-Ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride, 1-hydroxybenzotriazole, N,N-dimethylacetamide, rt, 2h; (ii) Trifluoroacetic acid, dichloromethane, 0℃, 30min; (iii) Carter's condensing agent, N,N-diisopropylethylamine, dichloromethane, rt, 2h; (iv) Acetonitrile, 90℃, reflux, 48h; Where n = 1, 2, 4, 5, 7; (3) The synthesis of target compounds 10a-10d and 13a-13f, the synthetic route is as follows: Reagents and conditions: (i) Triethylamine, dichloromethane, 0℃, 30 min; (ii) Carter's condensing agent, N,N-diisopropylethylamine, dichloromethane, rt, 2 h; (iii) Acetonitrile, 90℃, reflux, 48 h; Among them, R3 is , , , , R2 is , , , , , .

4. The use of the triptolide derivative targeting PRDX3 as described in claim 1 or 2 in the preparation of antitumor drugs.

5. The application as described in claim 4, wherein the antitumor drug is an antitumor drug targeting PRDX3.

6. An antitumor pharmaceutical composition comprising a triptolide derivative targeting PRDX3 as described in any one of claims 1 or 2 and one or more pharmaceutically acceptable carriers.

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