A tanshinone IIA derivative, a preparation method and application thereof, a breast-enlarging medicine and an anti-aging skin care product

Abstract

The application belongs to the technical field of chemical medicines, and particularly relates to a tanshinone IIA derivative, a preparation method and application thereof, a breast-enlarging medicine and an anti-aging skin care product. The tanshinone IIA derivative provided by the application has the structure shown in formula 1: wherein R1 is -H, -Br, -Cl, -CF3, -CH3, -OCH3 or -OH; R2 is -H, -Cl, -OCH3 or -OH; R3 is -H, -Br, -Cl, -CF3, -OCH3 or -OH; R1, R2 and R3 cannot be -H at the same time. The tanshinone IIA derivative provided by the application has good effects of promoting normal mammary gland cell proliferation, antioxidation and promoting tissue repair, and has a good breast-enlarging effect; and when the tanshinone IIA derivative is used for breast enlargement, it only needs to be dissolved in an ethanol aqueous solution and then applied to the chest and rubbed until completely absorbed, so that the tanshinone IIA derivative is convenient to use; and the effect can be seen after 7 days of use. Formula 1.

Description

Technical Field

[0001] This invention belongs to the field of chemical and pharmaceutical technology, specifically relating to a tanshinone IIA derivative and its preparation method and application, breast enhancement drugs, and anti-aging skin care products. Background Technology

[0002] In recent years, with women's increasing focus on their physical appearance and health, the demand for breast augmentation has continued to grow. Currently, there are two main types of breast augmentation methods on the market: one is the use of hormonal drugs, and the other is surgical intervention. Hormonal drugs include estrogen ointments. While these methods may change breast shape in the short term, long-term or excessive use of exogenous hormones can easily lead to endocrine system disorders, causing side effects such as menstrual irregularities and pigmentation. Surgical procedures can involve implant placement, but invasive surgery carries risks such as infection, capsular contracture, and implant displacement; both safety and naturalness are controversial.

[0003] Therefore, developing a product that has breast enhancement effects and is easy and safe to use has significant market value and application prospects. Summary of the Invention

[0004] In view of this, the present invention provides a tanshinone IIA derivative, its preparation method and application, a breast enhancement drug, and an anti-aging skin care product. The tanshinone IIA derivative provided by the present invention has a good breast enhancement effect and is easy and safe to use.

[0005] To solve the above-mentioned technical problems, the present invention provides a tanshinone IIA derivative having the structure shown in Formula 1: Formula 1; Where R1 is -H, -Br, -Cl, -CF3, -CH3, R1, R2, and R3 cannot all be -H, -OCH3, or -OH; R2 can be -H, -Cl, -OCH3, or -OH; R3 can be -H, -Br, -Cl, -CF3, -OCH3, or -OH; R1, R2, and R3 cannot all be -H at the same time.

[0006] The preferred tanshinone IIA derivative has the following structure: .

[0007] This invention also provides a method for preparing the tanshinone IIA derivative described in the above technical solution, comprising the following steps: Tanshinone IIA, compound 1, ammonium acetate and glacial acetic acid were mixed and then subjected to a Debus-Radziszewski imidazole synthesis reaction to obtain the tanshinone IIA derivative. The structure of tanshinone IIA is as follows: The structure of compound 1 is as follows: .

[0008] Preferably, the process after the Debus-Radziszewski imidazole synthesis reaction further includes: diluting the system after the Debus-Radziszewski imidazole synthesis reaction with water to adjust the pH to neutral, and then performing solid-liquid separation to obtain the tanshinone IIA derivative; The volume ratio of the system to water after the Debus-Radziszewski imidazole synthesis reaction is 0.8~1.2:1; The reagent used to adjust the pH value includes ammonia water, and the concentration of the ammonia water is 20-30%. The solid-liquid separation method includes pressure filtration.

[0009] Preferably, the molar ratio of tanshinone IIA to compound 1 is 1:1.1~1.5; The molar ratio of tanshinone IIA to ammonium acetate is 1:5~6; The mass ratio of tanshinone IIA to glacial acetic acid is 1g:20~25mL; The Debus-Radziszewski imidazole synthesis reaction was carried out at a temperature of 100-120℃ for a time of 0.8-1.5 h.

[0010] The present invention also provides the application of the tanshinone IIA derivatives described in the above technical solutions or the tanshinone IIA derivatives prepared by the preparation methods described in the above technical solutions as antioxidants.

[0011] The present invention also provides an anti-aging skin care product, comprising an antioxidant, wherein the antioxidant is a tanshinone IIA derivative described in the above technical solution or a tanshinone IIA derivative prepared by the preparation method described in the above technical solution.

[0012] The present invention also provides the application of the tanshinone IIA derivative described in the above technical solution or the tanshinone IIA derivative prepared by the preparation method described in the above technical solution in the preparation of breast enhancement drugs.

[0013] The present invention also provides a breast enhancement drug, comprising an aqueous ethanol solution and a tanshinone IIA derivative dissolved in the aqueous ethanol solution, wherein the tanshinone IIA derivative is the tanshinone IIA derivative described in the above technical solution or the tanshinone IIA derivative prepared by the preparation method described in the above technical solution.

[0014] Preferably, the volume ratio of ethanol to water in the ethanol-water solution is 1:8.5~9.5; The mass concentration of tanshinone IIA derivative in the breast enhancement drug is 0.4-0.6%; The dosage of the breast enhancement drug is once a day, 1.8 to 2.3 mL each time.

[0015] This invention provides a tanshinone IIA derivative having the structure shown in Formula 1: Formula 1; where R1 is -H, -Br, -Cl, -CF3, -CH3, R1, R2, and R3 can all be -H, -OCH3, or -OH; R2 can be -H, -Cl, -OCH3, or -OH; R3 can be -H, -Br, -Cl, -CF3, -OCH3, or -OH; R1, R2, and R3 cannot all be -H simultaneously. The tanshinone IIA derivative provided by this invention has excellent effects on promoting the proliferation of normal mammary gland cells, anti-oxidation, and promoting tissue repair, and exhibits a significant breast enhancement effect. Furthermore, when used for breast enhancement, it is simply dissolved in an ethanol-water solution and applied to the breast, rubbing until completely absorbed, making it convenient to use; results can be seen within 7 days. Attached Figure Description

[0016] Figure 1 The graph shows the promoting effect of the tanshinone IIA derivative prepared in Example 14 on fibroblast proliferation. Figure 2 A bar chart comparing the proliferation rates of different concentrations of tanshinone IIA derivative TA1013; Figure 3 The image shows the cell migration morphology after treatment with different concentrations of tanshinone IIA derivative TA1013 for different time periods. Figure 4 A bar chart showing the comparison of HSF cell migration rates after treatment with different concentrations of tanshinone IIA derivative TA1013 for different durations; Figure 5 The image shows the results of zebrafish tail fin wound regeneration after treatment with different concentrations of tanshinone IIA derivative TA1013. Figure 6 A statistical comparison of the caudal fin growth rate of zebrafish treated with different concentrations of tanshinone IIA derivative TA1013. Figure 7 The figure shows the effect of different test groups on reactive oxygen species in zebrafish after staining with fluorescent probes. Figure 8 A comparison of the relative fluorescence intensities of different test groups; Figure 9 A comparison chart of ROS inhibition rates in different test groups; Figure 10 A comparison chart showing the changes in breast volume before and after using TA1013 solution. Detailed Implementation

[0017] This invention provides a tanshinone IIA derivative having the structure shown in Formula 1: Formula 1; Where R1 is -H, -Br, -Cl, -CF3, -CH3, R1, R2, and R3 cannot all be -H, -OCH3, or -OH; R2 can be -H, -Cl, -OCH3, or -OH; R3 can be -H, -Br, -Cl, -CF3, -OCH3, or -OH; R1, R2, and R3 cannot all be -H at the same time.

[0018] In this invention, when R1 is -H, R2 can be -H, -Cl, or -OCH3, and R3 can be -CF3, -Br, -Cl, or -OCH3; when R1 is -CF3, R2 can be -H, and R3 can be -H; when R1 is -Cl, R2 can be -H or -Cl, and R3 can be -H; when R1 is -CH3, R2 can be -H, and R3 can be -H; when R1 is... When R1 is -OCH3, R2 can be -OCH3 and R3 can be -H; when R1 is -OH, R2 can be -H and R3 can be -OH; when R1 is -Br, R2 can be -H and R3 can be -H.

[0019] In this invention, the tanshinone IIA derivative has the following structure: .

[0020] This invention also provides a method for preparing the tanshinone IIA derivative described in the above technical solution, comprising the following steps: Tanshinone IIA, compound 1, ammonium acetate and glacial acetic acid were mixed and then subjected to a Debus-Radziszewski imidazole synthesis reaction to obtain the tanshinone IIA derivative. The structure of tanshinone IIA is as follows: The structure of compound 1 is as follows: .

[0021] In this invention, the molar ratio of tanshinone IIA to compound 1 can be 1:1.1 to 1.5, specifically 1:1.1, 1:1.2 or 1:1.3; the molar ratio of tanshinone IIA to ammonium acetate can be 1:5 to 6, specifically 1:5 or 1:6; the mass ratio of tanshinone IIA to glacial acetic acid can be 1g:20 to 25mL, specifically 1g:20mL or 1g:23mL.

[0022] In this invention, the temperature of the Debus-Radziszewski imidazole synthesis reaction can be 100~120℃, specifically 110℃; the reaction time can be 0.8~1.5h, specifically 1h. In this invention, stirring can be performed during the Debus-Radziszewski imidazole synthesis reaction. The Debus-Radziszewski imidazole synthesis reaction can be monitored by thin-layer chromatography (TLC).

[0023] In this invention, the equation for the Debus-Radziszewski imidazole synthesis reaction is shown in equation a: Formula a.

[0024] In this invention, the Debus-Radziszewski imidazole synthesis reaction may further include: diluting the system after the Debus-Radziszewski imidazole synthesis reaction with water to adjust the pH to neutral, and then performing solid-liquid separation to obtain the tanshinone IIA derivative. In this invention, the volume ratio of the system after the Debus-Radziszewski imidazole synthesis reaction to water can be 0.8~1.2:1, specifically 1:1; the reagent used to adjust the pH can include ammonia water, and the concentration of the ammonia water can be 20~30%, specifically 25%; the neutral pH value is 7; this invention has no special requirements on the amount of ammonia water used, as long as it is sufficient to make the pH value of the system neutral.

[0025] In this invention, the solid-liquid separation method may include pressure filtration, wherein the vacuum degree of the pressure filtration can be -0.08 to -0.12 MPa, specifically -0.1 MPa. This invention collects the solid after solid-liquid separation to obtain the tanshinone IIA derivative. This invention can also dry the solid after solid-liquid separation to obtain the tanshinone IIA derivative; this invention has no particular limitation on the drying process, as long as residual solvent is removed.

[0026] This invention also provides the application of the tanshinone IIA derivatives described in the above-described technical solutions or the tanshinone IIA derivatives prepared by the preparation methods described in the above-described technical solutions as antioxidants. In this invention, the tanshinone IIA derivatives have good antioxidant activity; when used as antioxidants, they can be used to prepare anti-aging skincare products and pharmaceuticals for anti-aging purposes.

[0027] The present invention also provides an anti-aging skin care product, comprising an antioxidant, wherein the antioxidant is a tanshinone IIA derivative described in the above technical solution or a tanshinone IIA derivative prepared by the preparation method described in the above technical solution.

[0028] The present invention also provides the application of the tanshinone IIA derivative described in the above technical solution or the tanshinone IIA derivative prepared by the preparation method described in the above technical solution in the preparation of breast enhancement drugs.

[0029] The present invention also provides a breast enhancement drug, comprising an aqueous ethanol solution and a tanshinone IIA derivative dissolved in the aqueous ethanol solution, wherein the tanshinone IIA derivative is the tanshinone IIA derivative described in the above technical solution or the tanshinone IIA derivative prepared by the preparation method described in the above technical solution.

[0030] In this invention, the volume ratio of ethanol to water in the ethanol-water solution can be 1:8.5~9.5, specifically 1:9; the mass concentration of tanshinone IIA derivative in the breast enhancement drug can be 0.4~0.6%, specifically 0.5%; the dosage of the breast enhancement drug can be once a day, each time 1.8~2.3mL, specifically 2mL. In this invention, continuous use for 7 days can achieve breast enhancement effects.

[0031] To further illustrate the present invention, the technical solutions provided by the present invention will be described in detail below with reference to the embodiments, but they should not be construed as limiting the scope of protection of the present invention.

[0032] Example 1 Synthesis of tanshinone IIA derivative TA01 In a 100 mL round-bottom flask, tanshinone IIA (1 g, 3.39 mmol, 1 eq), 2-trifluoromethylbenzaldehyde (0.65 g, 3.73 mmol, 1.1 eq), ammonium acetate (5 g, 64.87 mmol, 5 M), and 20 mL of glacial acetic acid were added sequentially and mixed thoroughly. The mixture was heated to 110 °C and subjected to a Debus-Radziszewski imidazole synthesis reaction (with stirring) for 1 h. The reaction progress was monitored by thin-layer chromatography (TLC). After the reaction was completed, the system was cooled to room temperature (25 °C) and diluted with an equal volume of water. Then, 25% ammonia solution was added dropwise to adjust the pH of the system to 7, precipitating the target product. The solution was filtered under reduced pressure to -0.1 MPa, the filter cake was collected, dried, and the target product TA01 was obtained; the yield was 91.1%. ESI-MS: (in CH3COOCH2CH3, m / z): 449.18, [M+H] + . 1 H NMR (500 MHz, DMSO) δ13.22 (s, 1H), 8.10 (d, J =8.6 Hz, 1H), 7.97 (d, J = 7.7 Hz, 1H), 7.94 - 7.83 (m,3H), 7.77 (t, J = 7.5 Hz, 1H), 7.62 (d, J = 8.6 Hz, 1H), 3.83 (t, J = 6.1 Hz, 2H), 2.54 (s, 3H), 1.90 (dd, J = 29.5, 9.6Hz, 2H), 1.72 (d, J = 5.5 Hz, 2H), 1.37 (d, J = 12.2 Hz, 6H). 13C NMR (126 MHz, DMSO) δ 150.11 (s), 146.08 (s), 143.95 (s), 142.61 (s), 137.37 (s), 133.99 (s), 133.48 (s), 132.05 (s), 130.98 (s), 129.57 (s), 128.07 (s), 126.35 (s), 125.14 (s), 124.11 (s), 119.06 (s), 118.34 (s), 116.55 (s), 113.09 (s), 39.80 (s), 35.64 (s), 33.27 (s), 32.03 (s), 27.70 (s), 20.86 (s), 10.80 (s). The test results show that the tanshinone IIA derivative prepared in Example 1 has the structure shown in TA01.

[0033] Example 2 The synthesis of tanshinone IIA derivative TA03 followed the same steps as in Example 1, except that an equimolar amount of p-trifluoromethylbenzaldehyde was used instead of 2-trifluoromethylbenzaldehyde, while the other raw materials, reagents, and reaction conditions remained unchanged. The yield was 90.2%.

[0034] ESI-MS (in CH3COOCH2CH3, m / z): 449.3 [M+H] + . 1 H NMR (500 MHz, DMSO) δ13.11 (s, 1H), 8.64 (d, J = 8.1 Hz,2H), 8.18 (d, J = 8.6 Hz, 1H), 8.05 (d, J =8.3 Hz, 2H), 8.01 (d, J = 1.3 Hz, 1H), 7.73(d, J = 8.6 Hz, 1H), 4.05 (t, J = 6.3Hz, 2H), 2.70 (d, J = 1.3 Hz, 3H), 2.11 - 1.99 (m,2H), 1.90 - 1.77 (m, 2H), 1.48 (s, 6H). 13C NMR (126 MHz, DMSO) δ 150.53 (s), 146.84 (s), 144.21 (s), 142.67 (s), 137.93 (s), 135.92 (s), 134.19 (s), 128.33 (s), 127.31 (s), 127.00(s), 126.78 (s), 125.46 (s), 124.66 (s), 123.93 (s), 119.15 (s),118.63 (s),116.67 (s), 113.06 (s), 39.80 (s), 35.68 (s), 33.28 (s), 32.16 (s), 20.98 (s), 11.09 (s). Example 3 The synthesis of tanshinone IIA derivative TA13 followed the same steps as in Example 1, except that 2-bromobenzaldehyde was used in place of 2-trifluoromethylbenzaldehyde in an equimolar amount, while the other raw materials, reagents, and reaction conditions remained unchanged. The yield was 81.2%.

[0035] ESI-MS (in CH3COOCH2CH3, m / z): 459.4 [M+H] + . 1 H NMR (500 MHz, DMSO) δ13.16 (s, 1H), 8.09 (d, J = 8.6 Hz, 1H), 7.89 (dd, J = 5.8, 1.3 Hz, 1H), 7.84 (dt, J = 2.2, 1.1 Hz, 1H), 7.80 (dt, J = 7.6, 3.8 Hz, 1H), 7.62 (s, 1H), 7.58 (d, J =1.2 Hz, 1H), 7.49 - 7.47 (m, 1H), 3.85 (t, J = 6.4 Hz, 2H), 2.52 (d, J = 1.3Hz,3H), 1.92 - 1.83 (m, 2H), 1.77 - 1.66 (m, 2H), 1.36 (s, 6H). 13C NMR (126 MHz, DMSO) δ 150.73 (s), 148.13 (s), 144.56 (s), 143.24 (s), 137.73 (s), 135.23 (s), 134.95 (s), 134.51 (s), 132.02 (s), 129.59 (s), 126.80 (s), 125.74 (s), 124.68 (s), 121.20 (s), 119.75 (s), 118.97 (s), 117.18 (s), 113.79 (s), 40.48(s), 36.32 (s), 33.95 (s), 32.94 (s), 21.55 (s), 11.47 (s). Example 4 The synthesis of tanshinone IIA derivative TA14 followed the same steps as in Example 1, except that an equimolar amount of p-bromobenzaldehyde was used instead of 2-trifluoromethylbenzaldehyde, while the other raw materials, reagents, and reaction conditions remained unchanged. The yield was 83.6%.

[0036] ESI-MS (in CH3COOCH2CH3, m / z): 461.3 [M+H] + . 1 H NMR (500 MHz, DMSO) δ13.65 (s, 1H), 9.11 - 9.04 (m, 2H), 8.87 (d, J = 8.6 Hz, 1H), 8.69 (d, J = 1.3 Hz,1H), 8.61 - 8.56 (m, 2H), 8.41 (d, J = 8.7 Hz, 1H), 4.73 (t, J = 6.3 Hz, 2H), 3.38 (d, J = 1.2 Hz, 2H), 2.82 - 2.66 (m, 2H), 2.60 - 2.51 (m, 2H), 2.17(s,6H). 13C NMR (126 MHz, DMSO) δ 151.77 (s), 148.85 (s), 145.51 (s), 144.06 (s), 139.22 (s), 135.59 (s), 134.47 (s), 132.77 (s), 131.24 (s), 128.48 (s), 126.76 (s), 125.36 (s), 124.92 (s), 120.57 (s), 119.95 (s), 118.08 (s), 114.56 (s), 41.29 (s), 37.14 (s), 34.76 (s), 33.62 (s), 22.45 (s), 12.55 (s). Example 5 The synthesis of tanshinone IIA derivative TA15 followed the same steps as in Example 1, except that 2-chlorobenzaldehyde was used in place of 2-trifluoromethylbenzaldehyde in an equimolar amount, while the other raw materials, reagents, and reaction conditions remained unchanged. The yield was 81.2%.

[0037] ESI-MS (in CH3COOCH2CH3, m / z): 415.5 [M+H] + . 1 H NMR (500 MHz, DMSO) δ13.95 (s, 1H), 8.90 (d, J = 8.6 Hz, 1H), 8.72 - 8.68 (m, 1H), 8.48 - 8.45 (m,1H), 8.42 (d, J = 8.7 Hz, 1H), 8.39 - 8.31 (m, 3H), 4.66 (t, J = 6.3Hz, 2H), 3.33(d, J = 1.2 Hz, 3H), 2.74 - 2.65 (m, 2H), 2.57 - 2.46 (m, 2H), 2.17 (s,6H). 13CNMR (126 MHz, DMSO) δ 151.56 (s), 147.73 (s), 145.41 (s), 144.05 (s), 138.70 (s), 135.43 (s), 135.16 (s), 133.67 (s), 132.91 (s), 129.99 (s), 127.75 (s), 126.59 (s), 125.56 (s), 121.95 (s), 120.57 (s), 119.80 (s), 119.00 (s), 118.01 (s), 114.57 (s), 41.28 (s), 37.13 (s), 34.76 (s), 33.72 (s), 22.36(s), 12.27(s). Example 6 The synthesis of tanshinone IIA derivative TA16 followed the same steps as in Example 1, except that 2-trifluoromethylbenzaldehyde was replaced with an equimolar amount of 4-chlorobenzaldehyde, while the other raw materials, reagents, and reaction conditions remained unchanged. The yield was 83.4%.

[0038] ESI-MS (in CH3COOCH2CH3, m / z): 415.3 [M+H] + . 1 H NMR (500 MHz, DMSO) δ13.65 (s, 1H), 9.15 (d, J = 8.6 Hz, 2H), 8.87 (d, J = 8.6Hz, 1H), 8.69 (d, J = 1.2Hz, 1H), 8.45 (d, J = 8.5 Hz, 2H), 8.42 (d, J = 8.5 Hz, 1H), 4.73 (t, J = 6.2 Hz,2H), 3.39 (s, 3H), 2.82 - 2.65 (m, 2H), 2.61 - 2.38 (m, 2H), 2.17 (s,6H). 13CNMR (126 MHz, DMSO) δ 151.76 (s), 148.81 (s), 145.51 (s), 144.06 (s), 139.22(s), 136.21 (s), 135.59 (s), 132.43 (s), 131.57 (s), 131.01 (s), 128.46 (s), 126.75 (s), 125.37 (s), 120.57 (s), 119.94 (s), 118.07 (s), 114.56 (s), 41.29(s), 37.14 (s), 34.76 (s), 33.63 (s), 22.45 (s), 12.55 (s). Example 7 The synthesis of tanshinone IIA derivative TA19 followed the same steps as in Example 1, except that 2-trifluoromethylbenzaldehyde was replaced with an equimolar amount of 4-methylbenzaldehyde, while the other raw materials, reagents, and reaction conditions remained unchanged. The yield was 83.5%.

[0039] ESI-MS (in CH3COOCH2CH3, m / z): 395.4 [M+H] + . 1 H NMR (500 MHz, DMSO) δ13.50 (s, 1H), 9.02 (d, J = 8.1 Hz, 2H), 8.87 (d, J = 8.6Hz, 1H), 8.68 (d, J = 1.3Hz, 1H), 8.40 (d, J = 8.7 Hz, 1H), 8.18 (d, J = 7.9 Hz, 2H), 4.75 (t, J = 6.2 Hz, 2H), 3.40 (d, J = 1.1 Hz, 3H), 3.20 (s, 3H), 2.80 - 2.69 (m, 2H), 2.62 - 2.50 (m, 2H), 2.17 (s, 6H). 13C NMR (126 MHz, DMSO) δ 151.54 (s), 150.11 (s), 145.30 (s), 143.95 (s), 141.15 (s), 139.14 (s), 135.55 (s), 132.01 (s), 130.93 (s),129.34 (s), 128.16 (s), 126.54 (s), 125.41 (s), 120.53 (s), 119.79 (s),118.06 (s), 114.62 (s), 41.34 (s), 37.13 (s), 34.78 (s), 33.65 (s), 23.82(s), 22.48 (s), 12.57 (s). Example 8 The synthesis of tanshinone IIA derivative TA20 followed the same steps as in Example 1, except that 2-trifluoromethylbenzaldehyde was replaced with an equimolar amount of 4-methanesulfonylbenzaldehyde, while the other raw materials, reagents, and reaction conditions remained unchanged. Yield: 81.2% ESI-MS (in CH3COOCH2CH3, m / z): 459.1 [M+H] + . 1 H NMR (500 MHz, DMSO) δ13.85 (s, 1H), 9.42 - 9.35 (m, 2H), 8.94 - 8.91 (m, 2H), 8.71 (d, J = 1.3 Hz, 1H), 8.44 (d, J = 8.7 Hz, 1H), 4.77 - 4.69 (m,1H), 4.10 (s, 3H), 3.40 (d, J = 1.3Hz, 3H), 2.81 - 2.66 (m, 2H), 2.63 - 2.50 (m, 2H), 2.17 (s, 6H). 13C NMR (126MHz, DMSO) δ 152.08 (s), 148.13 (s), 145.76 (s), 143.09 (s), 139.53 (s), 138.04 (s), 135.69 (s), 133.05 (s), 130.31 (s), 129.82 (s), 128.93 (s), 127.01 (s), 125.38 (s), 120.63 (s), 120.14 (s), 118.16 (s), 114.50 (s), 46.45(s), 41.25 (s), 37.16 (s), 34.75 (s), 32.83 (s), 21.48 (s), 12.57 (s). Example 9 The synthesis of tanshinone IIA derivative TA18 followed the same steps as in Example 1, except that 2-trifluoromethylbenzaldehyde was replaced with an equimolar amount of 3,4-dichlorobenzaldehyde, while the other raw materials, reagents, and reaction conditions remained unchanged. Yield: 87.3%. ESI-MS (in CH3COOCH2CH3, m / z): 449.3 [M+H] + . 1 H NMR (500 MHz, DMSO) δ13.96 (s, 1H), 8.90 (d, J = 8.6 Hz, 1H), 8.76 - 8.60 (m,2H), 8.51 - 8.39 (m,3H), 4.65 (t, J = 6.3 Hz, 2H), 3.33 (d, J = 1.2 Hz, 3H), 2.82 - 2.67(m, 2H), 2.62- 2.46 (m, 2H), 2.16 (dd, J = 14.1 2.6 Hz, 6H). 13C NMR (126 MHz, DMSO) δ 151.67(s), 146.67 (s), 145.51 (s), 144.12 (s), 138.77 (s), 137.21 (s), 136.25(s),135.46 (s), 132.49 (s), 132.14 (s), 130.20 (s), 127.88 (s), 126.71 (s), 125.51 (s), 122.05 - 121.68 (m), 120.59 (s), 119.87 (s), 118.01 (s), 114.52(s), 41.26 (s), 37.14 (s), 34.76 (s), 33.68 (s), 22.36 (s), 12.28 (s). Example 10 The synthesis of tanshinone IIA derivative TA26 followed the same steps as in Example 1, except that 2,3-dichlorobenzaldehyde was used in place of 2-trifluoromethylbenzaldehyde in an equimolar amount, while the other raw materials, reagents, and reaction conditions remained unchanged. The yield was 73.4%.

[0040] ESI-MS (in CH3COOCH2CH3, m / z ): 447.2 ([MH] - . 1 H NMR (600 MHz, DMSO) δ13.23 (s, 1H), 10.32 (s, 1H), 8.11 (d, J = 8.6 Hz, 1H), 7.83 (dd, J = 9.5, 2.8Hz, 3H), 7.64 (d, J = 8.7 Hz, 1H), 7.36 (d, J = 7.9Hz, 1H), 7.26 (d, J = 7.8 Hz, 1H), 7.13 (d, J = 7.9 Hz, 1H), 3.84 (t, J = 6.2 Hz, 2H), 1.94 - 1.87 (m, 2H), 1.75 - 1.72 (m, 2H), 1.37 (s, 6H). 13C NMR (151 MHz, DMSO) δ189.92 (s), 163.44 (s),149.32 (s), 144.83 (s), 143.15 (s), 141.79 (s),136.80 - 135.79 (m), 134.56(s), 133.10 - 132.87 (m), 132.38 (s), 131.72 - 131.29 (m), 129.94 (s), 129.25 (s), 128.77 (s), 127.61 (s), 125.44 (s), 124.52 (d, J =58.3 Hz), 123.18 (s), 118.24 (s), 117.51 ​​(s), 115.63 (s), 112.16 (s), 34.72 (s), 32.39 (s), 19.97 (s), 9.89 (s). Example 11 The synthesis of tanshinone IIA derivative TA0412 followed the same steps as in Example 1, except that an equimolar amount of 2,3-dimethoxybenzaldehyde was used instead of 2-trifluoromethylbenzaldehyde, while the other raw materials, reagents, and reaction conditions remained unchanged. The yield was 77.2%.

[0041] ESI-MS (in CH3COOCH2CH 3, m / z ): 441.3 [M+H] + . 1 H NMR (600 MHz, CDCl3) δ11.89 (s, 1H), 10.46 (s, 1H), 8.28 -8.20 (m, 2H), 7.65 - 7.57 (m, 2H), 7.02(dd, J = 8.1, 1.0 Hz, 1H), 4.07 (s, 3H), 4.01 (d, J = 4.8 Hz, 3H), 3.93 - 3.92(m, 1H), 3.49 (d, J = 6.3 Hz, 1H), 2.76 (s, 3H), 1.88 -1.83 (m, 2H), 1.68 (s,2H), 1.45 (d, J = 7.8 Hz, 6H). 13C NMR (151 MHz, CDCl3) δ190.21 (s), 152.74 (d, J =5.8 Hz), 149.18 (s), 146.53 (s), 146.02 (s), 142.68 (s), 140.40 (s), 136.16 -135.94 (m), 129.81 (s), 129.08 (s), 125.58 (s), 125.23(s), 124.11(d, J = 17.5Hz), 123.52 (s), 120.85 (s), 119.05 (d, J = 22.2 Hz), 118.10 (s), 116.98 (d, J =5.6 Hz), 112.72 (s), 62.38 (s), 61.37 (s), 56.00 (d, J = 12.5 Hz), 38.26 (s), 34.41 (s), 31.69 (d, J = 46.2 Hz), 30.18 (s), 19.71 (s), 9.67 (s). Example 12 The synthesis of tanshinone IIA derivative TA0423 followed the same steps as in Example 1, except that an equimolar amount of 3,4-dimethoxybenzaldehyde was used instead of 2-trifluoromethylbenzaldehyde, while the other raw materials, reagents, and reaction conditions remained unchanged. The yield was 67.3%.

[0042] ESI-MS (in CH3COOCH2CH3, m / z): 441.3 [M+H] + . 1 H NMR (600 MHz, CDCl3) δ9.87 (s, 1H), 8.25 (d, J = 8.4 Hz, 2H), 7.79 (d, J = 1.8 Hz, 2H), 7.58 (dd, J =30.9, 11.7 Hz, 3H), 7.52 - 7.38 (m, 4H), 6.97 (dd, J = 16.4, 8.1 Hz, 3H), 4.18- 4.09 (m, 2H), 4.05 (s, 5H), 2.09 (d, J= 30.0 Hz, 6H),1.91 - 1.79 (m, 4H),1.28 (d, J = 7.1 Hz, 3H). 13 C NMR (151 MHz, CDCl3) δ 172.02 - 170.53 (m), 154.51(s), 150.29 (s), 149.60 (d, J = 12.2 Hz), 140.62 (s), 130.14 (s), 126.91 (s), 124.05 (s), 117.99 - 117.50 (m), 111.12 (s), 110.25 - 110.02 (m), 109.89 (s),108.93 (s), 60.42 (s), 56.71 - 55.71 (m), 38.40 - 37.67 (m), 34.47 (s), 31.90(s), 30.74 - 30.13 (m), 21.06 (s), 19.77 (s), 14.21 (s), 9.77 (s). Example 13 The synthesis of tanshinone IIA derivative TA1012 followed the same steps as in Example 1, except that 2,3-dihydroxybenzaldehyde was used in place of 2-trifluoromethylbenzaldehyde in an equimolar amount, while the other raw materials, reagents, and reaction conditions remained unchanged. The yield was 87.2%.

[0043] ESI-MS (in CH3COOCH2CH3, m / z ): 408.9 [M-3H] - . 1 H NMR (600 MHz, DMSO) δ13.76 (s, 1H), 12.95 (d, J = 21.9 Hz, 1H),9.09 (s, 1H), 8.11 (d, J = 8.6 Hz, 1H),7.92 (s, 1H), 7.84 (d, J = 7.6 Hz, 1H), 7.66 (d, J = 8.6 Hz, 1H), 6.94 - 6.81 (m,2H), 3.78 (t, J = 6.2 Hz, 2H), 2.60 (s, 3H), 1.97 - 1.93(m, 2H), 1.77 (dd,J =6.7, 4.3 Hz, 2H), 1.37 (d, J = 9.7 Hz, 6H). 13 C NMR (151 MHz, DMSO) δ 170.82 (s), 149.97 - 149.61 (m), 148.31 (s), 146.61 (d, J = 11.7 Hz), 143.59 (s), 142.03(s), 133.15 (s), 132.06 (s), 124.87 (s), 124.39 (s), 122.01 (s), 118.71 (d, J =58.4 Hz), 118.51 (s), 117.62 (s), 116.98 - 116.58 (m), 115.79 (s), 113.68(s), 112.01 (s), 60.23 (s), 34.67 (d, J = 28.4 Hz), 32.05 (d, J = 52.9 Hz), 31.00(s), 21.21 - 20.41 (m), 20.03 (s), 14.55 (s), 10.21 (s). Example 14 The synthesis of tanshinone IIA derivative TA1013 followed the same steps as in Example 1, except that 2,4-dihydroxybenzaldehyde was used in place of 2-trifluoromethylbenzaldehyde in an equimolar amount, while the other raw materials, reagents, and reaction conditions remained unchanged. The yield was 81.7%.

[0044] ESI-MS (in CH3COOCH2CH3, m / z): 413.0 [M+H] + . 1 H NMR (600 MHz, DMSO) δ13.73 (s, 1H), 12.76 (d, J = 39.3 Hz, 1H), 10.02 - 9.73 (m, 1H), 8.17 (dd, J =18.9, 6.2 Hz, 1H), 8.10 (t, J = 8.3 Hz, 1H), 7.90 (d, J = 13.6 Hz, 1H), 7.67 -7.56 (m, 1H), 6.51 - 6.39 (m, 2H), 5.74 (d,J = 22.2 Hz, 1H), 3.74 (t, J = 6.2Hz, 2H), 2.60 (s, 2H), 1.97 - 1.92 (m, 2H), 1.82 - 1.72 (m, 2H), 1.37 (s,6H). 13 C NMR (151 MHz, DMSO) δ 160.43 (s), 159.68 (s), 149.27 (s), 148.68 (s), 143.35 (s), 141.94 (s), 133.00 (s), 132.02 (s), 127.96 (s), 124.63 (s), 123.96 (s), 121.94 (s), 118.45 (s), 117.40 (s), 115.65 (s), 112.05 - 111.55 (m), 107.32 (s), 105.66 (s), 103.48 (s), 60.23 (s), 34.73 (s), 32.15 (d, J =23.8 Hz), 30.95 (s), 20.00 (s), 14.55 (s), 10.18 (s). Test Example 1 The effects of the tanshinone IIA derivative compounds prepared in Examples 1-14 on the proliferation of normal human mammary epithelial cells (MCF-10A, ATCC cell bank) were tested according to the following method. Succinate dehydrogenase in the mitochondria of live cells can reduce MTT to water-insoluble blue-purple formazan crystals, while dead cells lack this function. The absorbance value of the formazan dissolved in DMSO (dimethyl sulfoxide) at 570 nm can indirectly reflect the number of live cells. Within a certain cell number range, the amount of MTT crystals formed is directly proportional to the cell number. The specific steps were as follows: Cryopreserved MCF-10A cells were seeded into cell culture flasks at an appropriate density, DMEM medium (10% FBS) was added, and the cells were cultured in a cell culture incubator at 37℃ and 5% CO2 for 24 h. After the MCF-10A cells reached the logarithmic growth phase, they were digested with trypsin, collected by centrifugation, resuspended in culture medium, and counted. The MCF-10A cells were then seeded into 96-well plates (5×10⁶ cells / wells). 3Cells were incubated in a 96-well plate with different concentrations of the compound (10, 5, 2.5, 1.25, 0.62, 0.31, and 0.16 μM) for 24 h. A blank control group was also included. After 72 h of incubation, MTT (5 mg / mL) was added to each well and incubated for 4 h. The supernatant was discarded, and DMSO was added to the plate to dissolve the formazan. The absorbance was measured at 570 nm, and cell viability was calculated. Data were statistically processed using GraphPad Prism 8.0 software. The results are shown in Table 1.

[0045] Table 1. Effects of different tanshinone IIA derivatives on the survival rate of MCF-10A cells

[0046] The data in Table 1 show that after treating MCF-10A normal human mammary cells with different concentrations of tanshinone IIA derivatives for 72 hours, the MCF-10A cells all exhibited varying degrees of proliferation.

[0047] Test Example 2 The effects of the tanshinone IIA derivative compounds prepared in Examples 1-14 on the proliferation of human fibroblasts (HSF cells) were tested according to the following method: Cryopreserved MCF-10A cells were seeded at an appropriate density into cell culture flasks, DMEM medium (10% FBS) was added, and the cells were cultured at 37°C and 5% CO2 for 24 hours. After the HSF cells reached the logarithmic growth phase, they were digested with trypsin, collected by centrifugation, resuspended in culture medium, and counted. The HSF cells were then seeded into 96-well plates (5 × 10⁻⁶ wells). 3 Cells were incubated in a 96-well plate for 24 hours. Compound concentrations were set at 10, 5, 2.5, 1.25 μM, 0.62, 0.31, and 0.16 μM, with a blank control group included. After 72 hours of incubation, MTT (5 mg / mL) was added to each well and incubated for 4 hours. The supernatant was discarded, and DMSO was added to the plate to dissolve formazan. The absorbance was measured at 570 nm, and cell viability was calculated. Data were statistically processed using GraphPad Prism 8.0 software. The results are shown in Table 2.

[0048] Table 2. Effects of different tanshinone IIA derivatives on HSF cell survival

[0049] The data in Table 2 show that after treatment of HSF human fibroblasts with different concentrations of tanshinone IIA derivatives for 72 hours, the HSF human fibroblasts all showed different degrees of proliferation.

[0050] Test Example 3 The promoting effect of the tanshinone IIA derivative prepared in Example 14 on the proliferation of human fibroblasts was tested according to the following method (EdU method); the specific steps were as follows: human skin fibroblasts (HSF cells) were collected, counted, and then stored at 1.0 × 10⁻⁶ cells per well. 5 Cells were seeded at a density of 1000 g / cm³ in 6-well plates and cultured overnight in 5 mL of complete culture medium. After cell adhesion, a gradient concentration (0.00 μM, 1.00 μM, 2.00 μM, and 4.00 μM) of tanshinone IIA derivative (TA1013) was added to the culture medium for 72 h. After treatment, the culture medium was discarded, and EdU probe solution diluted 1:1000 was added for further incubation for 4 h. After labeling, cells were fixed with 4% paraformaldehyde for 20 min and washed three times with PBS. Cells were permeabilized with PBS buffer containing 0.3% Triton X-100 for 5 min, washed with PBS, and then incubated with 0.5 mL of Click reaction solution in the dark for 30 min. After PBS washing, Hoechst 33342 staining solution was added and incubated in the dark for 5 min. After washing again, the cell nuclei (blue fluorescence) and EdU labeling (red fluorescence) were observed under a fluorescence microscope. The EdU positivity rate was calculated using Formula 1. EdU positivity rate (%) = [N EdU + / N Hoechst 33342 + ]×100% formula 1; Where, N EdU+ The number of EdU fluorescently positive cells, N Hoechst 33342 + The total number of cell nuclei labeled with Hoechst33342.

[0051] Figure 1 The image shows the promoting effect of the tanshinone IIA derivative prepared in Example 14 on fibroblast proliferation. Specifically, it is a cell proliferation image taken under a fluorescence microscope (40×) after HSF cells were treated with different concentrations (0.00, 1.00, 2.00 and 4.00 μM) of TA1013. The blue fluorescence is Hoechst 33342 nuclear dye, the red fluorescence is EdU-labeled proliferating cells, and Merge is an overlay image of the two channels.

[0052] Figure 1 The results of the EdU incorporation experiment are shown in red fluorescence, which represents proliferating cells treated with tanshinone IIA derivatives (0.00, 1.00, 2.00 and 4.00 μM) prepared in Example 14 for 72 h, and blue fluorescence represents cell nuclei stained with Hoechst 33342.

[0053] Depend on Figure 1It can be seen that the tanshinone IIA derivative prepared in Example 14 can promote the proliferation of HSF cells in vitro.

[0054] Figure 2 A bar chart showing the proliferation rate of different concentrations of tanshinone IIA derivatives. Figure 2 EdU assays were performed using the BeyoClick™ EdU Cell Proliferation Kit (C0078S, Beyotime). Data are presented as mean ± standard error (SEM) from three independent experiments. p <0.05, p <0.01, p <0.001.

[0055] Depend on Figure 2 It can be seen that after treatment with tanshinone IIA derivatives prepared in Example 14 at different concentrations (1.00, 2.00, and 4.00 μM), the cell proliferation rates were 33.29 ± 3.38%, respectively. p> 0.05), 36.90±0.88% p< 0.05) and 62.86±1.98% p< 0.001). Under medium to high concentrations (2 μM and 4 μM) of tanshinone IIA derivatives, HSF cell proliferation was significantly promoted and the cell number increased significantly.

[0056] Combination Figure 1 and Figure 2 This demonstrates that the tanshinone IIA derivative prepared in Example 14 can promote cell proliferation.

[0057] Test Example 4 The cell scratch assay was used to test the promoting effect of the tanshinone IIA derivative prepared in Example 14 on human fibroblast migration. The specific steps were as follows: HSF cells in logarithmic growth phase were washed twice with PBS, digested with trypsin, and centrifuged with DMEM medium (10% FBS) to terminate the digestion. The supernatant was discarded, and DMEM medium (10% FBS) was added to prepare a cell suspension. To avoid cell damage, dimethyl sulfoxide (DMSO) was used as a solvent. The tanshinone IIA derivative was dissolved in DMSO and diluted with deionized water to obtain different concentrations of the drug. 2 mL of cell suspension was added to each well of a 6-well plate and cultured in a cell culture incubator. After constructing cell scratch assays (simulating skin wounds), the cells were washed with PBS and treated with different concentrations of the drug (tanshinone IIA derivative) (0.00, 1.00, 2.00, and 4.00 μM) for 72 h. Serum-free DMEM medium was used. Photographs were taken of the same field of view from different groups at 0 h, 24 h, 48 h, and 72 h. The scratch distance (d) at the three locations at these time points was measured, and the cell migration rate and relative cell migration rate were calculated using the formula shown in Formula 2. Cell migration rate (%) = (d 0 h -d x h ) / d 0 h ×100% Formula 2; Where d 0 h The scratch spacing at time 0h is d. x h The scratch spacing is at time xh, where xh is 24h, 48h, or 72h.

[0058] Figure 3 The image shows the cell migration morphology after treatment with different concentrations of tanshinone IIA derivatives for different durations. Figure 4 This is a bar chart comparing the migration rates of HSF cells after treatment with different concentrations of tanshinone IIA derivatives for different durations. Data are presented as mean ± standard error (SEM) of three independent experiments. p <0.05, p <0.01, p <0.001.

[0059] Cell migration is a crucial biological event in wound healing, and its efficiency and coordination directly determine the speed, quality, and ultimate functional recovery of tissue repair. Fibroblasts, as the main repair cells in the dermis, are vital for granulation tissue formation through their migration to the wound bed. In vitro scratch assays are used to assess cell migration capacity, evaluating the ability of drugs to promote HSF cell migration based on the degree of wound healing. Figure 3 and Figure 4 It can be seen that the degree of cell healing becomes more and more obvious with the increase of drug concentration (tanshinone IIA derivative). High concentrations of the compound significantly increased the migration rate compared with the control group at 24, 48, and 72 h. At 24 h, there was no significant difference between the low and medium concentrations (1 μM, 2 μM) and the control group. At 24 h, the migration rate of the high concentration (4 μM) was 48.69%, significantly higher than the control group. At 48 h, the migration rate of the control group was 12.27%, while the migration rates after treatment with different concentrations of tanshinone IIA derivative were 12.27%, 22.94%, 22.54%, and 52.52%, respectively. At 72 h, the migration rate of the control group was 3.83±1.45%, while the migration rates after treatment with different concentrations of tanshinone IIA derivative were 17.30±2.12%. p< 0.01), 19.72±2.18% p< 0.01) and 41.05±1.61% ( p< The result of 0.001 indicates that tanshinone IIA derivatives can promote cell migration.

[0060] Test Example 5 The tanshinone IIA derivative prepared in Example 14 was dissolved in dimethyl sulfoxide (DMSO) and diluted with zebrafish culture water to obtain solutions with tanshinone IIA derivative concentrations of 0.00, 1.00, 2.00 and 4.00 μM, respectively.

[0061] The effect of the tanshinone IIA derivative prepared in Example 14 on zebrafish tissue repair was investigated using the following method: Wild-type AB zebrafish with normal development at 3 dpf were randomly selected under a stereomicroscope, and 90% of the caudal fin was surgically removed after anesthesia. After caudal fin removal, the zebrafish were incubated at 28℃ for 2 hours, and photographs were taken under a stereomicroscope. Then, juvenile zebrafish were transferred to 96-well plates, 20 fish per group. 200 µL of a gradient concentration (0 (blank control), 1 μmol / L, 2 μmol / L, and 4 μmol / L) of tanshinone IIA derivative solution was added to each well. After incubation at 28℃ for 72 hours, the zebrafish were anesthetized with 0.4% tricaine, photographed under a stereomicroscope, and the caudal fin growth before and after incubation was measured using ImageJ. The test groups with concentrations of 1.00, 2.00, and 4.00 μM were the experimental groups, and the test group with a concentration of 0 was the blank control group. Measurements were taken 2 hours after tail cutting, and the calculation formula is shown in Formula 3: Regeneration growth rate % = Experimental group (tail fin length 72h after tail cutting - tail fin length 2h after tail cutting) / Blank control group (tail fin length 72h after tail cutting - tail fin length 2h after tail cutting) × 100% Formula 3.

[0062] Figure 5 The image shows the results of zebrafish tail fin wound regeneration after treatment with different concentrations of tanshinone IIA derivatives.

[0063] Figure 6 A statistical comparison chart of caudal fin regeneration growth rate (n=20); the data is the average of 20 zebrafish, of which... p <0.05, p <0.01, p <0.001.

[0064] Depend on Figure 5 and Figure 6 It can be seen that zebrafish fins possess a strong regenerative capacity, and fin regeneration is a particularly effective model for studying tissue repair. After caudal fin amputation, the repair process can be divided into three stages: wound healing, bud formation, and regenerative growth. 72 hours after caudal fin removal, treatment with 0.00, 1.00, 2.00, and 4.00 μM tanshinone IIA derivatives, respectively, increased the caudal fin regeneration rate by 24.66% compared to the blank control group. p <0.001), 28.47% p <0.001) and 34.36% ( pThe result was <0.001, indicating that the tanshinone IIA derivative can significantly promote the regeneration of zebrafish tail fins, and that the tanshinone IIA derivative has the activity of promoting tissue regeneration.

[0065] Test Example 6 The tanshinone IIA derivative prepared in Example 14 was dissolved in dimethyl sulfoxide (DMSO) and diluted with zebrafish culture water to obtain tanshinone IIA derivative solutions with concentrations of 0.00, 1.00, 2.00 and 4.00 μM, respectively.

[0066] The effects of the tanshinone IIA derivative prepared in Example 14 on oxidative stress in zebrafish were investigated using the following method: 20 normally developed wild-type zebrafish embryos (6-9 hpf, hours post-fertilization) were randomly selected per well under a stereomicroscope. A blank control group, a model control group, and a compound group were set up. The culture water in the 6-well plates was aspirated. 5 mL of standard dilution water was added to each well in the blank control group, 4.75 mL of standard dilution water was added to each well in the model control group, and 4.75 mL of tanshinone IIA derivative solution of varying concentrations was added to each well in the compound group. After pretreatment for 1 h, 250 μL of LPS (lipopolysaccharide) stock solution (final LPS concentration 10 μg / mL) was added to each well in both the model control group and the compound group to construct an oxidative stress model. The models were incubated at 28℃ for 24 h. After 24 h of incubation, the embryos from each well were transferred to new 6-well plates, washed three times with culture water in each well, and finally 5 mL of standard dilution water was added. The plates were then incubated at 28℃ for 24 h. After 24 hours, each group was washed three times with culture water, and then 5 mL of standard dilution water was added to each well. The embryos were incubated at 28℃ for 3 days post-fertilization (dpf). After 3 dpf, the egg membranes were aspirated from each well, and 5.0 mL (20 μg / mL) of a fluorescent probe (DCHF-DA) was added to each well for 50 min in the dark. Finally, the embryos were washed three times with culture water, anesthetized with tricaine, photographed under a fluorescence microscope, and the fluorescence intensity was analyzed using ImageJ. The formulas for calculating the relative fluorescence intensity and inhibition rate of ROS (reactive oxygen species) are shown in Equations 4 and 5. ROS relative fluorescence intensity = FI of blank control group, model control group or compound group / MFI of model control group (Formula 4); ROS inhibition rate (%) = (MFI) 模型对照组 -FI 化合物组 ) / MFI 模型对照组 ×100% Formula 5; Wherein, FI (Fluorescence Intensity) is the fluorescence intensity, and MFI (Mean Fluorescence Intensity) is the mean fluorescence intensity; MFI 模型对照组FI represents the average fluorescence intensity of the model control group. 化合物组 denoted as the fluorescence intensity of the compound group.

[0067] Figure 7 The figure shows the effect of different test groups on reactive oxygen species in zebrafish after staining with fluorescent probes.

[0068] Figure 8 and Figure 9 The graphs show the relative fluorescence intensity and ROS inhibition rate of different test groups (n=20), and the data are averages. Compared with the blank control group: # p <0.05, ## p <0.01, ### p <0.001, compared with the model control group: p <0.05, p <0.01, p <0.001.

[0069] Lipopolysaccharide (LPS) is a major component of the cell wall of Gram-negative bacteria and an effective activator of innate immune responses, capable of inducing the production of large amounts of reactive oxygen species (ROS) in cells or tissues. This experiment utilized the interaction between a fluorescent probe (DCFH-DA, 2,7-dichlorofluorescein diacetate) and ROS to determine the distribution and content of ROS in vivo by measuring the intensity of the fluorescence signal. Zebrafish treated with tanshinone IIA derivatives at concentrations of 0.00, 1.00, 2.00, and 4.00 μM showed a relative fluorescence intensity reduction of 0.23 μM compared to the model control group. p >0.05), 0.26 ( p >0.05) and 0.52 ( p <0.001). By Figures 7-9 It can be seen that the tanshinone IIA derivative provided in this application has a certain antioxidant effect. High concentration (4.00 μM) of tanshinone IIA derivative can significantly inhibit the production of reactive oxygen species in zebrafish.

[0070] Test Example 7 The promoting effect of the tanshinone IIA derivative (TA1013) prepared in Example 14 on mammary gland proliferation was tested according to the following method: TA1013 was dissolved in an ethanol-water solution (ethanol to water volume ratio of 1:9) to obtain a TA1013 solution with a mass concentration of 0.5%; approximately 2 mL of the TA1013 solution was applied to the breast daily and massaged until completely absorbed for 7 consecutive days. MR images were taken before and after use, and the results are shown in the figure. Figure 10 The top two images show the results before using TA1013 solution, and the bottom two images show the results after using TA1013 solution. Before use, the volume of the left breast was 322.14 ml, and the volume of the right breast was 316.90 ml; after use, the volume of the left breast increased to 407.29 ml (an increase of 26.4%), and the volume of the right breast increased to 309.26 ml (an increase of 16.5%). This demonstrates that the tanshinone IIA derivative provided by this invention can promote mammary gland proliferation and achieve breast enhancement.

[0071] Although the above embodiments have provided a detailed description of the present invention, they are only some embodiments of the present invention, and not all embodiments. People can obtain other embodiments based on these embodiments without creative effort, and these embodiments all fall within the protection scope of the present invention.

Claims

1. A tanshinone IIA derivative, characterized in that, It has the structure shown in Equation 1: Formula 1; Where R1 is -H, -Br, -Cl, -CF3, -CH3, R1, R2, and R3 cannot all be -H, -OCH3, or -OH; R2 can be -H, -Cl, -OCH3, or -OH; R3 can be -H, -Br, -Cl, -CF3, -OCH3, or -OH; R1, R2, and R3 cannot all be -H at the same time.

2. The tanshinone IIA derivative according to claim 1, characterized in that, It has the following structure: 。 3. The method for preparing the tanshinone IIA derivative according to claim 1 or 2, characterized in that, Includes the following steps: Tanshinone IIA, compound 1, ammonium acetate and glacial acetic acid were mixed and then subjected to a Debus-Radziszewski imidazole synthesis reaction to obtain the tanshinone IIA derivative. The structure of tanshinone IIA is as follows: The structure of compound 1 is as follows: .

4. The preparation method according to claim 3, characterized in that, The Debus-Radziszewski imidazole synthesis reaction further includes: diluting the system after the Debus-Radziszewski imidazole synthesis reaction with water, adjusting the pH to neutral, and then performing solid-liquid separation to obtain the tanshinone IIA derivative; The volume ratio of the system to water after the Debus-Radziszewski imidazole synthesis reaction is 0.8~1.2:1; The reagent used to adjust the pH value includes ammonia water, and the concentration of the ammonia water is 20-30%. The solid-liquid separation method includes pressure filtration.

5. The preparation method according to claim 3, characterized in that, The molar ratio of tanshinone IIA to compound 1 is 1:1.1~1.5; The molar ratio of tanshinone IIA to ammonium acetate is 1:5~6; The mass ratio of tanshinone IIA to glacial acetic acid is 1g:20~25mL; The Debus-Radziszewski imidazole synthesis reaction was carried out at a temperature of 100-120℃ for a time of 0.8-1.5 h.

6. The application of the tanshinone IIA derivative according to claim 1 or 2 or the tanshinone IIA derivative prepared by the preparation method according to any one of claims 3 to 5 as an antioxidant.

7. An anti-aging skincare product, characterized in that, Includes an antioxidant, wherein the antioxidant is the tanshinone IIA derivative of claim 1 or 2 or the tanshinone IIA derivative prepared by the preparation method of any one of claims 3 to 5.

8. The use of the tanshinone IIA derivative according to claim 1 or 2 or the tanshinone IIA derivative prepared by the preparation method according to any one of claims 3 to 5 in the preparation of breast enhancement drugs.

9. A breast enhancement drug, characterized in that, It includes an aqueous ethanol solution and a tanshinone IIA derivative dissolved in the aqueous ethanol solution, wherein the tanshinone IIA derivative is the tanshinone IIA derivative of claim 1 or 2 or the tanshinone IIA derivative prepared by the preparation method of any one of claims 3 to 5.

10. The breast enhancement drug according to claim 9, characterized in that, The volume ratio of ethanol to water in the ethanol-water solution is 1:8.5~9.5; The mass concentration of tanshinone IIA derivative in the breast enhancement drug is 0.4-0.6%; The dosage of the breast enhancement drug is once a day, 1.8 to 2.3 mL each time.

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