Bird nest alkane diterpenoid compound and application thereof in preparation of medicine for treating Alzheimer disease

Abstract

The invention belongs to the technical field of medical microbial chemistry. The invention discloses a bird nest alkane diterpenoid compound with remarkable neuroinflammation resisting activity, neurotrophic protection effect, AD resisting activity and anti-aging activity. The bird nest alkane diterpenoid compound has the following structural formula. Wherein R < 1 > is COOH, COOCH3, CH2OH or CH3; r < 2 > is CH2OH or COOH; r3 is OH or H; r4 is H or = O; and C12 and C13 are single bonds or double bonds.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical microbial chemistry technology. Background Technology

[0002] Alzheimer's disease (AD), also known as senile dementia, is a common neurodegenerative disease in the elderly. Patients experience a gradual decline in brain function, leading to cognitive decline, emotional and personality changes, and ultimately severely impacting daily life. AD often occurs alongside aging, and the risk increases significantly with age. However, our understanding of the pathogenesis of AD is very limited. Known possible mechanisms include cholinergic dysfunction, Aβ (β-amyloid) plaques, tau protein aggregation, inflammation, DNA damage, and mitochondrial dysfunction. Current treatment strategies primarily focus on restoring neurotransmitter levels in the brain. Clinically used AD drugs, such as acetylcholinesterase inhibitors (donepezil, galantamine, and levamisole), have limited ability to improve disease progression. The unclear pathogenesis, complex causes, long and progressive course of AD severely restrict the development of anti-AD drugs. Summary of the Invention

[0003] In view of this, one object of the present invention is to provide a strychnine diterpenoid compound with excellent anti-AD activity. The strychnine diterpenoid compound has a typical strychnine diterpenoid skeleton structure, the general formula of which conforms to the following structure;

[0004]

[0005] in:

[0006] R1 is COOH, COOCH3, CH2OH, or CH3;

[0007] R2 is CH2OH or COOH;

[0008] R3 is OH or H;

[0009] R4 is H or =O;

[0010] There is a single or double bond between C12 and C13.

[0011] The present invention also provides a method for preparing the compound, comprising the following steps:

[0012] 1) A culture of Cyathus striatus CGMCC NO 5.1147 was obtained by culturing the strain in rice medium. The Cyathus striatus culture was subjected to three ultrasonic extractions after soaking in ethyl acetate and one ultrasonic extraction after soaking in ethanol, with each ultrasonic extraction lasting 1 hour. The organic phases were combined. The organic phase was concentrated using a vacuum rotary evaporator to obtain the total extract, which was then dissolved in ethyl acetate, filtered, and the filtrate was concentrated to obtain the extract.

[0013] 2) The extract (CS) was separated by normal silica gel column chromatography and eluted by dichloromethane-methanol gradient (v / v 50:1, 25:1, 10:1, 5:1, 0:100), yielding a total of 21 sub-fractions. Each gradient elution was 3 column volumes. After TLC and HPLC analysis, fractions with similar analytical results were combined into four fractions (CS-1 to CS-4). Bird's nest diterpenoids were found in fractions CS-2 and CS-3.

[0014] 3) The CS-2 obtained by gradient elution of dichloromethane-methanol (v / v 25:1) was subjected to gradient elution with 10%-100% methanol / acid water (0.1‰ trifluoroacetic acid added to the water, the same below) for 3 column volumes per elution, and 4 sub-fractions CS-2-A to D were obtained.

[0015] CS-2-A was separated by HPLC using a C8 semi-preparative column under the conditions of 35% acetonitrile and acid aqueous solution, followed by isocratic elution to obtain compound 10 (12.2 mg, t). R =22.9min).

[0016] CS5-2-B was separated by HPLC using a C8 semi-preparative column under the conditions of 33% acetonitrile and acid aqueous solution, followed by isocratic elution to obtain compound 9 (8.1 mg, t). R =23.9min), compound 4 (14.1mg, t R =25.3min), compound 7 (5.1mg, t R =26.0min).

[0017] 4) CS-3 obtained by gradient elution of dichloromethane-methanol (v / v 10:1) was subjected to ODS reverse-phase column elution with 10%-100% methanol / acid water to obtain 6 sub-fractions CS-3-A to F.

[0018] CS-3-B was separated by HPLC using a C18 semi-preparative column under isocratic elution conditions of 61% methanol and acid aqueous solution to obtain compound 11 (1.5 mg, t). R =20.5min), compound 1 (4878mg, t R=27.5min), compound 2 (6957mg, t R =30.0min).

[0019] CS-3-C was separated by HPLC using a C8 semi-preparative column under the conditions of 28% acetonitrile and acid aqueous solution, followed by isocratic elution to obtain compound 5 (3 mg, t). R =24.5min) Compound 3 (2.5mg, t R =25.5min).

[0020] CS-3-E was separated by HPLC using a C8 semi-preparative column under the conditions of 32% acetonitrile and acid aqueous solution, followed by isocratic elution to obtain compound 6 (7 mg, t). R =21.6min), compound 8 (16mg, t R =24.5min).

[0021] Preferably, in step 1), the fermentation conditions are static culture at 28°C for 4 weeks;

[0022] The culture medium used for fermentation was prepared as follows: 80g rice and 120mL distilled water, sterilized at 115℃ for 30min.

[0023] Preferably, in step 2), the filler in the normal phase silica gel column has a mesh size of 200-300.

[0024] Preferably, in step 3), the packing material in the ODS reverse C18 column has a size of 50 μm.

[0025] Preferably, in step 4), the packing material in the ODS reverse C18 column has a size of 50 μm.

[0026] The present invention also provides the application of the compound in the preparation of anti-neuroinflammatory and neurotrophic drugs, the preparation of Alzheimer's disease drugs, the preparation of drugs for delaying and / or improving aging, anti-neuroinflammatory activity, enhancing the activity of neurotrophic factors, and exercising neurotrophic activity by promoting synaptic growth.

[0027] In addition, products containing the above-mentioned diterpenoid compounds with excellent antibacterial activity (especially compounds shown in Formulas I-XI) or containing compositions of the above-mentioned compounds, as well as products with antineuritis, neurotrophic, anti-AD, and anti-aging activities, are also within the scope of protection of this invention.

[0028] In this invention, the anti-AD product may further include pharmaceutically permissible diluents, excipients, fillers, binders, wetting agents, disintegrants, absorption enhancers, surfactants, adsorbent carriers, lubricants, synergists, additives, and solvents. In preparing the anti-AD product, an effective dose of the compound can be mixed with pharmaceutically permissible diluents, excipients, fillers, binders, wetting agents, disintegrants, absorption enhancers, surfactants, adsorbent carriers, lubricants, synergists, additives, and solvents to prepare various pharmaceutical formulations. The drug may be in the form of oral preparations such as tablets, capsules, soft capsules, powders, granules, fine granules, liquids, pills, emulsions, or suspensions, or in non-oral preparations such as injections (e.g., powders, solutions, oils), suppositories, ointments, plasters, patches, sprays, tinctures, or eye drops. These preparations can all be obtained using preparation methods well-known and commonly used by those skilled in the art. The routes of administration may be oral, transdermal, intravenous, or intramuscular injection.

[0029] The present invention has the following beneficial effects:

[0030] This invention discloses a class of nidulan diterpenoid structures isolated from the fermentation products of *Cyathus striatus* CGMCC NO. 5.1147. These structures exhibit excellent activity in combating neuroinflammation, neurotrophic activity, anti-Alzheimer's disease, and delaying aging. The compounds provided by this invention possess anti-neuroinflammatory activity, exert neurotrophic activity by promoting synaptic growth, specifically reduce or eliminate β-amyloid (Aβ) deposition, significantly improve Aβ-toxicity-induced paralysis in nematodes, and markedly enhance nematode motility. Furthermore, they can improve motor function, learning and memory abilities in aged mice, reduce anxiety, and enhance cognitive function in aged mice, providing a new direction for the drug treatment of Alzheimer's disease. Attached Figure Description

[0031] Figure 1 This is the 1H NMR spectrum of compound 1 (dissolved in DMSO-d6, 500MHz).

[0032] Figure 2 This is the carbon NMR spectrum of compound 1 (dissolved in DMSO-d6, 125 MHz).

[0033] Figure 3 This is the 1H NMR spectrum of compound 2 (dissolved in DMSO-d6, 500MHz).

[0034] Figure 4 This is the carbon NMR spectrum of compound 2 (dissolved in DMSO-d6, 125 MHz).

[0035] Figure 5This is the 1H NMR spectrum of compound 3 (dissolved in DMSO-d6, 500MHz).

[0036] Figure 6 This is the carbon NMR spectrum of compound 3 (dissolved in DMSO-d6, 125 MHz).

[0037] Figure 7 This is the 1H NMR spectrum of compound 4 (dissolved in DMSO-d6, 500MHz).

[0038] Figure 8 This is the carbon NMR spectrum of compound 4 (dissolved in DMSO-d6, 125 MHz).

[0039] Figure 9 This is the 1H NMR spectrum of compound 5 (dissolved in DMSO-d6, 500MHz).

[0040] Figure 10 This is the carbon NMR spectrum of compound 5 (dissolved in DMSO-d6, 125 MHz).

[0041] Figure 11 This is the 1H NMR spectrum of compound 6 (dissolved in DMSO-d6, 500MHz).

[0042] Figure 12 This is the carbon NMR spectrum of compound 6 (dissolved in DMSO-d6, 125 MHz).

[0043] Figure 13 This is the 1H NMR spectrum of compound 7 (dissolved in DMSO-d6, 500MHz).

[0044] Figure 14 This is the carbon NMR spectrum of compound 7 (dissolved in DMSO-d6, 125 MHz).

[0045] Figure 15 This is the 1H NMR spectrum of compound 8 (dissolved in DMSO-d6, 500MHz).

[0046] Figure 16 This is the carbon NMR spectrum of compound 8 (dissolved in DMSO-d6, 125 MHz).

[0047] Figure 17 This is the 1H NMR spectrum of compound 9 (dissolved in DMSO-d6, 500MHz).

[0048] Figure 18 This is the carbon NMR spectrum of compound 9 (dissolved in DMSO-d6, 125 MHz).

[0049] Figure 19This is the 1H NMR spectrum of compound 10 (dissolved in DMSO-d6, 500MHz).

[0050] Figure 20 This is the carbon NMR spectrum of compound 10 (dissolved in DMSO-d6, 125 MHz).

[0051] Figure 21 This is the 1H NMR spectrum of compound 11 (dissolved in DMSO-d6, 500MHz).

[0052] Figure 22 This is the carbon NMR spectrum of compound 11 (dissolved in DMSO-d6, 125 MHz).

[0053] Figure 23 This is a microscopic image of NGF-induced neural synapse growth in PC-12 cells, scale bar = 50 μm.

[0054] Figure 24 This is a microscopic image of the amount of Aβ deposits in CL2331 nematodes induced by the toxicity of the compound to Aβ, scale bar = 10 μm. Detailed Implementation

[0055] To make the purpose and content of this invention clearer, the applicant will now describe the technical solution of this invention clearly and completely with reference to specific embodiments. The following embodiments are further illustrations of this invention, and not limitations thereof.

[0056] Unless otherwise specified, the experimental methods used in the following examples are conventional methods.

[0057] Unless otherwise specified, all materials and reagents used in the following examples are commercially available.

[0058] Unless otherwise specified, the quantitative experiments in the following examples are all repeated three times, and the results are averaged.

[0059] Example 1: Preparation of Fermentation Product

[0060] The strain used in this patent, Cyathus striatus, with the number CGMCC NO.5.1147, was purchased from the China General Microbiological Culture Collection Center (CGMCC).

[0061] The potato glucose medium (PDB medium) used in the patent: Peel 200g of potatoes, cut them into small strips and put them in an aluminum pot. Add 1000mL of water and boil for about 20-30 minutes until the potatoes are soft but not mushy. Filter the mixture through 6-8 layers of gauze, put the filtrate in the pot, add water to 1000mL, add 20g of glucose, and sterilize at 121℃ for 30 minutes.

[0062] Potato Dextrose Agar Medium (PDA Medium): Add 18g of agar to 1000mL of PDB medium and melt. Sterilize at 121℃ for 30min. Pour into 9cm diameter plates for later use.

[0063] Fermentation medium preparation: 80g rice and 120mL distilled water, sterilized at 115℃ for 30 minutes.

[0064] Seed culture preparation: *Heterotrophic purpureus* was inoculated onto several PDA plates for activation. After the bacteria on the plates showed good growth, they were inoculated into PDB medium and cultured at 28°C and 150 rpm for 7 days to obtain the seed culture. The seed culture was then inoculated into rice culture medium, and 16 kg of rice culture medium was co-fermented. The mixture was cultured at 25°C for 28 days.

[0065] The culture of *Eriocaulon rubrum* was subjected to three ultrasonic extractions after soaking in ethyl acetate and one ultrasonic extraction after soaking in ethanol, with each ultrasonic extraction lasting 1 hour. The organic phases were combined. The organic phase was concentrated using a vacuum rotary evaporator to obtain the total extract, which was then dissolved in a large amount of ethyl acetate, filtered, and concentrated to obtain the extract (number CS, 287g).

[0066] Example 2: Preparation of compounds 1-11

[0067] The extract (CS) was separated by normal silica gel column chromatography and eluted by dichloromethane-methanol gradient (v / v 50:1, 25:1, 10:1, 5:1, 0:100), yielding a total of 21 sub-fractions. After TLC and HPLC analysis, fractions with similar analytical results were combined into four fractions (CS-1 to CS-4). Bird's nest diterpenoids were found in fractions CS-2 and CS-3.

[0068] The CS-2 obtained by gradient elution of dichloromethane-methanol (v / v 25:1) was subjected to gradient elution with 10%-100% methanol / acid water (0.1‰ trifluoroacetic acid added to the water, the same below) for 3 column volumes per elution, and four sub-fractions CS-2-A to D were obtained.

[0069] CS-2-A was separated by HPLC using a C8 semi-preparative column under the conditions of 35% acetonitrile and acid aqueous solution, followed by isocratic elution to obtain compound 10 (12.2 mg, t). R =22.9min).

[0070] CS5-2-B was separated by HPLC using a C8 semi-preparative column under the conditions of 33% acetonitrile and acid aqueous solution, followed by isocratic elution to obtain compound 9 (8.1 mg, t). R =23.9min), compound 4 (14.1mg, t R=25.3min), compound 7 (5.1mg, t R =26.0min).

[0071] CS-3 obtained by gradient elution of dichloromethane-methanol (v / v 10:1) was subjected to ODS reverse-phase column elution with 10%-100% methanol / acid water gradient elution to obtain 6 sub-fractions CS-3-A to F.

[0072] CS-3-B was separated by HPLC using a C18 semi-preparative column under isocratic elution conditions of 61% methanol and acid aqueous solution to obtain compound 11 (1.5 mg, t). R =20.5min), compound 1 (4878mg, t R =27.5min), compound 2 (6957mg, t R =30.0min).

[0073] CS-3-C was separated by HPLC using a C8 semi-preparative column under the conditions of 28% acetonitrile and acid aqueous solution, followed by isocratic elution to obtain compound 5 (3 mg, t). R =24.5min), compound 3 (2.5mg, t R =25.5min).

[0074] CS-3-E was separated by HPLC using a C8 semi-preparative column under the conditions of 32% acetonitrile and acid aqueous solution, followed by isocratic elution to obtain compound 6 (7 mg, t). R =21.6min), compound 8 (16mg, t R =24.5min).

[0075] Example 3: Structural identification and physicochemical properties of compounds 1-11

[0076] The structures of compounds were resolved using high-resolution mass spectrometry (HR-ESI-Mass), ultraviolet spectroscopy (UV), infrared chromatography (IR), circular dichroism (ECD), specific rotation chromatography, nuclear magnetic resonance (NMR), computational chemistry, and X-ray single-crystal diffraction. In short, high-resolution mass spectrometry was used to determine the molecular weight and possible molecular formula of the compounds, combined with the compounds'... 1 H and 13 C10 NMR determines the number of carbon, hydrogen, and oxygen atoms in a compound, thus determining its molecular formula. Analysis of the compound's NMR data includes... 1 H and 13 C10 NMR was used to preliminarily determine the structural fragments of the compound; and HSQC was used to confirm the direct C-H correlation of the compound; through 1 H- 1H COSY determined the correlation between protons and hydrogens in the coupling system of the compound; HMBC determined the coupling information between protons and carbon in 2-3 bonds of the compound. The planar structure of the compound was determined by combining the molecular formula, and the relative configuration was determined by ROESY. X-ray single crystal diffraction, computational chemistry and other methods were used to further determine the structure and absolute configuration of the compound.

[0077] Compound 1, cyastriatin A, is a white amorphous powder. [α] 25 D +70.99 (c 1.0, methanol); CD (c 0.69 × 10⁻⁶) -3 M, methanol)λ max (Δε):224(+39.64); UV(methanol)λ max nm(logε): represents terminal absorption; IR(neat)ν max :3383, 2941, 2867, 1714, 1454, 1374, 1228, 1202, 1126, 1024, 1006, 833, 763, 650, 545cm -1 ;positive HR-ESI-MS m / z[M+H] + 367.2122 (Calculated value is C) 20 H 31 O6,367.2121), thus determining the molecular formula of the compound to be C. 20 H 30 O6; 1 H NMR(500MHz,DMSO-d6)δ1.41m(H-1),1.62m(H-1),2.13m(H-2),2.21m(H-2),2.18t(J=13.1,3.9,H-5),1.34m(H-7),1. 44m(H-7),1.45m(H-8),1.51m(H-8),1.65m(H-10),1.89td(J=13.1,4.0,H-10),4.13ddd(J=7.4,4.0,1.6,H-11),2.26 m(H-12),3.82t(J=5.2,H-13),3.42td(J=10.3,5.2,H-15),3.70m(H-15),0.91s(H-16),0.97s(H-17),3.65q(J=6.9,H -18),1.11d(J=6.9,H-19),5.60d(J=5.5,H-13-OH),4.97s(H-14-OH),4.67t(J=4.9,H-15-OH),12.00br.s(H-20-OH); 13C10 NMR (125MHz, DMSO-d6) δ 39.1 (C-1), 29.6 (C-2), 132.0 (C-3), 139.3 (C-4), 37.3 (C-5), 42.6 (C-6), 28.7 (C-7), 36.6 (C-8), 47.7 (C-9), 25.9 (C-10), 71.9 (C-11), 54.5 (C-12), 69.9 (C-13), 104.4 (C-14), 58.9 (C-15), 12.7 (C-16), 23.6 (C-17), 37.5 (C-18), 16.6 (C-19), 175.0 (C-20). Crystal data: Space group P21; Cell parameters Number of molecules per unit cell Z = 2; μ = 0.823 mm -1 F(000) = 416.0; cell size 0.36 × 0.07 × 0.01 mm 3 The values ​​of R1 and wR2 are 0.0350 (0.0374) and 0.0898 (0.0922), respectively; the Flack constant is 0.02 (8). The compound single crystal data are stored at the Cambridge Crystallographic Data Centre, number 2384747.

[0078] Based on the above data, the structure of the compound is determined as shown in Formula I, and its 1H and 1C NMR spectra (solvent: DMSO-d6) are shown below. Figure 1 and 2 .

[0079]

[0080] Compound 2, cyastriatin B, is a white amorphous powder. [α] 25 D +67.99 (c 1.0, methanol); CD (c 0.69 × 10⁻⁶) -3 M, methanol)λ max (Δε):224(+73.44);UV(methanol)λ max nm(logε): represents terminal absorption; IR(neat)ν max :3413, 3215, 2944, 2885, 2833, 1714, 1681, 1556, 1454, 1374, 1338, 1225, 1196, 1091, 1029, 988, 837, 761, 643cm -1 ;positive HR-ESI-MS m / z[M+H] +367.2121 (Calculated value is C) 20 H 31 O6,367.2121), thus determining the molecular formula of the compound to be C. 20 H 30 O6; 1 H NMR(500MHz,DMSO-d6)δ1.41m(H-1),1.62m(H-1),2.13m(H-2),2.21m(H-2),2.24d(J=12.6,H-5),1.38m(H-7), 1.47m(H-7),1.46m(H-8),1.52m(H-8),1.49m(H-10),1.93td(J=12.6,3.5,H-10),4.08m(H-11),2.10m(H-12), 4.23dd(J=7.7,5.9,H-13),3.27td(J=10.4,5.8,H-15),3.59m(H-15),0.90s(H-16),0.99s(H-17),3.63m(H-18 ),1.11d(J=6.9,H-19),5.50d(J=5.9,H-13-OH),4.94s(H-14-OH),4.31t(J=5.3,H-15-OH),11.98s(H-20-OH); 13 C10 NMR (125MHz, DMSO-d6) δ 39.3 (C-1), 29.5 (C-2), 132.0 (C-3), 139.7 (C-4), 37.1 (C-5), 42.3 (C-6), 29.1 (C-7), 36.6 (C-8), 47.7 (C-9), 30.5 (C-10), 74.0 (C-11), 48.1 (C-12), 68.0 (C-13), 105.6 (C-14), 60.0 (C-15), 12.5 (C-16), 23.5 (C-17), 37.5 (C-18), 16.4 (C-19), 175.0 (C-20). Crystal data: Space group P212121; Cell parameters 3 Number of molecules per unit cell Z = 4; μ = 0.751 mm -1 F(000) = 792.0; Cell size 0.21 × 0.08 × 0.06 mm 3 The values ​​of R1 and wR2 are 0.0319 (0.0347) and 0.0834 (0.0855), respectively; the Flack constant is -0.10 (7). The compound single crystal data are stored in the Cambridge Crystallographic Data Centre with the number 2384749.

[0081] Based on the above data, the structure of the compound is determined as shown in Formula II, and its 1H and 1C NMR spectra (solvent: DMSO-d6) are shown below. Figure 3 and 4 .

[0082]

[0083] Compound 3, cyastriatin C, is a white amorphous powder. [α] 25 D -11.0 (c 1.0, methanol); CD (c 0.69×10) -3 M, methanol)λ max (Δε):228,(-0.52);UV(methanol)λ max nm(logε): represents terminal absorption; IR(neat)ν max :3415, 2946, 1681, 1455, 1202, 1140, 1023, 836, 760, 689cm -1 ;positive HR-ESI-MS m / z[M+H] + 367.2132 (calculated value is C) 20 H 31 O6,367.2121), thus determining the molecular formula of the compound to be C. 20 H 30 O6; 1 HNMR(500MHz,DMSO-d6)δ1.37m(H-1),1.62m(H-1),2.06m(H-2),2.31m(H-2),2.17m(H-5),1.35m(H-7 ),1.46m(H-7),1.44m(H-8),1.51m(H-8),1.31m(H-10),2.18m(H-10),4.06m(H-11),2.09m(H-12),4.2 2dd(7.6,5.2)(H-13),3.27td(J=10.2,4.1,H-15),3.59m(H-15),0.90s(H-16),0.98s(H-17),3.62dd( J=14.2,7.3,H-18),1.02d(J=7.0,H-19),5.52d(J=5.9,H-13-OH),4.92s(H-14-OH),4.34s(H-15-OH); 13C NMR (125MHz, DMSO-d6) δ39.4(C-1),30.0(C-2),132.0(C-3),140.0(C-4),37.1(C-5),42.7(C-6),29.3(C-7),36.8(C-8),47.6(C-9),30.6( C-10),74.0(C-11),48.1(C-12),68.1(C-13),105.7(C-14),60.1(C-1 5),12.5(C-16),23.7(C-17),37.7(C-18),15.7(C-19),175.6(C-20).

[0084] Based on the above data, the structure of the compound is determined as shown in Formula III, and its 1H and 1C NMR spectra (solvent: DMSO-d6) are shown below. Figure 5 and 6 .

[0085]

[0086] Compound 4, 20-O-methyl-cyastriatin B, is a white amorphous powder. [α] 25 D 52.99 (c 1.0, methanol); CD (c 0.69×10) -3 M, methanol)λ max (Δε):224(+29.11); UV(methanol)λ max nm(logε): represents terminal absorption; IR(neat)ν max :3417, 2946, 2862, 1736, 1681, 1649, 1556, 1454, 1374, 1338, 1200, 1087, 1024, 995, 839, 767, 654, 533cm -1 ;positive HR-ESI-MS m / z[M+H] + 381.2279 (calculated value is C) 21 H 33 O6,381.2277), thus determining the molecular formula of the compound to be C. 21 H 32 O6; 1H NMR(500MHz,DMSO-d6)δ1.41m(H-1),1.62m(H-1),2.02m(H-2),2.18m(H-2),2.23m(H-5),1.37m(H-7),1.46m(H -7),1.46m(H-8),1.52m(H-8),1.43m(H-10),1.93td(J=12.6,3.5,H-10),4.08m(H-11),2.11m(H-12),4.23dd( J=7.6,5.8,H-13),3.27td(J=10.2,4.8,H-15),3.59m(H-15),0.90s(H-16),0.99s(H-17),3.73q(J=6.9,H-18) ,1.14d(J=6.9,H-19),5.50d(J=5.9,H-13-OH),4.95s(H-14-OH),4.30t(J=5.4,H-15-OH),3.55s(H-20-OCH3); 13 C NMR(125MHz,DMSO-d6)δ39.4(C-1),29.6(C-2),131.5(C-3),140.1(C-4), 37.1(C-5),42.4(C-6),29.1(C-7),36.6(C-8),47.7(C-9),30.5(C-10),74 .0(C-11),48.1(C-12),68.0(C-13),105.6(C-14),60.0(C-15),12.5(C-16 ),23.6(C-17),37.5(C-18),16.4(C-19),174.0(C-20),51.5(C-20-OCH3).

[0087] Based on the above data, the structure of the compound was determined as shown in Formula IV, and its 1H and 1C NMR spectra (solvent: DMSO-d6) are shown below. Figure 7 and 8 .

[0088]

[0089] Compound 5, cyastriatin D, is a white amorphous powder. [α] 25 D -12.0 (c 1.0, methanol); CD (c 0.69×10 -3 M, methanol)λ max (Δε):220(+8.07), 249(-0.92); UV(methanol)λ max nm(logε): represents terminal absorption; IR(neat)νmax :3382, 2940, 2877, 1676, 1450, 1378, 1203, 1140, 1023, 985, 723, 601cm -1 ;positive HR-ESI-MS m / z[M+H] + 353.2330 (Calculated value is C) 20 H 33 O5,353.2328), thus determining the molecular formula of the compound to be C. 20 H 32 O5; 1 H NMR(500MHz,DMSO-d6)δ1.34m(H-1),1.58m(H-1),2.09m(H-2),2.20m(H-2),2.13m(H-5),1.30m(H-7),1.40m(H-7),1 .41m(H-8),1.49m(H-8),1.51m(H-10),2.02td(J=12.9,3.9,H-10),4.10ddd(J=7.2,3.9,1.6,H-11),2.23m(H-12),3 .80t(J=5.3,H-13),3.40m(H-15),3.70m(H-15),0.92s(H-16),0.94s(H-17),2.84m(H-18),0.85d(J=6.7,H-19),3.1 9m(H-20), 3.34m(H-20), 5.63d(J=5.4,H-13-OH), 4.92s(H-14-OH), 4.69t(J=4.8,H-15-OH), 4.43t(J=5.9,H-20-OH); 13 C NMR (125MHz, DMSO-d6) δ39.5(C-1),29.4(C-2),135.7(C-3),138.1(C-4),37.4(C-5),42.5(C-6),28.9(C-7),36.8(C-8),47.4(C-9),26.4( C-10),72.0(C-11),54.5(C-12),69.9(C-13),104.6(C-14),59.0(C- 15),12.9(C-16),23.7(C-17),34.5(C-18),15.8(C-19),65.7(C-20).

[0090] Based on the above data, the structure of the compound is determined as shown in Formula V, and its 1H and 1C NMR spectra (solvent: DMSO-d6) are shown below. Figure 9 and 10 .

[0091]

[0092] Compound 6, cyastriatin E, is a yellow oil. [α] 25 D -6.0 (c 1.0, methanol); CD (c 0.69×10) -3 M, methanol)λ max (Δε):213(-0.03), 228(+0.08); UV(methanol)λ max nm(logε): represents terminal absorption; IR(neat)ν max :3383, 2945, 2863, 1675, 1450, 1377, 1228, 1202, 1128, 1024, 982, 836, 763, 689, 619cm -1 ;positive HR-ESI-MS m / z[M+H] + 353.2326 (Calculated value is C) 20 H 33 O5,353.2328), thus determining the molecular formula of the compound to be C. 20 H 32 O5; 1 H NMR(500MHz,DMSO-d6)δ1.37m(H-1),1.61m(H-1),2.16m(H-2),2.18m(H-2),2.14m(H-5),1.32m(H-7),1.42m(H-7), 1.42m(H-8),1.49m(H-8),1.61m(H-10),1.89td(J=13.4,3.9,H-10),4.11m(H-11),2.25m(H-12),3.81t(J=5.0,H-1 3),3.41td(J=10.3,5.3,H-15),3.70m(H-15),0.92s(H-16),0.96s(H-17),2.84m(H-18),0.91d(J=6.6,H-19),3.17 m(H-20),3.27m(H-20),5.58d(J=5.5,H-13-OH),4.93s(H-14-OH),4.65t(J=4.8,H-15-OH),4.34t(J=5.2,H-20-OH); 13C NMR (125MHz, DMSO-d6) δ39.9(C-1),28.7(C-2),136.2(C-3),137.6(C-4),37.3(C-5),42.5(C-6),28.9(C-7),36.8(C-8),47.4(C-9),26.5( C-10),71.9(C-11),54.5(C-12),69.9(C-13),104.5(C-14),58.9(C- 15),12.7(C-16),24.0(C-17),34.3(C-18),16.9(C-19),64.9(C-20).

[0093] Based on the above data, the structure of the compound was determined as shown in Formula VI, and its 1H and 1C NMR spectra (solvent: DMSO-d6) are shown below. Figure 11 and 12 .

[0094]

[0095] Compound 7, cyastriatin F, is a yellow oil. [α] 25 D -36.99 (c 1.0, methanol); CD (c 0.69×10) - 3 M, methanol)λ max (Δε):206(-0.66), 223(+1.48), 255(-0.27); UV(methanol)λ max nm(logε): represents terminal absorption; IR(neat)ν max :3374, 2944, 2865, 1681, 1649, 1556, 1454, 1396, 1374, 1203, 1138, 1092, 1025, 991, 840, 798, 734, 631, 525cm -1 ;positive HR-ESI-MS m / z[M+H] + 353.2333 (Calculated value is C) 20 H 33 O5,353.2328), thus determining the molecular formula of the compound to be C. 20 H 32 O5; 1H NMR(500MHz,DMSO-d6)δ1.34m(H-1),1.58m(H-1),2.09m(H-2),2.20m(H-2),2.19m(H-5),1.35m(H -7),1.44m(H-7),1.42m(H-8),1.50m(H-8),1.31m(H-10),2.08m(H-10),4.06m(H-11),2.09m(H-12 ),4.22d(J=7.7,H-13),3.27t(J=10.3,H-15),3.59dd(J=10.3,5.3,H-15),0.92s(H-16),0.97s(H -17),2.80m(H-18),0.84d(J=6.6,H-19),3.20dd(J=10.3,8.3,H-20),3.34dd(J=10.3,6.0,H-20); 13 C NMR(125MHz, DMSO-d6)δ39.9(C-1),29.1(C-2),135.8(C-3),138.2(C-4),37.0(C-5),42.3(C-6),29.3(C-7),36.8(C-8),47.4(C-9),31.0( C-10),74.1(C-11),48.1(C-12),68.0(C-13),105.7(C-14),60.1(C- 15),12.6(C-16),23.6(C-17),34.4(C-18),15.7(C-19),65.5(C-20).

[0096] Based on the above data, the structure of the compound is determined to be as shown in Formula VII, and its 1H and 1C NMR spectra (solvent: DMSO-d6) are shown below. Figure 13 and 14 .

[0097]

[0098] Compound 8, cyastriatin G, is a yellow oil. [α] 25 D -19.0 (c 1.0, methanol); CD (c 0.69×10 - 3 M, methanol)λ max (Δε):211(-1.14), 226(+1.92), 249(-0.52); UV(methanol)λ max nm(logε): represents terminal absorption; IR(neat)ν max:3385, 2946, 2863, 1677, 1454, 1375, 1202, 1137, 1090, 1028, 993, 924, 819, 610cm -1 ;positive HR-ESI-MS m / z[M+H] + 353.2329 (Calculated value is C) 20 H 33 O5,353.2328), thus determining the molecular formula of the compound to be C. 20 H 32 O5; 1 H NMR(500MHz,DMSO-d6)δ1.38m(H-1),1.61m(H-1),2.15m(H-2),2.18m(H-2),2.19m(H-5),1.36m(H-7),1.45m(H-7) ,1.44m(H-8),1.50m(H-8),1.48m(H-10),1.92td(J=12.7,3.6,H-10),4.06m(H-11),2.09m(H-12),4.22dd(J=7.8,5 .8,H-13),3.27m(H-15),3.59m(H-15),0.91s(H-16),0.98s(H-17),2.82m(H-18),0.89d(J=6.7,H-19),3.16m(H-20 ),3.24m(H-20),5.48d(J=5.8,H-13-OH),4.90s(H-14-OH),4.31dd(J=4.3,6.0,H-15-OH),4.29t(J=5.4,H-20-OH); 13 C NMR (125MHz, DMSO-d6) δ39.7(C-1),28.5(C-2),136.3(C-3),137.9(C-4),37.1(C-5),42.3(C-6),29.2(C-7),36.8(C-8),47.4(C-9),31.1( C-10),74.1(C-11),48.2(C-12),68.0(C-13),105.6(C-14),60.0(C- 15),12.5(C-16),23.9(C-17),34.3(C-18),16.7(C-19),64.9(C-20).

[0099] Based on the above data, the structure of the compound was determined to be as shown in Formula VIII, and its 1H and 1C NMR spectra (solvent: DMSO-d6) are shown below. Figure 15 and 16 .

[0100]

[0101] Compound 9, cyastriatin H, is a white amorphous powder. [α] 25 D -17.00 (c 1.0, methanol); CD (c 0.69 × 10⁻⁶) -3 M, methanol)λ max (Δε):225(25.70), 264(-3.85); UV(methanol)λ max nm(logε): represents terminal absorption; IR(neat)ν max :3304, 2935, 2860, 1789, 1769, 1697, 1573, 1538, 1454, 1417, 1373, 1338, 1245, 1178, 1050, 1024, 981, 852, 762, 735, 656, 549cm -1 ;positive HR-ESI-MSm / z[M+NH4] + 380.2080 (calculated value is C) 20 H 26 O6NH4 + (380.2073), thus determining the molecular formula of the compound to be C 20 H 26 O6; 1 H NMR(500MHz,DMSO-d6)δ1.39m(H-1),1.61m(H-1),2.11m(H-2),2.20m(H-2),2.2 9dt(J=12.6,3.6,H-5),1.26m(H-7),1.46m(H-7),1.43m(H-8),1.48m(H-8),1.6 0m(H-10),2.05td(J=12.6,4.3,H-10),4.80br.s(H-11),6.94s(H-13),0.90s(H -16),0.91s(H-17),3.64q(J=6.9,H-18),1.12d(J=6.9,H-19),6.90s(H-14-OH); 13C NMR(125MHz,DMSO-d6)δ39.4(C-1),29.6(C-2),131.6(C-3),140.0(C-4),38.8(C-5),41.0(C-6),29.8(C-7),36.6(C-8),47.8(C-9),25.6(C- 10),76.9(C-11),138.4(C-12),142.7(C-13),109.7(C-14),164.1(C- 15),11.4(C-16),23.7(C-17),37.6(C-18),16.5(C-19),175.0(C-20).

[0102] Based on the above data, the structure of the compound was determined as shown in Formula IX, and its 1H and 1C NMR spectra (solvent: DMSO-d6) are shown below. Figure 17 and 18 .

[0103]

[0104] Compound 10, cyastriatin I, is a yellow oil. [α] 25 D -76.9 (c 1.0, methanol); CD (c 0.69×10) - 3 M, methanol)λ max (Δε):204(-18.36), 231(-2.37), 262(-8.60); UV(methanol)λ max nm(logε): represents terminal absorption; IR(neat)ν max :3381, 2934, 2860, 1700, 1639, 1450, 1376, 1255, 1184, 1083, 1050, 1025, 979, 933, 763, 721, 612cm -1 ;positive HR-ESI-MS m / z[M+H] + 349.2015 (Calculated value: C) 20 H 29 O5,349.2015) thus determined the molecular formula of the compound to be C 20 H 28 O5; 1H NMR(500MHz,DMSO-d6)δ1.34m(H-1),1.57m(H-1),2.10m(H-2),2.18m(H-2),2.24m( H-5),1.26m(H-7),1.46m(H-7),1.41m(H-8),1.47m(H-8),1.45m(H-10),2.19m(H-1 0),4.78dd(J=3.1,1.8,H-11),6.91s(H-13),0.91s(H-16),0.88s(H-17),2.82dd(J =13.6,6.7,H-18),0.85d(J=6.7,H-19),3.20m(H-20),3.35dd(J=6.2,11.0,H-20); 13 C NMR(125MHz,DMSO-d6)δ39.6(C-1),29.3(C-2),135.2(C-3),138.6(C-4),38.8(C-5),40.8(C-6),30.0(C-7),36.8(C-8),47.5(C-9),26.2(C -10),77.0(C-11),138.4(C-12),142.7(C-13),109.8(C-14),164.2(C -15),11.6(C-16),23.8(C-17),34.6(C-18),15.7(C-19),65.6(C-20).

[0105] Based on the above data, the structure of the compound is determined as shown in Formula X, and its 1H and 1C NMR spectra (solvent: DMSO-d6) are shown below. Figure 19 and 20 .

[0106]

[0107] Compound 11, cyastriatin J, is a yellow amorphous powder. [α] 25 D -69.9 (c 1.0, methanol); CD (c 0.69 × 10⁻⁶) -3 M, methanol)λ max (Δε):213(+0.45), 248(-0.62), 290(-0.11), 326(-0.27); UV(methanol)λ max nm(logε):241(4.40); IR(neat)ν max :3366, 2934, 2872, 1678, 1616, 1456, 1409, 1380, 1255, 1202, 1139, 1050, 1031, 979cm-1 ;positive HR-ESI-MS m / z[M+H] + 347.1852 (calculated value is C) 20 H 27 O5,347.1858), thus determining the molecular formula of the compound as C 20 H 26 O5; 1 H NMR(500MHz,DMSO-d6)δ2.08s(H-1),2.09s(H-1),2.72dd(J=12.5,4.1,H-5),1.42d d(J=13.8,4.6,H-7),1.49s(H-7),1.51overlap(H-8),1.68m(H-8),1.52overlap(H -10),2.29td(J=12.5,3.1,H-10),4.85s(H-11),7.03s(H-13),0.91s(H-16),1.09s (H-17),2.99m(H-18),1.11d(J=7.1,H-19),1.10d(J=6.0,H-20),12.90s(H-15-OH); 13 C NMR(125MHz,DMSO-d6)δ51.7(C-1),207.0(C-2),142.2(C-3),174.1(C-4),40.3(C-5),43.1(C-6),29.1(C-7),35.7(C-8),41.3(C-9),25.2(C -10),76.8(C-11),138.4(C-12),142.5(C-13),109.6(C-14),164.0(C -15),11.4(C-16),26.1(C-17),24.4(C-18),20.4(C-19),20.1(C-20).

[0108] Based on the above data, the structure of the compound is determined as shown in Formula XI, and its 1H and 1C NMR spectra (solvent: DMSO-d6) are shown below. Figure 21 and 22 .

[0109]

[0110] Example 4: Evaluation of the anti-inflammatory activity of compounds 1-11

[0111] The anti-inflammatory activity of compounds 1-11 was evaluated after confirming that they were non-cytotoxic to BV-2 cells.

[0112] BV-2 cells were brought to a density of approximately 70%, lysed with trypsin, and then added to DMEM medium containing 10% FBS to adjust the concentration to 5 × 10⁶ cells / day. 5 Single-cell suspensions of cells / mL were added to each well of a 96-well plate (100 μL per well) and incubated at 37°C with 5% CO2 for 24 h. The supernatant was discarded. 100 μL of DMEM medium containing LPS was added to the experimental and LPS groups, while 100 μL of DMEM medium was added to the control group. After incubation at 37°C with 5% CO2 for 2 h, different samples were added to the experimental groups. 0.5% DMSO was added to the control and LPS groups, and incubation was performed at 37°C with 5% CO2 for 24 h. NO release was evaluated using Griess' reagent. Each group was tested in triplicate. The concentrations of the compounds, hydrocortisone, and dexamethasone were 50 μM, and the LPS concentration was 100 ng / mL (*p<0.05, **p<0.01 compared to the LPS group).

[0113] Experimental results showed that, compared with the positive control group, the LPS levels of compounds 1-11 were all below 100. Therefore, all 50 μM compounds exhibited certain inhibitory activity against LPS-induced NO release from BV-2 cells, demonstrating anti-inflammatory effects (Table 1). Figure 23 ).

[0114] Table 1. Anti-inflammatory activity and neuronal synaptic growth-promoting activity of compounds (Mean ± SD)

[0115]

[0116] Example 5: Evaluation of the neurotrophic activity of compounds 1-11

[0117] Immature PC-12 cells were cultured for 72 h in DMEM medium supplemented with 10% horse serum, 5% FBS, and 100 U / mL penicillin-streptomycin in a 5% CO2, 37°C, and saturated humidity incubator. Single-cell suspensions were then prepared using serum-free DMEM medium and seeded into 24-well plates at 4 × 10⁶ cells per well. 4 The compound and NGF were dissolved in DMSO and added, with the DMSO concentration below 0.1%. After 24 hours, at least three fields of view were randomly selected under an optical microscope for observation. The proportion of cells with synapses longer than twice the length of the cell body (positive cells) was counted, observed, counted, and photographed. Each group had three replicates, with a positive control group containing only NGF. The compound concentration was 50 μM, and the NGF concentration was 20 ng / mL (*p < 0.05 compared to the NGF group).

[0118] Experimental results showed that compounds 1, 7, and 9 promoted NGF-induced synaptic growth in PC-12 cells, with effects higher than those in the NGF group, demonstrating good neurotrophic activity (Table 1). Figure 23 ).

[0119] Example 6: Evaluation of the anti-AD activity of compound 1-11 based on a nematode model

[0120] Detection of nematode motility.

[0121] The L1 phase of the same generation containing GFP fused with human Aβ 1-42 The nematode CL4176 gene was added to NGM plates coated with E. coli OP50 and dried in a clean bench before being cultured at 16°C to the L4 larval stage. The appropriate dose of the compound and E. coli OP50 suspension were added to each plate, and the plates were dried. Each plate contained 20 L4-stage nematodes, and they were cultured at 25°C for 20 hours to induce Aβ deposition. The nematodes were then transferred to 96-well plates containing M9 buffer, and their body movements were recorded and counted over 20 seconds, with one left-right movement counted as one cycle. This experiment was repeated three times. The compound concentration was 50 μM.

[0122] Detection of Aβ deposition in nematodes.

[0123] Synchronized L4 phase containing GFP fused with human Aβ 1-42 The CL2331 nematode gene was transferred to NGM plates containing different concentrations of the compound and cultured at 20°C for 24 h, then transferred to 25°C for 60 h. The nematodes from different treatment groups were then washed off with an M9 syringe to remove excess E. coli. The nematodes were centrifuged at 4200 rpm for 2 min, and washed three times, discarding the supernatant. The nematodes were transferred to a slide containing 1% agar, smothered with a specific concentration of NaN3, and photographed under a fluorescence microscope. The fluorescence intensity was analyzed using ImageJ. The compound concentration was 50 μM.

[0124] Experiments on the body wiggling frequency of nematodes showed that, under culture conditions at 25℃, treatment with 50 μM compounds 1, 2, 5, 6, and 10 increased the number of sinusoidal movements per 20 seconds in the treated groups compared to the control group, thus improving their motility (Table 2). Figure 24 ).

[0125] Treating human Aβ containing GFP fusion with compounds 1-42 Fluorescence microscopy revealed that, compared with the control group, the fluorescence of nematodes in the compound treatment groups 1, 2, 5, 6, 10, and 11 was reduced (Table 2), indicating a decrease in Aβ accumulation in their bodies.

[0126] Table 2. Evaluation of the anti-AD activity of compounds 1-11 based on the nematode model (Mean ± SD)

[0127]

[0128]

[0129] Example 7: Evaluation of behavioral indicators of compound 2 in aging model mice

[0130] Open field experiment.

[0131] First, before the experiment, it was confirmed that the OF device was clean and odorless (especially paying attention to thoroughly cleaning up any mouse feces or urine left from the previous experiment). The experimenter recorded the mouse's number, date, and status in the operating software. Next, the experimental animals were transported to a special cage in the behavioral laboratory beforehand to acclimatize to the environment for about 3 hours, minimizing animal stress. The mice were removed from the cage (with their backs to the experimenter) and placed in the center of the OF experimental device. The experimenter quickly and gently closed the OF lid and turned on the video recording system to record the mouse's activities inside the OF for a total of 5 minutes. Finally, after the experiment, the mice were returned to the cage, the experimental device was wiped with 75% ethanol, and dried with a paper towel. (n=10⁻¹⁴, *p<0.05, **p<0.01 compared to the model group)

[0132] Dark avoidance experiment.

[0133] The dark avoidance test is a common experiment used in animal behavior research to test an animal's learning and memory functions. Rodents are nocturnal animals that prefer dark places and avoid light. When a mouse attempts to escape to a dark place, and is then given an electrical stimulus in the dark, it will be forced to return to the light and retain the memory of the stimulus.

[0134] Step 1: Adaptation. Place the animal in a bright enclosure, keeping the door closed, allowing the mouse to explore freely in the light. After 30 seconds, open the door, allowing the animal to move into a dark enclosure. After 30 seconds, regardless of whether the animal entered the dark enclosure, remove the animal from the device and return it to its original cage.

[0135] Step 2: Training. Place the animal in a bright box with the door open. When the animal enters a dark box, close the door and give it a mild foot shock. After the shock, the animal remains in the dark box for an additional 30 seconds.

[0136] Step 3: Testing. Animals were placed in a bright box, the door was opened, and they were removed from the device when they entered the dark compartment. The time was recorded, and the experiment ended. The maximum time set was 300 seconds. If an animal did not pass through the door, the maximum latency of 300 seconds was recorded as the latency to enter the dark compartment, and the animal was marked as not having entered the dark compartment. (n = 10⁻¹⁴, *p < 0.05, **p < 0.01 compared to the model group).

[0137] New object recognition experiment.

[0138] The novel object recognition experiment was used to assess the cognitive memory level of mice. The behavioral program consisted of three phases: training, reactivation, and testing. In the training phase (Day 1), two identical objects A were placed on opposite sides of a test box, approximately 10 cm from the box wall. During the training period, two identical cylinders A and B were placed in the lower left and lower right corners of the test box. The mouse was placed in the test box with its back to the two objects and allowed to explore freely for 5 minutes. In the reactivation phase (Day 2), object A in the lower left corner was removed and replaced with a new cube C. The recording device was turned on, and the mouse was placed in the test box for a 5-minute object recognition test. In the testing phase (Day 3), one of the familiar objects A in the test box was randomly replaced with object B (a new object), while maintaining its position. The rat was then placed in the test box and allowed to explore freely for 5 minutes before being removed. During the testing phase, the exploration time of rats for familiar and new objects was recorded separately. The discrimination index was calculated to assess memory ability, using the formula: Discrimination Index = (New object exploration time - Old object exploration time) / (New object exploration time + Old object exploration time) × 100%. The total exploration time for both familiar and new objects was calculated to assess exploration motivation. Simultaneously, the test box floor was divided into 4×4 squares, and the number of squares traversed by the rats during the testing phase was recorded to assess spontaneous activity ability. (n = 10⁻¹⁴, *p < 0.05, **p < 0.01 compared to the model group)

[0139] Statistical analysis. Each data set was independently repeated at least three times, and the values ​​are expressed as mean ± standard error. Statistical significance between two sets of data was assessed using the Student t-test. GraphPad Prism 10 was used for statistical analysis and graphing. A p-value less than 0.05 was considered statistically significant (*P<0.05, **P<0.01, and ***P<0.001).

[0140] Compared with the control group, compound 2 at a dose of 20 mg / kg increased the distance traveled and shortened the time spent at rest in mice (Table 3). The avoidance test showed that, compared with the control group, mice treated with compound 2 had a prolonged escape latency and fewer errors (Table 3). The new object recognition test showed that, compared with the control group, mice treated with compound 2 had a significantly increased exploration time and number of explorations of new objects (Table 3).

[0141] Table 3. Evaluation of the effects of compound 2 on behavioral indicators in aging model mice (Mean±SD)

[0142]

[0143] The compounds provided by this invention have anti-neuroinflammatory activity and can exert neurotrophic activity by promoting synaptic growth; they can specifically reduce or clear β-amyloid protein (Aβ) deposition, significantly improve Aβ toxicity-induced paralysis in nematodes, and significantly improve the motor ability of nematodes; they can also improve the motor ability of aging mice, improve the learning and memory ability of aging mice, reduce the anxiety state of aging mice, and improve the cognitive function of aging mice, providing a new direction for the drug treatment of Alzheimer's disease.

[0144] This invention has efficiently obtained a series of novel vesine diterpenoid compounds. Activity evaluation shows that these compounds have significant anti-neuroinflammatory activity, neurotrophic protective effect, anti-AD activity, and anti-aging activity.

Claims

1. Bird's nest diterpenoids, which have the following structural formula; in: R1 is COOH, COOCH3, CH2OH, or CH3; R2 is CH2OH or COOH; R3 is OH or H; R4 is H or =O; There is a single or double bond between C12 and C13.

2. The bird's nest diterpenoid compound according to claim 1, characterized in that, R1 is COOH; R2 is CH2OH; R3 is OH; R4 is H; and there is a single bond between C12 and C13.

3. The bird's nest diterpenoid compound according to claim 1, characterized in that, R1 is COO CH3; R2 is CH2OH; R3 is OH; R4 is H; and there is a single bond between C12 and C13.

4. The bird's nest diterpenoid compound according to claim 1, characterized in that, R1 is CH2OH; R2 is CH2OH; R3 is OH; R4 is H; and there is a single bond between C12 and C13.

5. The bird's nest diterpenoid compound according to claim 1, characterized in that, R1 is COOH; R2 is COOH; R3 is H; R4 is H; and there is a double bond between C12 and C13.

6. The bird's nest diterpenoid compound according to claim 1, characterized in that, R1 is CH2OH; R2 is COOH; R3 is H; R4 is H; and there is a double bond between C12 and C13.

7. The bird's nest diterpenoid compound according to claim 1, characterized in that, R1 is CH3; R2 is COOH; R3 is H; R4 is =O; and there is a double bond between C12 and C13.

8. The use of the vesine diterpenoid compound according to claim 1 in anti-inflammatory activity, neurotrophic activity, anti-AD activity, or anti-neuritis activity.

9. The use of the vesine diterpenoid compound according to claim 2 in the preparation of anti-aging drugs and drugs for treating Alzheimer's disease.

Images