Application of farrerol and its derivatives in the preparation of ferroptosis inhibitors

Abstract

The present invention relates to the field of pharmaceutical technology, and particularly to the use of farrerol and its derivatives in the preparation of ferroptosis inhibitors. The farrerol derivatives of the present invention have the structure shown in general formula (I). The present invention has confirmed that the derivatives obtained by introducing specific groups at the R1 and R2 positions of farrerol can have a good inhibitory effect on ferroptosis of vascular endothelial cells, have good medicinal potential, and are expected to become new candidate drugs for preventing, improving or treating ferroptosis-related cardiovascular diseases; at the same time, the preparation method of the new compounds provided by the present invention is simple, easy to operate and control, has low cost, is suitable for industrial production, the prepared compounds have high biological activity and significant drug-likeness, and have broad market prospects.

Description

Technical Field

[0001] The present invention relates to the field of pharmaceutical technology, and particularly to the use of farrerol and its derivatives in the preparation of ferroptosis inhibitors. Background Art

[0002] Cardiovascular diseases are one of the main diseases threatening human health. Vascular endothelial cells play an important role in maintaining and regulating cardiovascular function. Vascular endothelial dysfunction is closely related to the occurrence and development of diseases such as atherosclerosis, hypertension, coronary artery disease, peripheral artery disease, heart failure, diabetes, and chronic renal failure.

[0003] Ferroptosis is an iron-dependent programmed cell death mode caused by lipid peroxidation, which is significantly different from apoptosis, necroptosis, pyroptosis, etc. Its typical morphological characteristics are increased density of the mitochondrial double membrane, reduced volume, and fewer cristae. Recent studies have found that ferroptosis of vascular endothelial cells can lead to vascular endothelial dysfunction characterized by reduced NO release, increased release of pro-inflammatory factors, increased vascular permeability, abnormal vasoconstriction, and angiogenesis. Moreover, inhibiting ferroptosis of vascular endothelial cells can significantly improve vascular endothelial dysfunction. It has now been confirmed that ferroptosis inhibitors have therapeutic and alleviating effects on various cardiovascular diseases such as atherosclerosis, diabetes, and heart failure. Therefore, ferroptosis inhibitors are considered potential drugs for treating related diseases.

[0004] Currently, ferroptosis inhibitors mainly include antioxidants, iron chelators, acyl-CoA synthetase long-chain family member 4 inhibitors, lipoxygenase inhibitors, etc., but they have deficiencies such as poor bioavailability and high toxicity. Therefore, the research and development of new ferroptosis inhibitors are urgently needed.

[0005] Using natural active ingredients as lead compounds for structural optimization is one of the important ways to develop new drugs. Farrerol is a dihydroflavonoid compound derived from Rhododendron dauricum, and the inhibitory effect of farrerol on ferroptosis of vascular endothelial cells has not been reported. Summary of the Invention

[0006] The present invention provides a new use of farrerol and its derivatives, and provides the use of farrerol and its derivatives in the preparation of ferroptosis inhibitors, providing a theoretical basis for the treatment of cardiovascular diseases related to vascular endothelial dysfunction targeting ferroptosis.

[0007] To achieve the above object, the specific technical solutions of the present invention are as follows.

[0008] The object of the present invention is to provide a farrerol derivative, and the farrerol derivative has a structure shown in the general formula (I):

[0009]

[0010] Among them, R1 is selected from any one of ;

[0011] R2 is selected from any one of ; n is an integer from 1 to 8.

[0012] Previous studies of the present invention found that farrerol exerts a protective effect on vascular endothelial cells damaged by oxidative stress by regulating the GSK-3β / Nrf2 (an important regulator of ferroptosis) axis. The present invention discovers that farrerol has an inhibitory effect on ferroptosis of vascular endothelial cells induced by Erastin and RSL3 respectively. Molecular docking simulation shows that when farrerol exists in the ATP binding site of GSK-3β, there is an unoccupied cavity at the position of R' in formula (II), which can be used for the structural optimization of this type of compound. Therefore, using farrerol as a lead compound and GSK-3β as a target, through computer-aided drug design methods, by changing the position of substituents (ortho, meta, and para) on R' of formula (II); the type of substituents (N-methylpiperazinyl, dimethylamino, pyrrolyl, piperidyl, morpholinyl, and phenyl); the number of carbon atoms connected to the parent nucleus (2 or 3), a series of novel farrerol derivatives are designed to enhance the binding ability of this type of compound to GSK-3β, and ultimately enhance its ferroptosis inhibitory activity. And the structure-activity relationship shows that the inhibitory activity of ferroptosis of vascular endothelial cells can be enhanced by the substitution of groups at the ortho and para positions, and the types of substituents that can enhance the activity are: benzene ring, dimethylamino, piperidyl, pyrrolyl.

[0013]

[0014] In some technical solutions of the present invention, the structure of the farrerol derivative is one of the following compounds:

[0015]

[0016]

[0017] Another object of the present invention is to provide a preparation method of the farrerol derivative, including: adding intermediate 3, intermediate 4, boric acid, L-proline and magnesium oxide into glycerol, mixing evenly and heating to 115 °C for reaction, and obtaining a reaction product after the reaction ends, and the farrerol derivative is obtained after the reaction product is separated and purified;

[0018] The structural formula of the intermediate 3 is as follows:

[0019]

[0020] The general structural formula of the intermediate 4 is as follows:

[0021]

[0022] Among them, R3 is selected from any one of

[0023] R4 is selected from any one of; n is 2 or 3.

[0024] In some embodiments of the present invention, the molar ratio of intermediate 3, intermediate 4, boric acid, L-proline and magnesium oxide solution is 0.5-1.5:3.5-4.5:2.5-3.5:0.5-1.5:1.5-2.5; the volume of the glycerol is 0.5-1.5 mL.

[0025] In some embodiments of the present invention, the reaction time is 3-7 h.

[0026] In some embodiments of the present invention, the separation and purification include: dissolving the reaction product with ethanol, then adding silica gel for sample mixing, then drying by rotary evaporation under reduced pressure and silica gel column chromatography, and then eluting with an eluent to obtain a liquid, and the liquid is rotary evaporated under reduced pressure to obtain a solid powder, that is, the rhododendrin derivative is obtained.

[0027] Another object of the present invention is to provide the use of rhododendrin or a rhododendrin structural analogue in the preparation of an inhibitor of ferroptosis in vascular endothelial cells, and the rhododendrin structural analogue includes: the rhododendrin derivative and the stereoisomer of the rhododendrin derivative.

[0028] Another object of the present invention is the use of rhododendrin or a rhododendrin structural analogue in the preparation of a drug for preventing or treating ferroptosis-related cardiovascular diseases, and the rhododendrin structural analogue includes: the rhododendrin derivative and the stereoisomer of the rhododendrin derivative.

[0029] In some embodiments of the present invention, the ferroptosis-related cardiovascular diseases include: atherosclerosis, hypertension, coronary artery disease, peripheral artery disease, heart failure, diabetes and chronic renal failure.

[0030] Compared with the prior art, the present invention has the following beneficial effects:

[0031] The present invention designs and synthesizes a novel class of dihydroflavonoid rhododendrin derivatives, which can have a good inhibitory effect on ferroptosis, provides a theoretical basis for the treatment of ferroptosis-related cardiovascular diseases associated with vascular endothelial dysfunction, has good medicinal potential, and can be used as the main active ingredient for preparing ferroptosis inhibitors; at the same time, the preparation method of the new compound provided by the present invention is simple, easy to operate and control, has low cost, is suitable for industrial production, the prepared compound has high biological activity and significant drug-likeness, and has a broad market prospect.

[0032] In the previous research work of the applicant of the present invention, it was found that not only can farrerol protect vascular endothelial cells damaged by oxidative stress by regulating the important regulator Nrf2 of ferroptosis, but it also has an inhibitory effect on ferroptosis of vascular endothelial cells induced by Erastin and RSL3 respectively. Therefore, chemical structure modification with farrerol as a lead compound is of great research significance for the development of new ferroptosis inhibitors with high inhibitory activity and capable of treating cardiovascular diseases related to vascular endothelial dysfunction. Brief Description of the Drawings

[0033] Figure 1 It is a diagram showing the measurement results of the protective effects of farrerol and farrerol derivatives on the ferroptosis model of HUVEC cells induced by Erastin and RSL3 in the present invention; among them, Figure 1 A in represents the diagram showing the measurement results of the protective effects of farrerol and farrerol derivatives on the ferroptosis model of HUVEC cells induced by Erastin;

[0034] Figure 1 B in is the protective effect of farrerol and farrerol derivatives on the ferroptosis model of HUVEC cells induced by RSL3.

[0035] Figure 2 It is a line graph showing the inhibition of Erastin-induced ferroptosis of HUVEC cells by farrerol derivative G3 of the present invention.

[0036] Figure 3 It is a line graph showing the inhibition of RSL3-induced ferroptosis of HUVEC cells by farrerol derivative G3 of the present invention. Detailed Embodiments

[0037] The present invention will be described in detail below with reference to specific embodiments, but it should not be construed as a limitation of the present invention. Unless otherwise specified, the technical means used in the following embodiments are conventional means well-known to those skilled in the art. The materials, reagents, etc. used in the following embodiments can be obtained from commercial channels unless otherwise specified.

[0038] In the following preparation examples, 1 1H-NMR and 13 13C-NMR were measured using a Bruker Avance III HD 600 type nuclear magnetic resonance spectrometer. MS was measured using a Bruker impact HD type mass spectrometer. The anhydrous solvents used were all obtained by drying treatment according to standard methods. Unless otherwise stated, all reactions were monitored by TLC. The purification of the products was carried out by column chromatography using silica gel (200 - 300 mesh) unless otherwise stated.

[0039] Example 1 Synthesis of the Target Compound

[0040] Preparation Method Step 1: Synthesis of Intermediate 1

[0041] The synthesis route is as follows:

[0042]

[0043] Under ice bath conditions, prepare a mixed solution of concentrated nitric acid (2.3 mL) and concentrated sulfuric acid (5.0 mL). Subsequently, add 2.4 mL of m-xylene in batches at 40 °C. After the addition is complete, react for 5 min, cool, and after the reaction layers separate, remove the aqueous phase. Then add concentrated sulfuric acid (6.6 mL) and concentrated nitric acid (2.5 mL) again. React at 40 °C for 5 min and then raise the temperature to 115 °C and react for 3 h. After the reaction is completed, remove the aqueous phase, wash the product with sodium carbonate solution, filter by suction, and the obtained white solid is Intermediate 1.

[0044] Preparation Method Step 2: Synthesis of Intermediate 2

[0045] The synthesis route is as follows:

[0046]

[0047] Add Intermediate 1 (2.2 g) to 23 mL of concentrated hydrochloric acid, and add 8.8 g of tin powder at 45 °C. Then raise the temperature to 120 °C to react, and monitor the reaction progress by TLC. After the reaction is completed, adjust the pH of the reaction solution to 4 with 40% sodium hydroxide solution and then continue to heat and reflux for 24 h. After the reflux is completed, filter by suction to collect the filtrate, and wash the precipitate with hot water 3 times. After combining the filtrate and the washing solution, extract with ethyl acetate, dry over anhydrous sodium sulfate overnight, filter by suction, and rotary evaporate under reduced pressure to obtain Intermediate 2.

[0048] Preparation Method Step 3: Synthesis of Intermediate 3

[0049] The synthesis route is as follows:

[0050]

[0051] Dissolve Intermediate 2 (1 g) and anhydrous zinc chloride (1.8 g) in 30 mL of anhydrous acetonitrile. Under ice bath, pass dry hydrogen chloride gas into the solution until a large amount of yellowish-white solid precipitates. After sealing the reaction flask, place it at 4 °C overnight, and filter by suction to obtain a milky white solid. Dissolve the obtained solid in water, heat and reflux for 2 h, then filter by suction, and obtain Intermediate 3 after vacuum drying.

[0052] Preparation Method Step 4: General Method for the Synthesis of Intermediate 4 (Etherification)

[0053] Intermediate 4 is prepared by aldol condensation reaction and high-temperature boric acid method, specifically including: placing 2 mmol of hydroxybenzaldehyde, 2 mmol of chloride, 1.8 g of anhydrous stannous chloride, 829 mg of anhydrous potassium carbonate (6 mmol) and 2 mg of potassium iodide (catalyst) in a 50 ml eggplant-shaped flask, adding 30 ml of chromatographic acetonitrile, heating under reflux for 48 h, and monitoring the reaction using TLC. After the reaction is completed, filter by suction, add silica gel to the filtrate for sample mixing, rotary evaporate, and separate by silica gel column chromatography to obtain Intermediate 4. The reaction formula is as follows:

[0054]

[0055] Among them, R3 is selected from any one of;

[0056] R4 is selected from any one of; n is 2 or 3.

[0057] Step 5 of the preparation method: General method for the synthesis of the target compound

[0058] At 80 °C, add Intermediate 3 (1 mmol), Intermediate 4 (1 mmol), boric acid (3 mmol), L-proline (1 mmol) and magnesium oxide (2 mmol) to 1 mL of glycerol, mix well, then raise the temperature to 115 °C and react for 3 - 7 h, and monitor the reaction using TLC. After the reaction is completed, add absolute ethanol and dissolve by ultrasonic treatment, add 1 g of silica gel for sample mixing, the dosage ratio of absolute ethanol to silica gel is 20 mL:1 g, rotary evaporate under reduced pressure at 45 °C, separate by silica gel column chromatography, elute with an eluent, obtain a liquid, rotary evaporate under reduced pressure after separation to obtain a solid powder, and thus obtain the target compound (farrerol derivative). The general reaction formula is as follows:

[0059]

[0060] Specifically, the synthesis of each target compound is as follows:

[0061] (1) During the synthesis of Compound A1, R3 in Intermediate 4 is R4 is independently n = 3, the eluent is a mixed solution of dichloromethane and methanol with a volume ratio of 30:1, and the remaining steps are carried out with reference to the general method for the synthesis of the target compound in Step 5.

[0062] The chemical formula of Compound A1, 1 1H-NMR, 13 13C-NMR and MS data are as follows:

[0063]

[0064] Yellow solid, yield: 22%; mp: 181 - 182 °C;1 1H-NMR (600 MHz, CDCl3) δ 12.25 (s, 1H), 7.32 (t, J = 8.2 Hz, 1H), 7.03–6.98 (m, 2H), 6.91–6.87 (m, 1H), 5.37 (ddd, J = 15.3, 11.0, 3.9 Hz, 1H), 4.04 (t, J = 6.3 Hz, 2H), 3.02 (dd, J = 17.1, 12.3 Hz, 1H), 2.86 (dd, J = 17.1, 3.2 Hz, 1H), 2.57 (dq, J = 20.1, 12.4, 10.3 Hz, 10H), 2.33 (s, 3H), 2.08 (d, J = 5.5 Hz, 6H), 1.98 (dt, J = 13.5, 6.4 Hz, 2H); 13 13C-NMR (151 MHz, DMSO-d6) δ 196.71, 163.31, 159.21, 158.90, 157.52, 141.21, 130.14, 118.69, 114.66, 112.90, 103.87, 103.12, 102.09, 78.21, 66.33, 55.13, 54.81, 53.07, 46.06, 42.60, 26.64, 8.76, 8.08; MS (ESI) m / z 441.31 ([M+H] + )。

[0065] (2) In the synthesis of compound A2, R3 in intermediate 4 is R4 is independently n = 3, the eluent is a mixed solution of dichloromethane and methanol with a volume ratio of 25:1, and the remaining steps are carried out according to the general method for the synthesis of the target compound in step 5.

[0066] The chemical formula of compound A2, 1 1H-NMR, 13 13C-NMR and MS data are as follows:

[0067]

[0068] Yellow solid, yield: 29%; mp: 174 - 175 °C; 11H-NMR (600 MHz, CDCl3) δ 12.28 (s, 1H, 5-OH), 7.37 (d, J = 8.6 Hz, 2H), 6.94 (d, J = 8.7 Hz, 2H), 5.34 (dd, J = 12.8, 2.9 Hz, 1H), 4.04 (t, J = 6.3 Hz, 2H), 3.05 (dd, J = 17.0, 12.8 Hz, 1H), 2.81 (dd, J = 17.0, 3.0 Hz, 1H), 2.73–2.34 (m, 10H), 2.30 (s, 3H), 2.06 (d, J = 14.9 Hz, 6H), 1.98 (dt, J = 13.6, 6.5 Hz, 2H); 13 13C-NMR (151 MHz, DMSO) δ 197.01, 163.24, 159.13, 158.89, 157.73, 131.45, 128.31, 114.87, 103.77, 103.05, 102.10, 78.18, 66.35, 55.13, 54.80, 53.05, 46.05, 42.48, 26.66, 8.73, 8.07; MS (ESI) m / z 439.38 ([M-H]-).

[0069] (3) In the synthesis of compound A3, R3 in intermediate 4 is R4 independently is n = 3, the eluent is a mixed solution of dichloromethane and methanol with a volume ratio of 25:1. For the remaining steps, refer to the general synthetic method of the target compound in step 5.

[0070] The chemical formula of compound A3, 1 1H-NMR, 13 13C-NMR and MS data are as follows:

[0071]

[0072] Yellow solid, yield: 18%; mp: 75 - 76 °C; 1H-NMR(600 MHz, CDCl3) δ 12.31 (s, 1H), 7.61 (dd, J = 7.6, 1.3 Hz, 1H), 7.32 (td, J = 8.3, 1.6 Hz, 1H), 7.06–7.02 (m, 1H), 6.92 (d, J = 8.1 Hz, 1H), 5.70 (dd, J = 11.5, 4.5 Hz, 1H), 4.09–4.02 (m, 2H), 2.93–2.89 (m, 1H), 2.89–2.84 (m, 1H), 2.49 (q, J = 20.1, 10.3 Hz, 10H), 2.29 (s, 3H), 2.07 (d, J = 4.9 Hz, 6H), 1.97 (dt, J = 13.5, 6.3 Hz, 2H); 13 C-NMR(151 MHz, DMSO-d6) δ 197.03, 163.23, 158.91, 157.99, 155.83, 129.98, 127.59, 126.86, 121.00, 112.58, 103.84, 103.09, 101.97, 74.16, 66.62, 55.06, 54.85, 53.00, 46.01, 41.74, 26.60, 8.73, 8.07; MS(ESI) m / z 439.82 ([M-H]-).

[0073] (4) In the synthesis of compound B1, R3 in intermediate 4 is R4 independently is n = 3, the eluent is a mixed solution of dichloromethane and methanol with a volume ratio of 30:1. For the remaining steps, refer to the general synthetic method of the target compound in step 5.

[0074] The chemical formula of compound B1, 1 H-NMR, 13 C-NMR and MS data are as follows:

[0075]

[0076] Yellow solid, yield: 32%; mp: 171 - 172 °C; 1H-NMR(600MHz, DMSO-d6) δ 12.37 (s, 1H), 7.32 (t, J = 8.1 Hz, 1H), 7.09–7.04 (m, 2H), 6.92 (dd, J = 8.2, 2.1 Hz, 1H), 5.50 (dd, J = 12.1, 3.1 Hz, 1H), 4.02 (t, J = 6.4 Hz, 2H), 3.16 (dd, J = 17.0, 12.2 Hz, 1H), 2.83 (dd, J = 17.0, 3.2 Hz, 1H), 2.43 (t, J = 7.2 Hz, 2H), 2.20 (s, 6H), 1.97 (d, J = 10.1 Hz, 6H), 1.87 (p, J = 6.7 Hz, 2H); 13 C-NMR(151MHz, DMSO-d6) δ 196.61, 163.53, 159.18, 158.91, 157.51, 141.24, 130.14, 118.72, 114.61, 112.90, 103.89, 103.14, 102.02, 78.21, 66.19, 56.00, 45.37, 42.61, 27.07, 8.76, 8.09; MS(ESI) m / z 386.21 ([M+H] + )。

[0077] (5) During the synthesis of compound B2, R3 in intermediate 4 is R4 independently is n = 3, the eluent is a mixed solution of dichloromethane and methanol with a volume ratio of 20:1, and the remaining steps are carried out according to the general synthetic method of the target compound in step 5.

[0078] The chemical formula of compound B2, 1 H-NMR, 13 C-NMR and MS data are as follows:

[0079]

[0080] Yellow solid, yield: 30%; mp: 120 - 121 °C; 1 H-NMR(600MHz, DMSO-d6) δ 12.38 (s, 1H), 7.46 (d, J = 8.6 Hz, 2H), 7.00 (d, J = 8.7 Hz, 2H), 5.50 (dd, J = 12.1, 2.9 Hz, 1H), 4.08 (t, J = 5.9 Hz, 2H), 3.24–3.19 (m, 3H), 2.82 (s, 6H), 2.80–2.77 (m, 1H), 2.10 (dq, J = 12.2, 6.1 Hz, 2H), 1.95 (d, J = 7.0 Hz, 6H); 1313C-NMR (151 MHz, DMSO-d6) δ 197.17, 162.90, 158.87, 158.69, 157.69, 131.86, 128.36, 114.95, 103.75, 103.01, 102.21, 78.12, 65.27, 54.83, 42.97, 42.45, 24.51, 8.73, 8.08; MS (ESI) m / z 386.42 ([M+H] + )。

[0081] (6) During the synthesis of Compound B3, in Intermediate 4, R3 is R4 independently is n = 3, the eluent is a mixed solution of dichloromethane and methanol with a volume ratio of 30:1. For the remaining steps, refer to the general method for the synthesis of the target compound in Step 5.

[0082] The chemical formula of Compound B3, 1 1H-NMR, 13 13C-NMR and MS data are as follows:

[0083]

[0084] Yellow solid, yield: 35%; mp: 158 - 159 °C; 1 1H-NMR (600 MHz, DMSO-d6) δ 12.36 (s, 1H), 7.54 (d, J = 6.8 Hz, 1H), 7.37–7.31 (m, 1H), 7.07–7.01 (m, 2H), 5.67 (dd, J = 12.8, 2.8 Hz, 1H), 4.04 (tt, J = 9.5, 4.6 Hz, 2H), 3.09 (dd, J = 17.0, 12.8 Hz, 1H), 2.77 (dd, J = 17.0, 3.0 Hz, 1H), 2.39 (tt, J = 11.8, 6.2 Hz, 2H), 2.14 (s, 6H), 1.97 (s, 6H), 1.86 (p, J = 6.7 Hz, 2H); 13 13C-NMR (151 MHz, DMSO-d6) δ 196.85, 163.55, 158.93, 157.96, 155.77, 129.93, 127.63, 126.82, 120.98, 112.47, 103.86, 103.13, 101.86, 74.14, 66.47, 56.09, 45.39, 41.77, 27.10, 8.74, 8.09; MS (ESI) m / z 386.13 ([M+H] + )。

[0085] (7) During the synthesis of compound C1, R3 in intermediate 4 is R4 is independently n = 3, the eluent is a mixed solution of dichloromethane and methanol with a volume ratio of 25:1, and the remaining steps are carried out according to the general synthesis method of the target compound in step 5.

[0086] The chemical formula of compound C1, 1 1H-NMR, 13 13C-NMR and MS data are as follows:

[0087]

[0088] Yellow solid, yield: 25%; mp: 81 - 82 °C; 1 1H-NMR(600MHz,CDCl3)δ12.27(s,1H),7.29(t,J = 8.1Hz,1H),6.99(dd,J = 4.1,2.3Hz,2H),6.85(dd,J = 8.1,1.8Hz,1H),5.33(dd,J = 12.3,3.1Hz,1H),4.03(td,J = 6.2,1.9Hz,2H),2.98(dd,J = 17.0,12.3Hz,1H),2.85–2.82(m,1H),2.79(dd,J = 8.1,5.4Hz,2H),2.73(s,4H),2.06(d,J = 1.8Hz,8H),1.87(dq,J = 9.6,6.1,4.8Hz,4H); 13 13C-NMR(151MHz,CDCl3)δ195.78,159.31,159.06,157.41,140.73,129.81,118.13,114.27,112.11,104.20,103.22,102.45,78.29,66.02,54.11,53.12,43.33,28.07,23.38,8.07,7.30; MS(ESI)m / z 410.57([M-H]-).

[0089] (8) During the synthesis of compound C2, R3 in intermediate 4 is R4 is independently n = 3, the eluent is a mixed solution of dichloromethane and methanol with a volume ratio of 30:1, and the remaining steps are carried out according to the general synthesis method of the target compound in step 5.

[0090] The chemical formula of compound C2, 1 1H-NMR, 13 13C-NMR and MS data are as follows:

[0091]

[0092] Yellow solid, yield: 25%; mp: 162 - 163 °C; 1 1H-NMR (600 MHz, DMSO-d6) δ 12.37 (s, 1H), 9.85 (s, 1H), 7.45 (d, J = 8.6 Hz, 2H), 6.99 (d, J = 8.7 Hz, 2H), 5.49 (dd, J = 12.1, 2.8 Hz, 1H), 4.08 (t, J = 6.0 Hz, 2H), 3.65–3.54 (m, 2H), 3.34–3.26 (m, 2H), 3.20 (dd, J = 17.0, 12.2 Hz, 1H), 3.04 (dq, J = 14.1, 6.9 Hz, 2H), 2.80 (dd, J = 17.0, 3.1 Hz, 1H), 2.16–2.07 (m, 2H), 2.02 (dq, J = 12.4, 6.7, 4.7 Hz, 2H), 1.95 (d, J = 6.1 Hz, 6H), 1.87 (dt, J = 14.8, 7.4 Hz, 2H); 13 13C-NMR (151 MHz, DMSO) δ 197.15, 162.94, 158.88, 158.69, 157.69, 131.87, 128.34, 114.95, 103.79, 103.05, 102.21, 78.11, 65.23, 53.80, 51.91, 42.45, 25.79, 23.08, 8.70, 8.05; MS (ESI) m / z 410.76 ([M-H]-).

[0093] (9) During the synthesis of compound C3, R3 in intermediate 4 is R4 is independently n = 3, the eluent is a mixed solution of dichloromethane and methanol with a volume ratio of 40:1, and the remaining steps are carried out according to the general method for the synthesis of the target compound in step 5.

[0094] The chemical formula of compound C3, 1 1H-NMR, 13 13C-NMR and MS data are as follows:

[0095]

[0096] Yellow solid, yield: 30%; mp: 110 - 111 °C; 1H-NMR (600 MHz, CDCl3) δ 12.24 (s, 1H), 7.63–7.56 (m, 1H), 7.37–7.30 (m, 1H), 7.07 (t, J = 7.5 Hz, 1H), 6.90 (d, J = 8.2 Hz, 1H), 5.62 (dd, J = 13.1, 2.7 Hz, 1H), 4.12 (t, J = 5.7 Hz, 2H), 3.09 (t, J = 7.7 Hz, 6H), 2.94 (dd, J = 17.0, 13.1 Hz, 1H), 2.82 (dd, J = 17.0, 2.9 Hz, 1H), 2.32 (dt, J = 13.4, 6.4 Hz, 2H), 2.08 (d, J = 2.8 Hz, 6H), 2.04 (t, J = 7.6 Hz, 4H); 13 C-NMR (151 MHz, CDCl3) δ 196.90, 161.69, 159.23, 157.96, 154.73, 129.57, 127.38, 126.49, 121.43, 111.44, 103.54, 102.55, 102.51, 74.42, 65.27, 53.99, 53.20, 42.41, 26.55, 23.36, 8.02, 7.21; MS (ESI) m / z 410.52 ([M-H]-).

[0097] (10) In the synthesis of compound D1, R3 in intermediate 4 is R4 independently is n = 3, the eluent is a mixed solution of dichloromethane and methanol with a volume ratio of 30:1, and the remaining steps are carried out according to the general synthesis method of the target compound in step 5.

[0098] The chemical formula of compound D1, 1 H-NMR, 13 C-NMR and MS data are as follows:

[0099]

[0100] Yellow solid, yield: 72%; mp: 131 - 132 °C; 11H-NMR (600 MHz, DMSO-d6) δ 12.37 (s, 1H), 7.32 (t, J = 8.1 Hz, 1H), 7.06 (d, J = 6.5 Hz, 2H), 6.91 (dd, J = 8.2, 1.7 Hz, 1H), 5.49 (dd, J = 12.1, 3.1 Hz, 1H), 4.01 (d, J = 12.8 Hz, 2H), 3.14 (dd, J = 17.0, 12.1 Hz, 1H), 2.83 (dd, J = 17.0, 3.2 Hz, 1H), 2.43 (t, J = 7.2 Hz, 2H), 2.38 (s, 4H), 1.97 (s, 3H), 1.96 (s, 3H), 1.88 (p, J = 6.6 Hz, 2H), 1.50 (p, J = 5.5 Hz, 4H), 1.42–1.34 (m, 2H); 13 13C-NMR (151 MHz, DMSO-d6) δ 196.44, 163.80, 159.20, 158.93, 157.49, 141.27, 130.12, 118.68, 114.62, 112.90, 103.91, 103.17, 101.95, 78.18, 66.38, 55.49, 54.44, 42.61, 26.56, 25.86, 24.42, 8.76, 8.10; MS (ESI) m / z 424.31 ([M-H]−).

[0101] (11) During the synthesis of compound D2, R3 in intermediate 4 is R4 is independently n = 3, the eluent is a mixed solution of dichloromethane and methanol with a volume ratio of 30:1, and the remaining steps are carried out according to the general synthetic method of the target compound in step 5.

[0102] The chemical formula of compound D2, 1 1H-NMR, 13 13C-NMR and MS data are as follows:

[0103]

[0104] Yellow solid, yield: 35%; mp: 186 - 187 °C; 11H-NMR (600 MHz, DMSO-d6) δ 12.37 (s, 1H), 7.44 (d, J = 8.7 Hz, 2H), 6.98 (d, J = 8.7 Hz, 2H), 5.48 (dd, J = 12.2, 3.0 Hz, 1H), 4.05 (t, J = 6.1 Hz, 2H), 3.20 (dd, J = 17.0, 12.3 Hz, 1H), 3.01–2.81 (m, 6H), 2.79 (dd, J = 17.0, 3.1 Hz, 1H), 2.11–2.03 (m, 2H), 1.95 (d, J = 6.6 Hz, 6H), 1.72–1.64 (m, 4H), 1.49 (s, 2H); 13 13C-NMR (151 MHz, DMSO-d6) δ 197.13, 163.01, 158.93, 158.88, 157.77, 131.65, 128.33, 114.92, 103.78, 103.05, 102.18, 78.16, 65.97, 54.64, 53.45, 42.47, 25.12, 24.31, 23.08, 8.74, 8.08; MS (ESI) m / z 424.38 ([M-H]-).

[0105] (12) During the synthesis of compound D3, R3 in intermediate 4 is R4 is independently n = 3, the eluent is a mixed solution of dichloromethane and methanol with a volume ratio of 36:1, and the remaining steps are carried out according to the general synthesis method of the target compound in step 5.

[0106] The chemical formula of compound D3, 1 1H-NMR, 13 13C-NMR and MS data are as follows:

[0107]

[0108] Yellow solid, yield: 45%; mp: 82.7 - 84 °C; 1H-NMR(600 MHz, DMSO-d6) δ 12.36 (s, 1H), 7.53 (d, J = 7.3 Hz, 1H), 7.37–7.30 (m, 1H), 7.09–6.99 (m, 2H), 5.66 (dd, J = 12.8, 2.8 Hz, 1H), 4.03 (tt, J = 9.5, 4.6 Hz, 2H), 3.10 (dd, J = 17.0, 12.8 Hz, 1H), 2.75 (dd, J = 17.0, 2.9 Hz, 1H), 2.38 (t, J = 7.2 Hz, 2H), 2.29 (s, 4H), 1.97 (s, 3H), 1.96 (s, 3H), 1.86 (p, J = 6.4 Hz, 2H), 1.45 (p, J = 5.5 Hz, 4H), 1.37–1.31 (m, 2H); 13 C-NMR(151 MHz, DMSO-d6) δ 196.77, 163.68, 158.94, 157.96, 155.84, 129.94, 127.63, 126.87, 120.96, 112.53, 103.85, 103.13, 101.82, 74.16, 66.64, 55.55, 54.43, 41.73, 26.60, 25.91, 24.47, 8.75, 8.08; MS(ESI) m / z 424.25 ([M-H]-).

[0109] (13) In the synthesis of compound E1, R3 in intermediate 4 is R4 independently is n = 3, the eluent is a mixed solution of dichloromethane and methanol with a volume ratio of 50:1, and the remaining steps are carried out according to the general synthetic method of the target compound in step 5.

[0110] The chemical formula of compound E1, 1 H-NMR, 13 C-NMR and MS data are as follows:

[0111]

[0112] Yellow solid, yield: 50%; mp: 182 - 183 °C; 11H-NMR (600 MHz, DMSO-d6) δ 12.37 (s, 1H), 9.76 (s, 1H), 7.33 (t, J = 8.1 Hz, 1H), 7.07 (m, 2H), 6.93 (d, J = 8.3 Hz, 1H), 5.52 (dd, J = 12.1, 3.2 Hz, 1H), 4.03 (t, J = 6.4 Hz, 2H), 3.57 (t, J = 4.6 Hz, 4H), 3.19 (dd, J = 17.1, 12.2 Hz, 1H), 2.85 (dd, J = 17.1, 3.3 Hz, 1H), 2.43 (t, J = 7.2 Hz, 2H), 2.38 (s, 4H), 1.98 (s, 3H), 1.96 (s, 3H), 1.88 (q, J = 6.8 Hz, 2H); 13 13C-NMR (151 MHz, DMSO-d6) δ 196.87, 162.98, 159.20, 158.90, 157.54, 141.18, 130.14, 118.71, 114.65, 112.92, 103.87, 103.09, 102.20, 78.24, 66.63, 66.28, 55.30, 53.81, 42.61, 26.29, 8.72, 8.05; MS (ESI) m / z 426.26 ([M-H]-).

[0113] (14) In the synthesis of compound E2, R3 in intermediate 4 is R4 independently is n = 3, the eluent is a mixed solution of dichloromethane and methanol with a volume ratio of 60:1, and the remaining steps are carried out according to the general method for the synthesis of the target compound in step 5.

[0114] The chemical formula of compound E2, 1 1H-NMR, 13 13C-NMR and MS data are as follows:

[0115]

[0116] Yellow solid, yield: 50%; mp: 132 - 133 °C; 1H-NMR(600 MHz, DMSO-d6) δ 12.37 (s, 1H), 7.42 (d, J = 8.6 Hz, 2H), 6.97 (d, J = 8.6 Hz, 2H), 5.46 (dd, J = 12.3, 3.0 Hz, 1H), 4.02 (t, J = 6.3 Hz, 2H), 3.57 (t, J = 4.5 Hz, 4H), 3.18 (dd, J = 17.0, 12.3 Hz, 1H), 2.78 (dd, J = 17.0, 3.1 Hz, 1H), 2.43 (t, J = 7.2 Hz, 2H), 2.38 (s, 4H), 1.96 (s, 3H), 1.95 (s, 3H), 1.88 (p, J = 6.6 Hz, 2H); 13 C-NMR(151 MHz, DMSO-d6) δ 197.15, 162.93, 159.13, 158.89, 157.75, 131.45, 128.30, 114.88, 103.77, 103.02, 102.20, 78.20, 66.64, 66.30, 55.28, 53.81, 42.49, 26.31, 8.71, 8.05; MS(ESI) m / z 428.17 ([M+H] + )。

[0117] (15) During the synthesis of compound E3, R3 in intermediate 4 is R4 is independently n = 3, the eluent is a mixed solution of dichloromethane and methanol with a volume ratio of 50:1. For the remaining steps, refer to the general method for the synthesis of the target compound in step 5.

[0118] The chemical formula of compound E3, 1 H-NMR, 13 C-NMR and MS data are as follows:

[0119]

[0120] Yellow solid, yield: 65%; mp: 185 - 186 °C; 1 H-NMR(600 MHz, DMSO-d6) δ 12.35 (s, 1H), 9.76 (s, 1H), 7.54 (s, 1H), 7.36 (s, 1H), 7.05 (d, J = 20.2 Hz, 2H), 5.67 (d, J = 9.2 Hz, 1H), 4.06 (s, 2H), 3.53 (s, 4H), 3.12 (d, J = 11.9 Hz, 1H), 2.77 (d, J = 14.9 Hz, 1H), 2.41 (s, 2H), 2.31 (s, 4H), 1.97 (s, 6H), 1.21 (d, J = 34.1 Hz, 2H);13 C-NMR (151 MHz, DMSO-d6) δ 197.16, 162.94, 158.90, 158.00, 155.81, 129.97, 127.57, 126.84, 121.00, 112.55, 103.84, 103.07, 102.06, 74.20, 66.59, 66.53, 55.32, 53.77, 41.75, 26.26, 8.71, 8.05; MS (ESI) m / z 426.27 ([M-H] - )。

[0121] (16) During the synthesis of compound F1, R3 in intermediate 4 is R4 independently is n = 2, the eluent is a mixed solution of dichloromethane and methanol with a volume ratio of 30:1, and the remaining steps are carried out according to the general method for the synthesis of the target compound in step 5.

[0122] The chemical formula of compound F1, 1 H-NMR, 13 C-NMR and MS data are as follows:

[0123]

[0124] Yellow solid, yield: 33%; mp: 115 - 116 °C; 1 H-NMR (600 MHz, DMSO-d6) δ 12.36 (s, 1H), 7.33 (t, J = 7.9 Hz, 1H), 7.08 (d, J = 8.0 Hz, 2H), 6.94 (dd, J = 8.3, 1.9 Hz, 1H), 5.51 (dd, J = 12.1, 3.1 Hz, 1H), 4.09 (t, J = 5.9 Hz, 2H), 3.17 (dd, J = 17.0, 12.2 Hz, 1H), 2.84 (dd, J = 17.0, 3.2 Hz, 1H), 2.68 (t, J = 5.9 Hz, 2H), 2.46 (s, 4H), 1.97 (d, J = 9.7 Hz, 6H), 1.50 (p, J = 5.6 Hz, 4H), 1.41–1.36 (m, 2H); 1313C-NMR (151 MHz, DMSO-d6) δ 196.81, 163.16, 159.04, 158.90, 157.54, 141.20, 130.14, 118.80, 114.72, 112.96, 103.86, 103.10, 102.14, 78.24, 65.94, 57.70, 54.81, 42.61, 25.91, 24.28, 8.74, 8.07; MS (ESI) m / z 410.31 ([M-H]−).

[0125] (17) During the synthesis of compound F2, in intermediate 4, R3 is R4 independently is n = 2, the eluent is a mixed solution of dichloromethane and methanol with a volume ratio of 30:1. For the remaining steps, refer to the general method for the synthesis of the target compound in step 5.

[0126] The chemical formula of compound F2, 1 1H-NMR, 13 13C-NMR and MS data are as follows:

[0127]

[0128] Yellow solid, yield: 25%; mp: 180 - 181 °C; 1 1H-NMR (600 MHz, DMSO-d6) δ 12.38 (s, 1H), 7.43 (d, J = 8.7 Hz, 2H), 6.98 (d, J = 8.7 Hz, 2H), 5.47 (dd, J = 12.3, 3.0 Hz, 1H), 4.08 (t, J = 5.9 Hz, 2H), 3.20 (dd, J = 17.0, 12.3 Hz, 1H), 2.78 (dd, J = 17.0, 3.1 Hz, 1H), 2.68 (t, J = 5.9 Hz, 2H), 2.45 (s, 4H), 1.95 (d, J = 7.1 Hz, 6H), 1.50 (p, J = 5.6 Hz, 4H), 1.41–1.35 (m, 2H); 13 13C-NMR (151 MHz, DMSO-d6 δ 197.10, 163.08, 158.97, 158.89, 157.73, 131.53, 128.32, 114.93, 103.75, 103.03, 102.15, 78.18, 66.02, 57.72, 54.81, 42.47, 25.94, 24.31, 8.73, 8.07; MS (ESI) m / z410.49 ([M-H] - ).

[0129] (18) During the synthesis of compound F3, R3 in intermediate 4 is R4 is independently n = 2, the eluent is a mixed solution of dichloromethane and methanol with a volume ratio of 36:1, and the remaining steps are carried out according to the general synthetic method of the target compound in step 5.

[0130] The chemical formula of compound F3, 1 1H-NMR, 13 13C-NMR and MS data are as follows:

[0131]

[0132] Yellow solid, yield: 30%; mp: 201 - 202 °C; 1 1H-NMR (600 MHz, DMSO-d6) δ 12.38 (s, 1H), 7.63–7.49 (m, 1H), 7.36 (s, 1H), 7.08 (dd, J = 26.3, 6.4 Hz, 2H), 5.71 (d, J = 12.1 Hz, 1H), 4.31–4.14 (m, 2H), 3.17–3.10 (m, 1H), 2.86 (d, J = 15.2 Hz, 2H), 2.82 (s, 1H), 2.73–2.53 (m, 4H), 1.97 (s, 6H), 1.52 (s, 4H), 1.42–1.34 (m, 2H); 13 13C-NMR (151 MHz, DMSO-d6) δ 197.27, 162.90, 158.91, 158.03, 155.79, 141.85, 130.03, 128.74, 127.43, 126.93, 126.26, 120.96, 112.34, 103.81, 103.06, 102.12, 74.17, 67.43, 41.72, 32.12, 30.92, 8.73, 8.08; MS (ESI) m / z 410.54 ([M-H]-).

[0133] (19) During the synthesis of compound G1, R3 in intermediate 4 is R4 is independently n = 3, the eluent is a mixed solution of dichloromethane and methanol with a volume ratio of 18:1, and the remaining steps are carried out according to the general synthetic method of the target compound in step 5.

[0134] The chemical formula of compound G1, 1 1H-NMR, 13 13C-NMR and MS data are as follows:

[0135]

[0136] Yellow solid, yield: 35%; mp: 158 - 159 °C; 1 1H-NMR (600 MHz, DMSO-d6) δ 12.36 (s, 1H), 9.68 (s, 1H), 7.33 (t, J = 8.0 Hz, 1H), 7.28 (t, J = 7.5 Hz, 2H), 7.23 (d, J = 7.3 Hz, 2H), 7.19 (d, J = 7.5 Hz, 1H), 7.08 (d, J = 6.9 Hz, 2H), 6.95–6.90 (m, 1H), 5.51 (dd, J = 12.1, 2.8 Hz, 1H), 3.99 (t, J = 6.3 Hz, 2H), 3.17 (dd, J = 17.0, 12.2 Hz, 1H), 2.85 (dd, J = 17.0, 3.0 Hz, 1H), 2.75 (t, J = 7.6 Hz, 2H), 2.06–2.00 (m, 2H), 1.98 (s, 3H), 1.97 (s, 3H); 13 13C-NMR (151 MHz, DMSO-d6) δ 196.92, 162.95, 159.19, 158.90, 157.56, 141.83, 141.20, 130.16, 128.78, 126.29, 118.75, 114.67, 112.96, 103.88, 103.10, 102.22, 78.24, 67.21, 42.61, 31.96, 30.81, 8.73, 8.06; MS (ESI) m / z 417.24 ([M - H]-).

[0137] (20) During the synthesis of compound G2, R3 in intermediate 4 is R4 independently is n = 3, the eluent is a mixed solution of dichloromethane and methanol with a volume ratio of 12:1, and the remaining steps are carried out according to the general synthetic method of the target compound in step 5.

[0138] The chemical formula of compound G2, 1 1H-NMR, 13 13C-NMR and MS data are as follows:

[0139]

[0140] Yellow solid, yield: 34%; mp: 140 - 141 °C; 11H-NMR (600 MHz, DMSO-d6) δ 12.39 (s, 1H), 9.68 (s, 1H), 7.43 (d, J = 8.5 Hz, 2H), 7.29 (t, J = 7.4 Hz, 2H), 7.24 (d, J = 7.3 Hz, 2H), 7.19 (t, J = 7.1 Hz, 1H), 6.98 (d, J = 8.5 Hz, 2H), 5.47 (dd, J = 12.3, 2.6 Hz, 1H), 3.98 (t, J = 6.2 Hz, 2H), 3.21 (dd, J = 17.0, 12.5 Hz, 1H), 2.78 (dd, J = 17.1, 2.8 Hz, 1H), 2.76–2.71 (m, 2H), 2.04–2.00 (m, 2H), 1.96 (s, 3H), 1.95 (s, 3H); 13 13C-NMR (151 MHz, DMSO-d6) δ 197.22, 162.93, 159.11, 158.88, 157.76, 141.82, 131.47, 128.81, 128.35, 126.30, 114.87, 103.74, 103.01, 102.19, 78.21, 67.19, 42.47, 31.94, 30.83, 8.74, 8.07; MS (ESI) m / z 417.69 ([M-H]-).

[0141] (21) During the synthesis of compound G3, R3 in intermediate 4 is R4 is independently n = 3, the eluent is a mixed solution of dichloromethane and methanol with a volume ratio of 20:1, and the remaining steps are carried out according to the general synthetic method of the target compound in step 5.

[0142] The chemical formula of G3, 1 1H-NMR, 13 13C-NMR and MS data are as follows:

[0143]

[0144] Yellow solid, yield: 30%; mp: 166 - 167 °C; 1H-NMR(600MHz,DMSO-d6)δ12.37(s,1H),9.71(s,1H),7.54(d,J=7.1Hz,1H),7.36–7.31 (m,1H),7.23(t,J=7.5Hz,2H),7.17–7.12(m,3H),7.03(t,J=7.6Hz,2H),5.65(dd,J=12. 9,2.8Hz,1H),4.02(tt,J=9.4,4.7Hz,2H),3.16(dd,J=17.0,12.9Hz,1H),2.80(dd,J=1 7.0,2.9Hz,1H),2.72(h,J=6.3Hz,2H),2.03(q,J=6.7Hz,2H),1.98(s,3H),1.97(s,3H); 13 C-NMR(151MHz,DMSO-d6)δ197.27,162.90,158.91,158.03,155.79,141.85,130.03,128.74,127.43,126.93,126.26, 120.96,112.33,103.81,103.05,102.12,74.17,67.43,41.72,32.12,30.92,8.73,8.08; MS(ESI)m / z417.31([MH]-).

[0145] Example 2 Inhibitory activity of the compounds of the present invention on ferroptosis of HUVEC vascular endothelial cells

[0146] 1. Experimental materials:

[0147] Cell line: HUVEC human umbilical vein endothelial cells were purchased from Zhejiang Meisen Cell Technology Co., Ltd.

[0148] The ferroptosis inducer Erastin was purchased from Aladdin, RSL3 was purchased from MCE, rhododendron standard was purchased from China Food and Drug Administration, MTT was purchased from Solebol, and ECM culture medium, fetal bovine serum and double antibody were purchased from Siencell.

[0149] Test samples: the compound synthesized in Example 1 of the present invention (rhododendronine derivative) and rhododendronine.

[0150] 2. Experimental methods

[0151] HUVEC cell culture conditions: ECM culture medium + 5% fetal bovine serum + 1% primary endothelial cell culture additive + 1% double antibody (containing 10000 U / mL each of penicillin and streptomycin); 37°C, 5% CO2 incubator.

[0152] Preparation of farrerol, farrerol derivatives, ferroptosis inducer Erastin and RSL3: Weigh an appropriate amount of farrerol, farrerol derivatives, Erastin and RSL3 precisely, and prepare stock solutions with concentrations of 40 mmol / L, 40 mmol / L, 10 mmol / L, 1 mmol / L and 1 mmol / L respectively using dimethyl sulfoxide (DMSO). Dilute to the required concentration with blank ECM medium before use.

[0153] The inhibitory activities of farrerol and its derivatives on ferroptosis induced by Erastin and RSL3 in HUVEC cells were determined by MTT assay: HUVEC cells in the logarithmic growth phase were inoculated into 96-well plates for culture. After the cells adhered, the following treatments were carried out: 1. Erastin-induced ferroptosis screening model: control group, model group (Erastin 5 μmol / L), Erastin + farrerol derivative (10 μmol / L) group, Erastin + farrerol (10 μmol / L) group; 2. RSL3-induced ferroptosis screening model: control group, model group (RSL3 1 μmol / L), RSL3 + farrerol derivative (10 μmol / L) group, RSL3 + farrerol (10 μmol / L) group; 3 replicates were set for each compound. After treatment for 24 h and 12 h respectively, 10 μL of MTT solution was added to each well and cultured for another 4 h. The absorbance value at 490 nm was detected by an enzyme-labeling instrument, and the cell survival rate (%) was calculated using the following formula: A experimental group / A control group × 100%.

[0154] 3. Experimental results

[0155] The effects of farrerol and farrerol derivatives on the survival rate of HUVEC cells with ferroptosis induced by Erastin and RSL3 respectively are shown in Figure 1 A and B.

[0156] The results are as Figure 1 shown in A and B. Some of the compounds synthesized in the present invention (farrerol derivatives B3, F3, G2, G3) showed significant inhibitory effects on ferroptosis in HUVEC cells induced by Erastin and RSL3 respectively. Among them, farrerol derivative G3 showed a better inhibitory effect on ferroptosis in HUVEC cells induced by Erastin and RSL3 than farrerol, and the inhibitory effect on ferroptosis was particularly significant, with its EC 50 being 2.027 and 1.484 μmol / L respectively.

[0157] Figure 2 It indicates that the inhibitory effect of farrerol derivative G3 on ferroptosis induced by Erastin in HUVEC cells is enhanced with the increase of concentration, and the EC 50It is 2.027 μmol / L.

[0158] Figure 3 It indicates that the inhibition of ferroptosis of HUVEC cells induced by RSL3 by farrerol derivative G3 is enhanced with the increase of concentration, and the EC 50 is 1.484 μmol / L.

[0159] Although the preferred embodiments of the present invention have been described, those skilled in the art can make additional changes and modifications once they learn the basic creative concept. Therefore, the appended claims are intended to be construed as including the preferred embodiments as well as all changes and modifications falling within the scope of the present invention.

[0160] Obviously, those skilled in the art can make various changes and modifications to the present invention without departing from the spirit and scope of the present invention. Thus, if these modifications and variations of the present invention fall within the scope of the claims of the present invention and their equivalent technologies, the present invention is also intended to include these modifications and variations.

Claims

1. A farrerol derivative, characterized in that, The rhododendrin derivative has the structure shown below: , , or 。 2. The preparation method of the farrerol derivative according to claim 1, characterized in that, Including: Intermediate 3, Intermediate 4, boric acid, L-proline and magnesium oxide are added to glycerol, and after mixing evenly, the temperature is raised to 105-115 °C for reaction. After the reaction is completed, a reaction product is obtained. The reaction product is separated and purified to obtain the rhododendrin derivative; The structural formula of the Intermediate 3 is as follows: ； The general structural formula of the Intermediate 4 is as follows: ； wherein, R3 is ; R4 is .

3. The preparation method according to claim 2, wherein The molar ratio of the Intermediate 3, Intermediate 4, boric acid, L-proline and magnesium oxide is 0.5-1.5:3.5-4.5:2.5-3.5:0.5-1.5:1.5-2.5; the volume of the glycerol is 0.5-1.5 mL.

4. The preparation method according to claim 2, characterized in that, The reaction time is 3-7 h.

5. The preparation method according to claim 2, characterized in that, The separation and purification includes: dissolving the reaction product with ethanol, then adding silica gel for sample mixing, then rotary evaporation under reduced pressure and silica gel column chromatography, and then eluting with an eluent to obtain a liquid. The liquid is rotary evaporated under reduced pressure to obtain a solid powder, which is the rhododendrin derivative.

6. Use of the rhododendrin derivative according to claim 1 in the preparation of an inhibitor of ferroptosis in vascular endothelial cells.

7. Use of the rhododendrin derivative according to claim 1 in the preparation of a drug for preventing or treating ferroptosis-related cardiovascular diseases.

8. The application according to claim 7, characterized in that The ferroptosis-related cardiovascular diseases are atherosclerosis, hypertension, coronary artery disease, peripheral artery disease, heart failure, diabetes and chronic renal failure.

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