A bibobunin monomer derivative, and a preparation method and application thereof

Abstract

This invention discloses a monomeric derivative of magnolol, its preparation method, and its applications. The derivative has the structural formula shown in Formula I. This invention provides a series of novel monomeric derivatives of magnolol. Activity screening results in SH-SY5Y cells show that these derivatives can effectively antagonize FA-induced cytotoxicity. In a *C. elegans* model, they can significantly improve the survival rate of nematodes exposed to FA and reduce FA levels in nematodes, demonstrating a good FA detoxification effect. Furthermore, in an AD model of nematodes, these derivatives can delay the progression of paralysis, improve cognitive dysfunction, and reduce Aβ expression and accumulation, exhibiting significant neuroprotective effects.

Description

Technical Field

[0001] This invention relates to the field of organic synthesis technology, and in particular to a mono- and di-magnoliol monomer derivative, its preparation method, and its application. Background Technology

[0002] Bi-magnolignan (BiM) is a lignan-based natural product isolated from the dried leaves of the traditional medicinal plant Magnolia officinalis. This molecule possesses a unique bibenzofuran skeleton, which can be considered as two identical monomers linked by a C-C bond. The monomers have a bibenzofuran core structure with allyl and phenolic hydroxyl groups substituted on the aromatic ring. Compared to structurally similar magnolol compounds, BiM has a more complex molecular structure and larger molecular size, and its unique structure may affect its biological activity and pharmacokinetic properties. Current research on the biological activity of BiM mainly focuses on its cytotoxic effects. Research by Ma Wenzhe's group shows that BiM has broad-spectrum inhibitory effects on tumor cells from various tissues, with an IC50 ranging from 0.4 to 7.5 μM, while exhibiting low toxicity to normal cells, demonstrating some selectivity. Drug-likeness assessments indicate that BiM has good drug development potential, and the molecule possesses moderate blood-brain barrier penetration ability, providing a theoretical basis for the application of BiM in central nervous system diseases such as Alzheimer's disease.

[0003] Alzheimer's disease (AD) is a progressive neurodegenerative disease of the central nervous system, clinically manifested as memory impairment, aphasia, apraxia, agnosia, visuospatial impairment, and behavioral and personality changes. Drug therapy is currently the main clinical treatment for AD; however, the efficacy of existing drugs is not ideal, only alleviating the patient's mental symptoms and failing to halt disease progression. Therefore, the development of anti-AD drugs is urgently needed. The pathological features of AD include amyloid plaques formed by the abnormal deposition of amyloid β-protein (Aβ) and neurofibrillary tangles (NFTs) formed by the hyperphosphorylation and accumulation of tau protein. With a deeper understanding of the pathogenesis of AD, we have found that formaldehyde (FA) plays a key role in several pathogenic hypotheses. Pathological FA accumulation accelerates the formation of amyloid plaques and NFTs by promoting Aβ oligomerization and tau protein phosphorylation, while Aβ inhibition of ADH-5 inversely induces FA accumulation, creating a vicious cycle. Excessive fatty acids (FAs) can also promote Ca2+ influx, increasing ROS production and inducing oxidative stress; and by inhibiting COX activity, they can block the electron transport chain, thereby reducing ATP synthesis and inducing neuronal death. Furthermore, FAs can also promote AD development by inhibiting ChAT activity and reducing ACh levels.

[0004] Therefore, the search for effective compounds with anti-FA effects provides a new approach for the development of anti-AD drugs, which has important theoretical significance and practical value. Summary of the Invention

[0005] The present invention aims to at least solve one of the technical problems existing in the prior art. To this end, the first aspect of the present invention proposes a monomeric derivative of magnolol, which can effectively antagonize FA-induced neurocytotoxicity.

[0006] The second aspect of the present invention also provides a method for preparing a monomeric derivative of magnolol.

[0007] The third aspect of the present invention also provides an application of a derivative of the homologous magnolol monomer.

[0008] According to a first aspect of the present invention, a monomeric derivative of magnolol is provided, having the structural formula shown in Formula I: ; Among them, R1 and R2 are each independently selected from C. 1~6 alkyl, C 2~6 alkenyl, C 2~6 alkynyl group, C 2~6 Acyl group, , ; n represents an integer from 1 to 5, and R3 are independently selected from H and C. 1~6 alkyl, C 1~6 alkoxy, C 1~6 Halogenated alkyl groups, nitro groups, hydroxyl groups, and halogens; Alternatively, R3 may form an oxygen-doped 3- to 6-membered heterocycle with the adjacent phenyl group; R4 is selected from H or C. 1~6 Alkyl groups.

[0009] According to a preferred embodiment of the present invention, R1 and R2 are each independently selected from C. 1~3 alkyl, C 2~4 alkenyl, C 2~4 alkynyl group, C 2~4 Acyl group, , .

[0010] According to a preferred embodiment of the present invention, R3 is independently selected from H and C. 1~3 alkyl, C 1~3 alkoxy, C 1~3 Halogenated alkyl groups, nitro groups, hydroxyl groups, and halogens; Alternatively, R3 can form an oxygen-doped 3- to 6-membered heterocycle with the adjacent phenyl group.

[0011] According to a preferred embodiment of the present invention, R4 is selected from H or C. 1~3 Alkyl groups.

[0012] According to a preferred embodiment of the present invention, the simulin monomer derivative is selected from the following structural formulas: , , , , , , , , , , , , , , , , , , , , , , , , , , , , .

[0013] The monoclonal derivative of magnolol according to embodiments of the present invention has at least the following beneficial effects: This invention provides a series of novel monomeric derivatives of magnolol, and activity screening results in SH-SY5Y cells show that these derivatives can effectively antagonize FA-induced cytotoxicity. In a *C. elegans* model, they significantly improve the survival rate of nematodes exposed to FA and reduce FA levels in nematodes, demonstrating a good FA detoxification effect. Furthermore, in an AD model of nematodes, these derivatives can delay the progression of paralysis, improve cognitive dysfunction, and reduce Aβ expression and accumulation, exhibiting significant neuroprotective effects.

[0014] According to a second aspect of the present invention, a method for preparing a monomeric derivative of magnolol is provided, comprising the following steps: The halide corresponding to compound A and R1 is obtained by nucleophilic substitution reaction; Alternatively, it can be obtained by reacting compound A with the acid anhydride corresponding to R1; Alternatively, compound A and compound B can be esterified to obtain the product. Alternatively, compound B can be reacted with a hydroxyl protecting agent first, then esterified with compound 9, and finally deprotected to obtain the product. The structural formula of compound A is as follows: ; The structural formula of compound B is as follows: .

[0015] According to a preferred embodiment of the present invention, the esterification reaction is carried out under the conditions of EDCI and DMAP.

[0016] According to a preferred embodiment of the present invention, the hydroxyl protecting agent comprises tert-butyldimethylchlorosilane.

[0017] According to a preferred embodiment of the present invention, the nucleophilic substitution reaction further includes a raw material base.

[0018] The third aspect of this invention provides the use of the doxycycline monomer derivative described in the first aspect of this invention in the preparation of a medicament for treating methanol-induced neurotoxicity.

[0019] A fourth aspect of the present invention provides the use of a compound magnolol monomer derivative in the preparation of a drug for treating and / or preventing Alzheimer's disease, wherein the compound magnolol monomer derivative has the structural formula shown in Formula II: ; Among them, R1 and R2 are each independently selected from H and C. 1~6 alkyl, C 2~6 alkenyl, C 2~6 alkynyl group, C 2~6 Acyl group, , ; n represents an integer from 1 to 5, and R3 are independently selected from H and C. 1~6 alkyl, C 1~6 alkoxy, C 1~6 Halogenated alkyl groups, nitro groups, hydroxyl groups, and halogens; Alternatively, R3 may form an oxygen-doped 3- to 6-membered heterocycle with the adjacent phenyl group; R4 is selected from H or C.1~6 Alkyl groups.

[0020] Definitions and General Terms “C 1-6 "alkyl" indicates an alkyl group with a total number of 1-6 carbon atoms, including C64. 1-6 straight-chain alkyl, C 1-6 Branched alkyl groups and C 3-6 The cycloalkyl group can be, for example, a straight-chain alkyl group with a total of 1, 2, 3, 4, 5, or 6 carbon atoms; a branched-chain alkyl group with a total of 1, 2, 3, 4, 5, or 6 carbon atoms; or a cycloalkyl group with a total of 3, 4, 5, or 6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, n-hexyl, cyclopropyl, methylcyclopropyl, ethylcyclopropyl, cyclopentyl, methylcyclopentyl, cyclohexyl, etc. Regarding "C 1-3 "alkyl" has a similar interpretation, except that the number of carbon atoms is different.

[0021] “C 1-6 "alkoxy group" refers to an alkoxy group with a total number of 1-6 carbon atoms, including C64 and C64. 1-6 straight-chain alkoxy, C 1-6 Branched alkoxy groups and C 2-6 The cycloalkoxy group can be, for example, a straight-chain alkoxy group with a total of 1, 2, 3, 4, 5, or 6 carbon atoms; a branched-chain alkoxy group with a total of 1, 2, 3, 4, 5, or 6 carbon atoms; or a cycloalkoxy group with a total of 2, 3, 4, 5, or 6 carbon atoms, such as methoxy, ethoxy, n-propoxy, isopropoxy, etc. Regarding "C 1-3 The "alkoxy group" has a similar explanation, except that the number of carbon atoms is different.

[0022] “C 2-6 "Alkenyl" refers to a straight-chain or branched hydrocarbon group having one or more double bonds, and the total number of carbon atoms in the alkenyl group is 2-6, with the double bonds in any position. 2~4 "Alkenyl" has a similar definition.

[0023] “C 2-6 "Alkyne group" indicates a straight-chain or branched hydrocarbon group with one or more triple bonds, and the total number of carbon atoms in the alkynyl group is 2-6. The alkynyl bonds in this group can be in any position. 2~4 The "alkynyl group" has a similar definition.

[0024] “C 1-6 "Hydroalkyl" indicates that it is related to the above "C" 1-6 The definition of "alkyl" is similar, except that it is substituted with one or more of the same or different halogen atoms, for example... CH2Cl, CF3 CCl3, CH2CF3, CH2CCl3, etc.

[0025] “C 2~6 The "acyl" group indicates the structural formula -C(=0)-CR, with a total of 6 carbon atoms. Examples include -C(=0)-CH3, -C(=0)-CH2CH3, etc.

[0026] "Halogen" means any one or more of fluorine, chlorine, bromine, and iodine.

[0027] "Oxygen-doped 3- to 6-membered heterocycles" means that the ring atom has at least one oxygen-doped 3- to 6-membered heterocycle. Examples include... .

[0028] Other features and advantages of the invention will be set forth in the description which follows, and will be apparent in part from the description, or may be learned by practicing the invention. Attached Figure Description

[0029] The above and / or additional aspects and advantages of the present invention will become apparent and readily understood from the description of the embodiments taken in conjunction with the following drawings, in which: Figure 1 This is a graph showing the survival rates of N2 nematodes treated with different concentrations of compounds 16c, 16f, 9, and BiM in this invention after exposure to 20 mMFA. Figure 2 This is a graph showing the survival rate of N2 nematodes treated with 30 μM compounds 16c, 16f, 9, and BiM in this invention after exposure to 20 mM FA. Figure 3 These are FA fluorescence images of N2 nematodes treated with compounds 16c, 16f, 9, and BiM according to embodiments of the present invention. Figure 4 These are FA fluorescence images of N2 and CL4176 nematodes treated with compounds 16c, 16f, 9, and BiM according to embodiments of the present invention. Figure 5 These are typical microscopic images of CL4176 nematodes in normal and paralyzed states; Figure 6 This is a chemotactic analysis diagram of CL2355 nematodes treated with compounds 16c, 16f, 9, and BiM according to embodiments of the present invention. Figure 7 This is a diagram showing the Aβ mRNA level in CL4176 nematodes after treatment with compounds 16c, 16f, 9, and BiM according to embodiments of the present invention, detected by RT-qPCR. Figure 8This is a graph showing the protein levels of Aβ oligomers in CL2122 and GMC101 nematodes detected by Western blot. Detailed Implementation

[0030] The following are specific embodiments of the present invention, and the technical solutions of the present invention will be further described in conjunction with the embodiments, but the present invention is not limited to these embodiments.

[0031] Unless otherwise specified, the reagents, methods and equipment used in this invention are all conventional reagents, methods and equipment in this technical field.

[0032] The synthesis of compound 9 and natural product BiM in this embodiment of the invention was carried out with reference to the literature (Lu SY, Wang HM, Feng N, et al. Total synthesis of bi-magnolignan[J]. RSC Adv, 2023, 13(13):8844-8846.). The structural formulas of compound 9 and natural product BiM are as follows: .

[0033] The steps for detecting cell viability using the CCK-8 assay in this invention are as follows: SH-SY5Y cells in logarithmic growth phase were seeded into 96-well plates and cultured at 37 °C for 12 h to ensure full adhesion. Cells were divided into a control group, a model group, and a treatment group, with three replicates per group. Cells in each group were exposed to serum-free DMEM medium containing DMSO or 30 μM iM derivative and cultured at 37 °C for 12 h, followed by the addition of 0.3 mM FA and a further 12 h of culture. The old medium was discarded, and cells were treated with a CCK-8 assay kit. A blank control group (containing no cells) was also included. Absorbance was measured at 450 nm using a microplate reader.

[0034] Cell viability = [(experimental wells - blank wells) / (control wells - blank wells)] × 100%.

[0035] Example 1 This example provides a monomeric derivative of honokiol (10a), and the reaction equation and preparation method are as follows:

[0036] Compound 9 (50 mg, 0.18 mmol) and potassium carbonate (124 mg, 0.90 mmol) were added to a pressure-resistant tube. Under nitrogen protection, 1.8 mL of acetone was added and stirred to dissolve the compound. Then, 3-bromopropene (64 mg, 0.54 mmol) was added, and the mixture was refluxed at 57 °C overnight. After the reaction was completed by TLC monitoring, the reaction solution was cooled to room temperature, filtered to remove insoluble salts, and the filtrate was concentrated under vacuum to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain 50 mg of pale yellow solid product 10a, with a yield of 77%.

[0037] The 1H and 1C NMR spectra of the prepared derivative 10a are as follows: 1 H NMR (500 MHz, CDCl3) δ 7.65 (d, J = 1.7 Hz, 1H), 7.46 (d, J = 8.4 Hz,1H), 7.30 (s, 1H), 7.21 (dd, J = 8.4, 1.9 Hz, 1H), 6.21 – 5.99 (m, 4H), 5.49(dd, J = 17.4, 1.7 Hz, 1H), 5.41 (dd, J = 17.2, 1.7 Hz, 1H), 5.31 (dd, 1H), 5.25(dd, J = 10.3, 1.5 Hz, 1H), 5.19 – 5.00 (m, 4H), 4.66 (d, J = 1.6 Hz, 2H), 4.62(d, 2H), 3.75 (d, J = 1.7 Hz, 2H), 3.53 (d, J = 6.6 Hz, 2H). HRMS calcd forC24H24O3Na [M+Na] ＋ 383.1623, found 383.1628. 13 C NMR (126 MHz, CDCl3) δ 155.5, 150.4, 148.8, 146.6, 138.1, 136.0,134.5, 134.3, 133.6, 127.0, 125.1, 119.9, 118.9, 118.6, 117.6, 117.5, 115.8,115.6, 111.5, 103.2, 74.6, 70.6, 40.3, 29.0. Example 2 This example provides a monomeric derivative of honokiol (10b), and the reaction equation and preparation method are as follows:

[0038] The synthetic method was similar to that of compound 10a. Starting from compound 9 (50 mg, 0.18 mmol), it was reacted with potassium carbonate (124 mg, 0.90 mmol) and 3-bromopropyne (64 mg, 0.54 mmol) to give 32 mg of white solid product 10b in 50% yield.

[0039] The 1H and 1C NMR spectra of the prepared derivative 10b are as follows: 1 H NMR (500 MHz, CDCl3) δ 7.68 (s, 1H), 7.47 (d, J = 8.4 Hz, 1H), 7.44(s, 1H), 7.23 (dd, J = 8.4, 1.8 Hz, 1H), 6.19 – 5.99 (m, 2H), 5.17 – 5.08 (m,3H), 5.05 (dd, J = 10.0, 1.6 Hz, 1H), 4.84 (d, J = 2.4 Hz, 2H), 4.81 (d, J = 2.5Hz, 2H), 3.82 (d, 2H), 3.54 (d, J = 6.6 Hz, 2H), 2.56 (t, J = 2.7 Hz, 1H), 2.49(t, J = 2.4 Hz, 1H). HRMS calcd for C24H20O3Na [M+Na] ＋ : 379.1310, found379.1313. 13 C NMR (126 MHz, CDCl3) δ 155.6, 150.7, 147.5, 145.7, 138.0, 135.8,134.5, 127.3, 124.8, 120.1, 119.5, 119.4, 115.9, 115.8, 111.6, 104.3, 79.5,78.7, 76.0, 75.5, 61.0, 57.7, 40.2, 29.2. Example 3 This example provides a monomeric derivative of honokiol (10c), prepared by the following method:

[0040] Compound 9 (50 mg, 0.18 mmol) was added to a reaction tube, followed by 2 mL of DCM, stirred to dissolve, and placed in an ice bath. Triethylamine (54 mg, 0.54 mmol) was added at 0 °C and stirred for 15 min, followed by acetic anhydride (37 mg, 0.36 mmol). The ice bath was removed, and the reaction was allowed to proceed overnight at room temperature. After the reaction was monitored by TLC until complete, the reaction was quenched with water, and the mixture was extracted three times with DCM. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under vacuum to obtain the crude product. Purification by silica gel column chromatography yielded 44 mg of a white solid, product 10c, in 67% yield.

[0041] The 1H and 1C NMR spectra of the prepared derivative 10c are as follows: 1 H NMR (500 MHz, CDCl3) δ 7.67 (s, 1H), 7.64 (s, 1H), 7.48 (d, J = 8.4Hz, 1H), 7.28 (dd, J = 8.5, 1.9 Hz, 1H), 6.09 – 5.92 (m, 2H), 5.17 – 5.04 (m,4H), 3.67 (d, J = 1.7 Hz, 2H), 3.53 (d, 2H), 2.34 (s, 3H), 2.33 (s, 3H). HRMScalcd for C22H20O5Na [M+Na] ＋ : 387.1208, found 387.1213. 13 C NMR (126 MHz, CDCl3) δ 169.0, 168.5, 155.7, 152.7, 139.9, 138.7,137.8, 134.9, 134.4, 128.2, 124.2, 121.8, 120.6, 118.3, 116.4, 116.1, 112.6,111.7, 40.1, 29.4, 20.9, 20.6. Example 4 This example provides a monoclonal derivative of honokiol (10d), prepared by the following method:

[0042] Compound 9 (50 mg, 0.18 mmol) and potassium carbonate (75 mg, 0.54 mmol) were added to a reaction tube. Under nitrogen protection, 1.8 mL of DMF was added and stirred to dissolve the compound. Iodomethane (51 mg, 0.36 mmol) was then added, and the reaction was allowed to proceed overnight at room temperature. After the reaction was monitored by TLC until complete, water was added to quench the reaction, and the mixture was extracted three times using EA. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under vacuum to obtain the crude product. Purification by silica gel column chromatography yielded 34 mg of a colorless oily product for 10 days, with a yield of 62%.

[0043] The 10-day and 10-day NMR spectra of the prepared derivatives are as follows: 1 H NMR (500 MHz, CDCl3) δ 7.68 (s, 1H), 7.46 (d, J = 8.4 Hz, 1H), 7.29(s, 1H), 7.21 (dd, J = 8.4, 1.8 Hz, 1H), 6.19 – 6.00 (m, 2H), 5.17 – 5.02 (m,4H), 3.97 (s, 3H), 3.90 (s, 3H), 3.74 (d, J = 1.7 Hz, 2H), 3.54 (d, J = 6.6 Hz,2H). HRMS calcd for C20H20O3Na [M+Na] ＋ : 331.1310, found 331.1314. 13 C NMR (126 MHz, CDCl3) δ 155.5, 150.1, 150.0, 147.3, 138.1, 136.1,134.3, 126.9, 125.1, 119.8, 118.8, 118.4, 115.8, 115.6, 111.5, 101.0, 61.5,56.5, 40.3, 28.8. Example 5 This example provides a series of reaction equations and preparation methods for the monomeric derivatives of honokiol (12a~12q):

[0044] Cinnamic acid compounds (0.45 mmol, 11a-q) were added to a reaction tube, followed by 1.8 mL of DCM, stirred to dissolve, and placed in an ice bath. At 0 °C, EDCI·HCl (0.72 mmol), DMAP (0.054 mmol), and compound 9 (0.18 mmol) were added sequentially. The ice bath was removed, and the reaction was allowed to proceed at room temperature for 1 h. After the reaction was complete as monitored by TLC, it was extracted with DCM. The organic phase was washed sequentially with 0.1 M dilute hydrochloric acid, saturated sodium bicarbonate aqueous solution, and saturated brine, then dried over anhydrous sodium sulfate, and concentrated under vacuum to obtain the crude product. This crude product was purified by silica gel column chromatography to obtain product 12a-q.

[0045] The 1H and 1C NMR spectra of derivative 12a are as follows: 1 H NMR (500 MHz, CDCl3) δ 7.89 (dd, J = 21.0, 16.0 Hz, 2H), 7.76 (s,1H), 7.71 (d, J = 1.8 Hz, 1H), 7.57 – 7.46 (m, 5H), 7.44 – 7.27 (m, 7H), 6.66(d, J = 16.0 Hz, 1H), 6.60 (d, J = 16.0 Hz, 1H), 6.11 – 5.98 (m, 2H), 5.20 – 5.02(m, 4H), 3.73 (d, 2H), 3.55 (d, J = 6.6 Hz, 2H). HRMS calcd for C36H28O5Na [M+Na] ＋ : 563.1834, found 563.1837. 13 C NMR (126 MHz, CDCl3) δ 165.1, 164.7, 155.8, 152.8, 147.7, 147.3,140.2, 139.0, 137.8, 134.9, 134.4, 134.1 (d, J = 6.6 Hz), 131.0, 130.9, 129.1(d, J = 7.9 Hz), 128.5 (d, J= 7.4 Hz), 128.2, 124.4, 121.8, 120.6, 118.6, 116.7,116.6, 116.2, 116.1, 112.6, 111.7, 40.2, 29.4. The 1H and 1C NMR spectra of derivative 12b are as follows: 1 H NMR (500 MHz, CDCl3) δ 7.83 (dd, J = 20.3, 15.9 Hz, 2H), 7.74 (s,1H), 7.70 (d, J = 1.7 Hz, 1H), 7.53 – 7.45 (m, 3H), 7.45 – 7.38 (m, 2H), 7.28(dd, J = 8.4, 1.8 Hz, 1H), 6.91 – 6.85 (m, 2H), 6.85 – 6.80 (m, 2H), 6.51 (d, J =15.9 Hz, 1H), 6.46 (d, J = 15.9 Hz, 1H), 6.10 – 5.97 (m, 2H), 5.19 – 5.03 (m,4H), 3.83 (s, 3H), 3.81 (s, 3H), 3.72 (d, 2H), 3.54 (d, J = 6.6 Hz, 2H). HRMScalcd for C38H32O7Na [M+Na] ＋ : 623.2046, found 623.2042. 13 C NMR (126 MHz, CDCl3) δ 165.5, 165.1, 161.9, 161.8, 155.7, 152.7,147.3, 146.9, 140.4, 139.2, 137.9, 134.8, 134.5, 130.3 (d, J = 9.2 Hz), 128.1, 126.9 (d, J = 6.3 Hz), 124.4, 121.7, 120.6, 118.6, 116.5, 116.0, 114.5 (d, J =7.8 Hz), 114.1, 113.6, 112.6, 111.6, 55.5 (d, J= 4.1 Hz), 40.2, 29.4. The 1H and 1C NMR spectra of derivative 12c are as follows: 1 H NMR (500 MHz, CDCl3) δ 7.86 (dd, J = 20.7, 16.0 Hz, 2H), 7.75 (s,1H), 7.70 (d, J = 1.8 Hz, 1H), 7.51 (d, J = 8.4 Hz, 1H), 7.43 (d, J = 7.9 Hz, 2H), 7.38 (d, J = 7.9 Hz, 2H), 7.29 (dd, J = 8.5, 1.8 Hz, 1H), 7.17 (d, J = 7.9 Hz, 2H), 7.13 (d, J = 7.8 Hz, 2H), 6.61 (d, J = 15.9 Hz, 1H), 6.55 (d, J = 16.0 Hz, 1H), 6.11 – 5.98 (m, 2H), 5.19 – 5.04 (m, 4H), 3.72 (d, 2H), 3.54 (d, J = 6.6 Hz,2H), 2.37 (s, 3H), 2.35 (s, 3H). HRMS calcd for C38H32O5Na [M+Na] ＋ :591.2147, found 591.2152. 13 C NMR (126 MHz, CDCl3) δ 165.4, 164.9, 155.8, 152.7, 147.6, 147.3,141.5, 141.4, 140.3, 139.1, 137.9, 134.9, 134.4, 131.4 (d, J = 6.2 Hz), 129.8 (d, J = 7.5 Hz), 128.5 (d, J= 7.4 Hz), 128.1, 124.4, 121.7, 120.6, 118.6, 116.5,116.1, 115.6, 115.1, 112.6, 111.6, 40.2, 29.4, 21.6 (d, J = 3.5 Hz). The 1H and 1C NMR spectra of derivative 12d are as follows: 1 H NMR (500 MHz, CDCl3) δ 7.87 (t, J = 15.7 Hz, 2H), 7.75 (s, 1H), 7.71(d, J = 1.7 Hz, 1H), 7.63 – 7.55 (m, 8H), 7.52 (d, J = 8.5 Hz, 1H), 7.31 (dd, J =8.6, 1.8 Hz, 1H), 6.72 (d, J = 16.0 Hz, 1H), 6.66 (d, J = 16.0 Hz, 1H), 6.10 –5.97 (m, 2H), 5.18 – 5.05 (m, 4H), 3.73 (d, J = 6.3 Hz, 2H), 3.55 (d, J = 6.6 Hz,2H). HRMS calcd for C38H26O5F6Na [M+Na] ＋ : 699.1582, found 699.1583. 13 C NMR (126 MHz, CDCl3) δ 164.5, 164.1, 155.8, 152.8, 145.7, 145.4,139.9, 138.7, 137.8, 137.3 (d, J = 9.2 Hz), 135.0, 134.3, 128.6 (d, J = 8.0 Hz),128.4, 126.2 – 125.9 (m), 124.9, 124.2, 122.7, 122.0, 120.6, 119.2, 118.8,118.6, 116.7, 116.1, 112.6, 111.7, 40.2, 29.4. 19F NMR (471 MHz, CDCl3) δ -63.0. The 1H and 1C NMR spectra of derivative 12e are as follows: 1 H NMR (500 MHz, CDCl3) δ 8.25 – 8.17 (m, 4H), 8.00 – 7.85 (m, 2H), 7.74 (s, 1H), 7.70 (s, 2H), 7.69 – 7.63 (m, 3H), 7.52 (d, J = 8.4 Hz, 1H), 7.31(dd, J = 8.4, 1.8 Hz, 1H), 6.78 (d, J = 16.1 Hz, 1H), 6.72 (d, J = 16.0 Hz, 1H), 6.10 – 5.95 (m, 2H), 5.17 – 5.04 (m, 4H), 3.72 (d, J = 1.7 Hz, 2H), 3.54 (d, J =6.6 Hz, 2H). HRMS calcd for C36H26N2O9Na [M+Na] ＋ : 653.1536, found 653.1533. 13 C NMR (126 MHz, CDCl3) δ 164.2, 163.7, 155.8, 152.8, 149.0, 148.9,144.6, 144.3, 139.9, 139.8, 139.7, 138.6, 137.7, 135.1, 134.2, 129.1 (d, J =9.0 Hz), 128.5, 124.4 (d, J = 6.0 Hz), 124.1, 122.2, 120.8, 120.6, 120.4,118.5, 116.7, 116.2, 112.5, 111.8, 40.1, 29.4. The 1H and 1C NMR spectra of derivative 12f are as follows: 1 H NMR (500 MHz, CDCl3) δ 7.89 – 7.78 (m, 2H), 7.74 (s, 1H), 7.70 (d, J= 1.8 Hz, 1H), 7.55 – 7.49 (m, 3H), 7.49 – 7.44 (m, 2H), 7.29 (dd, J = 8.5, 1.8Hz, 1H), 7.11 – 6.98 (m, 4H), 6.57 (d, J = 16.0 Hz, 1H), 6.52 (d, J = 16.0 Hz,1H), 6.10 – 5.97 (m, 2H), 5.14 – 5.04 (m, 4H), 3.72 (d, J = 1.6 Hz, 2H), 3.54(d, 2H). HRMS calcd for C36H26O5F2Na [M+Na] ＋ : 599.1646, found 599.1645. 13 C NMR (126 MHz, CDCl3) δ 165.4, 165.3, 165.0, 164.6, 163.4, 163.3,155.8, 152.8, 146.3, 145.9, 140.1, 138.9, 137.8, 134.9, 134.4, 130.6 – 130.1(m), 128.2, 124.3, 121.9, 120.6, 118.6, 116.6, 116.4 (d, J = 2.3 Hz), 116.3,116.2, 116.2, 116.1, 116.0 (d, J = 2.5 Hz), 112.6, 111.7, 40.2, 29.4. 19 F NMR (471 MHz, CDCl3) δ -108.2 – -108.3 (m, J = 5.4 Hz), -108.5 – -108.6 (m). The 1H and 1C NMR spectra of 12g of derivative are as follows: 1 H NMR (500 MHz, CDCl3) δ 7.81 (dd, J = 18.1, 16.0 Hz, 2H), 7.74 (s,1H), 7.70 (d, J = 1.8 Hz, 1H), 7.51 (d, J= 8.4 Hz, 1H), 7.47 – 7.42 (m, 2H), 7.42 – 7.37 (m, 2H), 7.37 – 7.32 (m, 2H), 7.32 – 7.27 (m, 3H), 6.61 (d, J =16.0 Hz, 1H), 6.56 (d, J = 16.0 Hz, 1H), 6.10 – 5.96 (m, 2H), 5.18 – 5.03 (m,4H), 3.72 (d, J = 1.6 Hz, 2H), 3.54 (d, 2H). HRMS calcd for C36H26O5Cl2Na [M+Na] ＋ : 631.1055, found 631.1053. 13 C NMR (126 MHz, CDCl3) δ 164.9, 164.4, 155.8, 152.8, 146.2, 145.8,140.1, 138.9, 137.8, 137.1, 136.9, 135.0, 134.3, 132.5, 132.5, 129.6 (d, J =7.7 Hz), 129.4 (d, J = 8.0 Hz), 128.3, 124.3, 121.9, 120.6, 118.6, 117.2,116.8, 116.6, 116.1, 112.6, 111.7, 40.2, 29.4. The 12-hour proton and carbon NMR spectra of the derivative are as follows: 1 H NMR (500 MHz, CDCl3) δ 7.79 (t, 2H), 7.74 (s, 1H), 7.70 (d, J = 1.8Hz, 1H), 7.53 – 7.48 (m, 3H), 7.48 – 7.42 (m, 2H), 7.39 – 7.35 (m, 2H), 7.34– 7.31 (m, 2H), 7.29 (dd, J = 8.5, 1.8 Hz, 1H), 6.63 (d, J= 16.0 Hz, 1H), 6.59(d, 1H), 6.10 – 5.96 (m, 2H), 5.17 – 5.03 (m, 4H), 3.71 (d, J = 6.2 Hz, 2H), 3.54 (d, J = 6.6 Hz, 2H). HRMS calcd for C36H26O5Br2Na [M+Na] ＋ : 719.0045, found 719.0043. 13 C NMR (126 MHz, CDCl3) δ 164.9, 164.4, 155.8, 152.8, 146.2, 145.9,140.1, 138.8, 137.8, 135.0, 134.3, 132.9, 132.9, 132.4 (d, J = 8.0 Hz), 129.8(d, J = 7.0 Hz), 128.3, 125.5, 125.3, 124.3, 121.9, 120.6, 118.6, 117.3, 116.9,116.6, 116.1, 112.6, 111.7, 40.2, 29.4. The proton and carbon NMR spectra of derivative 12i are as follows: 1 H NMR (400 MHz, CDCl3) δ 7.92 – 7.79 (m, 2H), 7.76 (s, 1H), 7.71 (d, J = 1.8 Hz, 1H), 7.51 (d, J = 8.4 Hz, 1H), 7.37 – 7.14 (m, 9H), 6.64 (d, J = 16.0Hz, 1H), 6.58 (d, J = 16.0 Hz, 1H), 6.12 – 5.96 (m, 2H), 5.20 – 5.03 (m, 4H), 3.72 (d, J = 1.6 Hz, 2H), 3.55 (d, J = 6.6 Hz, 2H), 2.33 (s, 3H), 2.29 (s, 3H).HRMS calcd for C38H32O5Na [M+Na] ＋: 591.2147, found 591.2151. 13 C NMR (101 MHz, CDCl3) δ 165.2, 164.8, 155.8, 152.8, 147.9, 147.5,140.3, 139.0, 138.8, 138.7, 137.8, 134.9, 134.4, 134.1, 134.0, 131.8, 131.7,129.2 (d, J = 1.5 Hz), 129.0, 128.9, 128.1, 125.8, 125.6, 124.4, 121.8, 120.6,118.6, 116.5 (d, J = 5.3 Hz), 116.1 (d, J = 1.5 Hz), 112.6, 111.7, 40.2, 29.4,21.4 (d, J = 5.7 Hz). The 1H and 1C NMR spectra of derivative 12j are as follows: 1 H NMR (500 MHz, CDCl3) δ 7.82 (dd, J = 19.1, 16.0 Hz, 2H), 7.75 (s,1H), 7.71 (d, J = 1.8 Hz, 1H), 7.51 (d, J = 8.4 Hz, 1H), 7.38 – 7.27 (m, 4H), 7.27 – 7.24 (m, 1H), 7.24 – 7.20 (m, 1H), 7.20 – 7.14 (m, 1H), 7.12 – 7.04(m, 2H), 6.64 (d, J = 16.0 Hz, 1H), 6.58 (d, J = 16.0 Hz, 1H), 6.10 – 5.96 (m,2H), 5.20 – 5.01 (m, 4H), 3.72 (d, J = 1.6 Hz, 2H), 3.54 (d, J = 6.6 Hz, 2H).HRMS calcd for C36H26O5F2Na [M+Na] ＋ : 599.1646, found 599.1651. 13 C NMR (101 MHz, CDCl3) δ 164.7, 164.3, 161.8 (d), 155.8, 152.8,146.2 (d), 145.9 (d), 140.0, 138.8, 137.8, 136.2 (t, J = 7.7 Hz), 135.0, 134.3,130.8 – 130.5 (m), 128.3, 124.5 (dd, J = 7.6, 2.9 Hz), 124.3, 121.9, 120.6,118.6, 118.1 (d), 117.9 (d, J = 7.3 Hz), 117.7 (d, J = 5.1 Hz), 116.6, 116.1,114.8 (d, J = 4.6 Hz), 114.6 (d, J = 4.5 Hz), 112.6, 111.7, 40.2, 29.4. 19 F NMR (471 MHz, CDCl3) δ -112.1 – -112.2 (m), -112.2 – -112.3 (m). The 1H and 1C NMR spectra of derivative 12k are as follows: 1 H NMR (400 MHz, CDCl3) δ 7.80 (t, J = 15.8 Hz, 2H), 7.75 (s, 1H), 7.70(d, J = 1.8 Hz, 1H), 7.54 – 7.47 (m, 2H), 7.47 – 7.43 (m, 1H), 7.42 – 7.23 (m,7H), 6.65 (d, J = 16.0 Hz, 1H), 6.59 (d, J = 16.0 Hz, 1H), 6.12 – 5.95 (m, 2H), 5.19 – 5.03 (m, 4H), 3.72 (d, J = 1.6 Hz, 2H), 3.55 (d, J = 1.6 Hz, 2H). HRMScalcd for C36H26O5Cl2Na [M+Na] ＋: 631.1055, found 631.1060. 13 C NMR (101 MHz, CDCl3) δ 164.6, 164.2, 155.8, 152.8, 146.0, 145.7,140.0, 138.8, 137.8, 135.8 (d), 135.2 (d, J = 6.5 Hz), 135.0, 134.3, 130.9,130.8, 130.3 (d, J = 6.5 Hz), 128.3, 128.2 (d, J = 1.9 Hz), 126.6, 126.5, 124.3,121.9, 120.6, 118.6, 118.1, 117.7, 116.6, 116.1, 112.6, 111.7, 40.2, 29.4. The 1H and 1C NMR spectra of derivative 12l are as follows: 1 H NMR (500 MHz, CDCl3) δ 8.17 (dd, J = 18.7, 16.2 Hz, 2H), 7.75 (s,1H), 7.70 (d, J = 1.8 Hz, 1H), 7.53 – 7.48 (m, 2H), 7.48 – 7.44 (m, 1H), 7.38 –7.27 (m, 3H), 6.96 – 6.82 (m, 4H), 6.77 (d, J = 16.2 Hz, 1H), 6.72 (d, J = 16.1Hz, 1H), 6.11 – 5.98 (m, 2H), 5.20 – 5.03 (m, 4H), 3.82 (s, 3H), 3.80 (s,3H), 3.72 (d, 2H), 3.54 (d, J = 6.6 Hz, 2H). HRMS calcd for C38H32O7Na [M+Na] ＋ : 623.2046, found 623.2047. 13C NMR (126 MHz, CDCl3) δ 165.8, 165.4, 158.8, 158.7, 155.7, 152.7,143.1, 142.8, 140.5, 139.2, 137.9, 134.8, 134.5, 132.1, 132.0, 129.7 (d, J =2.4 Hz), 128.0, 124.5, 123.2, 123.1, 121.6, 120.7 (d, J = 6.2 Hz), 120.6,118.6, 117.3, 116.8, 116.5, 116.0, 112.7, 111.6, 111.2 (d, J = 5.8 Hz), 55.5 (d, J = 4.6 Hz), 40.2, 29.5. The 1H and 1C NMR spectra of the derivative at 12m are as follows: 1 H NMR (500 MHz, CDCl3) δ 8.18 (dd, J = 15.9, 12.4 Hz, 2H), 7.77 (s,1H), 7.71 (d, J = 1.8 Hz, 1H), 7.61 – 7.56 (m, 1H), 7.56 – 7.48 (m, 2H), 7.32 –7.24 (m, 3H), 7.23 – 7.13 (m, 4H), 6.59 (d, J = 15.9 Hz, 1H), 6.54 (d, J = 15.9Hz, 1H), 6.11 – 5.98 (m, 2H), 5.20 – 5.04 (m, 4H), 3.74 (d, J = 1.7 Hz, 2H), 3.55 (d, J = 6.6 Hz, 2H), 2.40 (s, 3H), 2.39 (s, 3H). HRMS calcd for C38H32O5Na[M+Na] ＋ : 591.2147, found 591.2149. 13C NMR (126 MHz, CDCl3) δ 165.2, 164.7, 155.8, 152.8, 145.2, 144.9,140.2, 139.0, 138.2, 138.1, 137.8, 134.9, 134.4, 133.1, 133.0, 131.1, 131.0,130.8, 130.6, 128.2, 126.7, 126.7, 126.6, 126.5, 124.4, 121.8, 120.6, 118.5,117.7, 117.1, 116.5, 116.1, 112.6, 111.7, 40.2, 29.5, 19.9. The 1H and 1C NMR spectra of derivative 12n are as follows: 1 H NMR (500 MHz, CDCl3) δ 8.30 (dd, J = 17.2, 16.0 Hz, 2H), 7.78 (s,1H), 7.71 (d, J = 1.9 Hz, 1H), 7.64 (dd, J = 7.7, 1.8 Hz, 1H), 7.61 (dd, J = 7.7, 1.7 Hz, 1H), 7.51 (d, J = 8.4 Hz, 1H), 7.42 – 7.35 (m, 2H), 7.34 – 7.21 (m,5H), 6.66 (d, J = 16.0 Hz, 1H), 6.61 (d, J = 16.0 Hz, 1H), 6.11 – 5.98 (m, 2H), 5.20 – 5.05 (m, 4H), 3.74 (d, J = 1.6 Hz, 2H), 3.55 (d, J = 1.6 Hz, 2H). HRMScalcd for C36H26O5Cl2Na [M+Na] ＋ : 631.1055, found 631.1052. 13C NMR (126 MHz, CDCl3) δ 164.6, 164.1, 155.8, 152.8, 143.3, 143.0,140.1, 138.9, 137.8, 135.4, 135.4, 134.9, 134.3, 132.4, 132.3, 131.7, 131.6,130.4, 130.3, 128.2, 127.9, 127.2, 127.2, 124.3, 121.8, 120.6, 119.3, 118.8,118.6, 116.6, 116.1, 112.6, 111.7, 40.2, 29.4. The proton and carbon NMR spectra of derivative 12O are as follows: 1 H NMR (500 MHz, CDCl3) δ 7.95 (d, J = 1.8 Hz, 1H), 7.90 (d, J = 1.4 Hz,1H), 7.79 (s, 1H), 7.72 (d, J = 1.8 Hz, 1H), 7.52 (d, J = 8.4 Hz, 1H), 7.41 –7.31 (m, 10H), 7.31 (dd, 1H), 6.11 – 5.99 (m, 2H), 5.21 – 5.05 (m, 4H), 3.74(d, J = 6.3 Hz, 2H), 3.55 (d, J = 1.9 Hz, 2H), 2.21 (d, J = 1.4 Hz, 3H), 2.19 (d, J =1.4 Hz, 3H). HRMS calcd for C38H32O5Na [M+Na] ＋ : 591.2147, found 591.2150. 13C NMR (126 MHz, CDCl3) δ 166.9, 166.5, 155.7, 152.7, 141.5, 141.2,140.6, 139.2, 137.9, 135.5, 135.5, 134.9, 134.5, 130.0, 129.9, 129.0, 128.9,128.6, 128.6, 128.1, 127.4, 127.1, 124.5, 121.6, 120.6, 118.6, 116.5, 116.1,112.6, 111.7, 40.2, 29.5, 14.4, 14.3. The 1H and 1C NMR spectra of derivative 12p are as follows: 1 H NMR (500 MHz, CDCl3) δ 7.84 (dd, J = 19.3, 15.9 Hz, 2H), 7.76 (s,1H), 7.72 (d, J = 1.8 Hz, 1H), 7.53 (d, J = 8.5 Hz, 1H), 7.31 (dd, J = 8.5, 1.8 Hz,1H), 7.15 – 7.04 (m, 3H), 7.02 (d, J = 2.0 Hz, 1H), 6.85 (d, J = 8.3 Hz, 1H), 6.82 (d, 1H), 6.55 (d, J = 15.9 Hz, 1H), 6.49 (d, J = 15.9 Hz, 1H), 6.12 – 6.00(m, 2H), 5.22 – 5.06 (m, 4H), 3.93 (s, 3H), 3.92 (s, 3H), 3.90 (s, 3H), 3.86(s, 3H), 3.75 (d, J = 1.6 Hz, 2H), 3.57 (d, J = 1.6 Hz, 2H). HRMS calcd forC40H36O9Na [M+Na] ＋ : 683.2257, found 683.2258. 13C NMR (126 MHz, CDCl3) δ 165.5, 165.1, 155.7, 152.8, 151.8, 151.6,149.4, 149.3, 147.5, 147.2, 140.4, 139.1, 137.8, 134.9, 134.4, 128.1, 127.1,127.0, 124.4, 123.4, 123.3, 121.7, 120.6, 118.6, 116.5, 116.1, 114.3, 113.8,112.6, 111.7, 111.1, 111.0, 109.7 (d, J = 1.8 Hz), 56.1, 56.1, 56.0, 55.9,40.2, 29.4. The proton and carbon NMR spectra of derivative 12q are as follows: 1 H NMR (500 MHz, CDCl3) δ 7.82 – 7.71 (m, 3H), 7.69 (d, J = 1.8 Hz, 1H), 7.50 (d, J = 8.5 Hz, 1H), 7.28 (dd, J = 8.5, 1.8 Hz, 1H), 7.04 – 6.98 (m, 2H), 6.98 – 6.92 (m, 2H), 6.79 (d, J = 7.9 Hz, 1H), 6.75 (d, J = 7.8 Hz, 1H), 6.46 (d, J = 15.9 Hz, 1H), 6.40 (d, J = 15.9 Hz, 1H), 6.10 – 5.94 (m, 6H), 5.21 – 4.99(m, 4H), 3.71 (d, J = 1.6 Hz, 2H), 3.54 (d, J = 6.6 Hz, 2H). HRMS calcd forC38H28O9Na [M+Na] ＋ : 651.1631, found 651.1635. 13C NMR (126 MHz, CDCl3) δ 165.4, 164.9, 155.7, 152.8, 150.2, 150.1,148.5, 148.5, 147.3, 147.0, 140.3, 139.1, 137.9, 134.9, 134.4, 128.6, 128.5,128.1, 125.3, 125.2, 124.4, 121.7, 120.6, 118.6, 116.5, 116.1, 114.5, 114.1,112.6, 111.7, 108.7, 108.6, 106.8, 106.8, 101.8, 101.8, 40.2, 29.4. Example 6 This example provides a series of mono- and di-homonasin monomeric derivatives (16a~16h), and the reaction equations and preparation methods are as follows:

[0046] In a 100 mL round-bottom flask, phenolic acid compounds (6.1 mmol, 13a-h), imidazole (12.2 mmol), and DMAP (0.61 mmol) were added. Under nitrogen protection, 20 mL of DCM was added, stirred to dissolve, and the mixture was placed in an ice bath. TBSCl (7.3 mmol) was added at 0 °C. The ice bath was removed, and the reaction was allowed to proceed at room temperature for 3 h. After the reaction was complete as monitored by TLC, the mixture was extracted three times with DCM. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under vacuum to obtain the crude product. The crude product was then purified by silica gel column chromatography to obtain the intermediate product (14a-h). (The equivalent amounts of imidazole, DMAP, and TBSCl were increased proportionally according to the number of hydroxyl groups in the phenolic acid structure.) The intermediate (14a-h, 0.62 mmol) was added to a reaction tube, followed by 2.5 mL of DCM, stirred to dissolve, and placed in an ice bath. At 0 °C, EDCI·HCl (1.0 mmol), DMAP (0.075 mmol), and compound 9 (0.25 mmol) were added sequentially. The ice bath was removed, and the reaction was allowed to proceed at room temperature for 1 h. After the reaction was complete as monitored by TLC, it was extracted with DCM. The organic phase was washed sequentially with 0.1 M dilute hydrochloric acid, saturated sodium bicarbonate aqueous solution, and saturated brine, then dried over anhydrous sodium sulfate. The crude product was concentrated under vacuum and purified by silica gel column chromatography to obtain the intermediate (15a-h).

[0047] The intermediate (15a-h, 0.19 mmol) was added to a reaction tube and dissolved by stirring with 2.0 mL of THF under nitrogen protection. Then, 1 M TBAF in THF (0.42 mmol) was added dropwise, and the reaction was allowed to proceed at room temperature for 20 min. After the reaction was complete as monitored by TLC, the reaction was quenched with saturated ammonium chloride solution, and the mixture was extracted three times using EA. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under vacuum to obtain the crude product, which was then purified by silica gel column chromatography to obtain the product (16a-h). (The amount of TBAF equivalent was increased proportionally according to the number of hydroxyl groups in the phenolic acid structure.) The 1H and 1C NMR spectra of derivative 16a are as follows: 1 H NMR (500 MHz, DMSO) δ 10.12 (s, 2H), 8.06 (s, 1H), 7.97 (s, 1H), 7.83 – 7.66 (m, 3H), 7.60 (d, 2H), 7.54 (d, 2H), 7.37 (dd, J = 8.5, 1.8 Hz,1H), 6.77 (d, 2H), 6.74 (d, 2H), 6.65 (d, J = 15.9 Hz, 1H), 6.57 (d, J = 15.9 Hz,1H), 6.13 – 6.01 (m, 1H), 6.01 – 5.89 (m, 1H), 5.16 – 5.01 (m, 4H), 3.64 (d, J = 6.4 Hz, 2H), 3.54 (d, J = 6.6 Hz, 2H). HRMS calcd for C36H28O7Na [M+Na] ＋ :595.1733, found 595.1731. 13 C NMR (126 MHz, DMSO) δ 164.7, 164.5, 160.4, 160.4, 154.9, 151.7,147.7, 147.2, 140.3, 139.1, 138.0, 135.0, 134.2, 131.0, 130.8, 128.3, 124.7(d, J = 4.0 Hz), 123.6, 120.9 (d), 120.7, 117.8, 116.6, 115.9, 115.8 (d, J= 3.5Hz), 113.3, 112.3, 111.8, 111.7, 59.8, 54.9, 28.7, 20.8, 14.1. The 1H and 1C NMR spectra of derivative 16b are as follows: 1 H NMR (500 MHz, DMSO) δ 9.73 (s, 1H), 9.71 (s, 1H), 8.06 (s, 1H), 7.98 (s, 1H), 7.78 (d, J = 15.9 Hz, 1H), 7.75 – 7.66 (m, 2H), 7.40 – 7.34 (m,2H), 7.32 (d, J = 2.0 Hz, 1H), 7.16 (dd, J = 8.2, 2.0 Hz, 1H), 7.11 (dd, J = 8.2,2.0 Hz, 1H), 6.80 – 6.70 (m, 3H), 6.67 (d, J = 15.9 Hz, 1H), 6.12 – 6.02 (m,1H), 6.02 – 5.91 (m, 1H), 5.16 – 5.02 (m, 4H), 3.78 (s, 3H), 3.74 (s, 3H), 3.64 (d, J = 6.4 Hz, 2H), 3.54 (d, J = 6.6 Hz, 2H). HRMS calcd for C38H32O9Na [M+Na] ＋ : 655.1944, found 655.1943. 13 C NMR (126 MHz, DMSO) δ 164.8, 164.6, 154.9, 151.7, 150.0, 149.9,148.0, 148.0 (d, J= 2.2 Hz), 147.5, 140.3, 139.1, 137.9, 135.0, 134.2, 128.3,125.2 (d), 124.1, 123.9, 123.6, 120.9, 120.7, 117.8, 116.6, 115.9, 115.5 (d), 113.3, 112.6, 112.1, 111.6, 111.4, 111.3, 55.7, 55.6, 28.7. The 1H and 1C NMR spectra of derivative 16c are as follows: 1 H NMR (500 MHz, CDCl3) δ 7.83 – 7.73 (m, 2H), 7.73 (s, 1H), 7.70 (s,1H), 7.51 (d, J = 8.4 Hz, 1H), 7.29 (dd, J = 8.5, 1.8 Hz, 1H), 6.76 (s, 2H), 6.72(s, 2H), 6.52 (d, J = 15.9 Hz, 1H), 6.46 (d, J = 15.9 Hz, 1H), 6.09 – 5.98 (m,2H), 5.84 (s, 1H), 5.81 (s, 1H), 5.19 – 4.95 (m, 4H), 3.87 (s, 6H), 3.83 (s,6H), 3.72 (d, 2H), 3.54 (d, J = 6.6 Hz, 2H). HRMS calcd for C40H36O11Na [M+Na] ＋ : 715.2155, found 715.2150. 13 C NMR (126 MHz, CDCl3) δ 165.4, 165.0, 155.8, 152.8, 147.8, 147.5,147.4, 147.3, 140.3, 139.1, 137.8, 137.7, 134.9, 134.4, 128.2, 125.6, 125.5,124.4, 121.8, 120.6, 118.6, 116.5, 116.1, 114.4, 113.9, 112.6, 111.7, 105.5,105.4, 56.4, 56.4, 40.2, 29.4. The 1H and 1C NMR spectra of derivative 16d are as follows: 1 H NMR (500 MHz, DMSO) δ 9.72 (d, J = 10.1 Hz, 2H), 9.17 (d, J = 7.3 Hz,2H), 8.05 (s, 1H), 7.97 (d, J = 1.8 Hz, 1H), 7.74 – 7.62 (m, 3H), 7.37 (dd, J =8.5, 1.8 Hz, 1H), 7.13 – 7.03 (m, 3H), 7.00 (dd, J = 8.2, 2.1 Hz, 1H), 6.73(dd, J = 18.0, 8.1 Hz, 2H), 6.52 (d, J = 15.9 Hz, 1H), 6.44 (d, J = 15.7 Hz, 1H), 6.11 – 6.01 (m, 1H), 6.01 – 5.90 (m, 1H), 5.16 – 5.02 (m, 4H), 3.63 (d, J = 6.3Hz, 2H), 3.54 (d, J = 6.7 Hz, 2H). HRMS calcd for C36H28O9Na [M+Na] ＋ :627.1631, found 627.1626. 13 C NMR (126 MHz, DMSO) δ 164.7, 164.4, 154.9, 151.7, 149.1, 149.0,148.1, 147.7, 145.6, 140.3, 139.1, 138.0, 135.1, 134.2, 128.4, 125.2, 123.6,122.2, 120.9, 120.7, 117.8, 116.6, 116.0, 115.8, 115.7, 115.2, 115.0, 113.4,112.0, 111.7, 111.6, 28.7. The 1H and 1C NMR spectra of derivative 16e are as follows: 1H NMR (500 MHz, CDCl3) δ 10.31 (s, 1H), 10.22 (s, 1H), 7.98 (dd, J =8.0, 1.7 Hz, 1H), 7.86 (s, 1H), 7.81 (dd, J = 8.1, 1.7 Hz, 1H), 7.75 (d, J = 1.7Hz, 1H), 7.55 (d, J = 8.4 Hz, 1H), 7.51 – 7.45 (m, 1H), 7.45 – 7.40 (m, 1H), 7.33 (dd, J = 8.5, 1.8 Hz, 1H), 7.00 – 6.95 (m, 2H), 6.91 – 6.84 (m, 1H), 6.77– 6.72 (m, 1H), 6.11 – 5.96 (m, 2H), 5.18 – 5.02 (m, 4H), 3.76 (d, J = 6.3 Hz, 2H), 3.56 (d, J = 6.7 Hz, 2H). HRMS calcd for C32H24O7Na [M+Na] ＋ : 543.1420, found 543.1418. 13 C NMR (126 MHz, CDCl3) δ 168.4, 168.2, 162.2, 162.2, 155.9, 152.9,139.3, 138.1, 137.7, 137.0, 136.8, 135.2, 134.0, 130.3, 130.1, 128.6, 124.1,122.3, 120.7, 119.8, 119.7, 118.9, 117.9, 117.9, 116.9, 116.2, 112.7, 111.8,111.3, 111.0, 40.2, 29.4. The 1H and 1C NMR spectra of derivative 16f are as follows: 1 H NMR (500 MHz, CDCl3) δ 7.84 (s, 1H), 7.76 (dd, J = 8.4, 1.9 Hz, 1H), 7.71 (d, J= 1.7 Hz, 1H), 7.67 (dd, J = 8.4, 1.9 Hz, 1H), 7.55 (d, J = 1.9 Hz, 1H), 7.52 (d, J = 8.5 Hz, 1H), 7.49 (d, J = 1.9 Hz, 1H), 7.29 (dd, J = 8.5, 1.8 Hz, 1H), 6.92 (d, J = 8.3 Hz, 1H), 6.84 (d, J = 8.3 Hz, 1H), 6.27 – 5.96 (m, 4H), 5.16 –5.01 (m, 4H), 3.84 (s, 3H), 3.74 – 3.72 (m, 5H), 3.54 (d, J = 6.6 Hz, 2H). HRMScalcd for C34H28O9Na [M+Na] ＋ : 603.1631, found 603.1633. 13 C NMR (126 MHz, CDCl3) δ 164.6, 164.2, 155.7, 152.7, 150.9, 150.7,146.4, 146.2, 140.4, 139.2, 137.8, 134.9, 134.4, 128.1, 125.3, 125.2, 124.4,121.7, 121.0, 120.7, 120.6, 118.7, 116.5, 116.1, 114.4, 114.3, 112.7, 112.3,112.1, 111.7, 56.2, 56.0, 40.2, 29.5. The 1H and 1C NMR spectra of 16g ​​of derivative are as follows: 1 H NMR (500 MHz, CDCl3) δ 7.86 (s, 1H), 7.72 (d, J = 1.8 Hz, 1H), 7.52(d, J= 8.4 Hz, 1H), 7.38 (s, 2H), 7.32 – 7.28 (m, 3H), 6.10 – 5.98 (m, 2H), 5.16 – 5.01 (m, 4H), 3.85 (s, 6H), 3.77 – 3.71 (m, 8H), 3.54 (d, J = 6.6 Hz,2H). HRMS calcd for C36H32O11Na [M+Na] ＋ : 663.1842, found 663.1846. 13 C NMR (126 MHz, CDCl3) δ 164.6, 164.2, 155.7, 152.6, 146.9, 146.7,140.3, 140.2, 140.0, 139.1, 137.8, 134.9, 134.5, 128.2, 124.4, 121.7, 120.6,119.8, 119.5, 118.6, 116.4, 116.1, 112.8, 111.7, 107.4, 107.3, 56.5, 56.3,40.1, 29.5. The 16-hour NMR spectra of the derivative are as follows: 1 H NMR (500 MHz, Acetone) δ 7.97 (s, 1H), 7.96 (d, J = 1.8 Hz, 1H), 7.62 (d, J = 8.4 Hz, 1H), 7.39 (dd, J = 8.5, 1.8 Hz, 1H), 7.21 (s, 2H), 7.17 (s,2H), 6.13 – 5.96 (m, 2H), 5.19 – 4.96 (m, 4H), 3.70 (d, J = 6.3 Hz, 2H), 3.58(d, J = 6.7 Hz, 2H). HRMS calcd for C32H24O11Na [M+Na] ＋ : 607.1216, found607.1213. 13C NMR (126 MHz, Acetone) δ 165.0, 164.6, 156.4, 153.2, 146.2, 146.1,141.9, 140.9, 139.7, 139.5, 138.9, 136.2, 135.3, 129.1, 125.0, 122.1, 121.6,120.3, 120.0, 119.1, 116.7, 116.0, 113.9, 112.3, 110.5, 110.4, 40.6, -0.0. Activity test 1. Cells were treated with 0.3 mM FA to establish an FA injury model, and the cell rescue effect of the compound magnolol monomer derivative of this invention on cell damage was further evaluated. The CCK-8 experimental results are shown in Table 1.

[0048] Table 1

[0049] As shown in Table 1, compared with the model group, the derivatives of this invention all improved the viability of damaged cells to varying degrees. Among them, derivatives 16c, 16f, and compound 9 exhibited the strongest cytoprotective effects, increasing cell viability by 120.3%, 116.6%, and 67.3%, respectively, with significantly better protective effects than the natural product BiM. BiM not only failed to provide protection but also further reduced cell viability. These results indicate that the derivatives obtained by selectively modifying the structure of the natural product BiM can effectively antagonize FA-induced neurocytotoxicity.

[0050] 2. The monomeric derivative of magnolol improves FA-induced damage in Caenorhabditis elegans. This study established a FA (fat-induced toxicity) injury model in *Caenorhabditis elegans* to further verify the protective effect of the target compound and screen its optimal concentration. Synchronized N2 nematodes were incubated to the L1 stage and then inoculated onto NGM agar plates with different treatments. When the nematodes reached the L2 stage, they were collected using M9 buffer and washed three times. After natural sedimentation, the supernatant was discarded. 20 mM FA solution was added, and the nematode density was adjusted. 100 μL of the suspension was pipetted into 96-well plates, and the nematode motility index was detected using a wMicroTracker system, with data collected every 2 h until the nematodes died. The results are as follows: Figure 1 As shown, treatment with derivatives 16c, 16f, and compound 9 delayed nematode mortality in a concentration-dependent manner, and each compound exhibited the best protective effect at a concentration of 30 μM.

[0051] Furthermore, to compare the protective efficacy of each compound at its optimal concentration, derivatives 16c and 16f, monomer 9, and BiM were compared at a concentration of 30 μM. The results are as follows: Figure 2 As shown, the survival curve of the 16c treatment group was significantly better than that of the other groups, exhibiting the strongest protective effect (p<0.01). This is consistent with the results of the aforementioned CCK-8 experiment. In summary, treatment with 30 μM of 16c, 16f, and compound 9 can effectively improve the survival rate of nematodes exposed to FA. To ensure consistency in subsequent experiments, a concentration of 30 μM was chosen for further research on the target compounds.

[0052] 3. The monomeric derivatives of magnolol and ligustilide reduce FA levels in nematodes. Pathological FA accumulation can directly damage synaptic function and induce AD-like pathological symptoms. Therefore, whether candidate compounds can effectively reduce abnormally elevated FA levels in nematodes is a key efficacy indicator for assessing their potential anti-AD activity. This study used the fluorescent probe NA-SF to detect FA levels in nematodes.

[0053] Synchronized N2 nematodes were incubated to the L1 stage and then inoculated onto NGM agar plates with different treatments, and cultured at 20 °C to the L3 stage. The nematodes were collected and washed using M9 buffer. Then, 12 mM FA was added, and the nematodes were cultured for another 4 h. After this, the FA solution was discarded, and the washing was repeated three times with M9 buffer. Similarly, CL4176 nematodes were cultured at 15 °C for 36 h, then incubated at 25 °C for another 36 h to the L3 stage. The nematodes were collected and washed. Then, 20 μM NA-SF solution was added for staining. N2 and CL4176 nematodes were incubated at 20 °C and 25 °C, respectively, for 30 min. After this, the staining solution was discarded, and the washing was repeated three times with M9 buffer. The nematodes were then anesthetized with sodium azide, mounted on agarose slides, and observed and photographed under an upright fluorescence microscope in GFP mode. Quantitative analysis was performed using ImageJ. The fluorescence results are shown below. Figure 3 As shown, where Figure 3 In the image, A represents the FA fluorescence image of N2 nematode. Figure 3 In this context, B represents the quantified value of FA fluorescence intensity. Compared with untreated N2 nematodes, 12 mM FA treatment led to a sharp increase in FA levels within the nematodes, while treatments with derivatives 16c, 16f, monomer 9, and BiM reversed the abnormal increase in FA levels caused by acute FA exposure to varying degrees. Among them, derivative 16c and compound 9 showed comparable effects, exhibiting the strongest FA scavenging activity. p <0.001) Furthermore, to investigate the ability of the target compound to regulate endogenous FA levels under pathological conditions, FA levels in the AD model nematode CL4176 were measured. Fluorescence chromatogram is shown below. Figure 4 As shown, where Figure 4 In the image, A represents the FA fluorescence images of N2 and CL4176 nematodes. Figure 4 In this context, B represents the quantified value of FA fluorescence intensity. Experimental results show that the basal FA level of CL4176 nematodes is significantly higher than that of wild-type N2 nematodes. Treatment with the above compounds significantly reduced the abnormal endogenous FA level in CL4176 nematodes. Derivative 16c and monomer 9 still showed outstanding performance in endogenous FA scavenging. p <0.001).

[0054] The experimental results above indicate that derivatives 16c, 16f, monomer 9, and BiM can not only effectively reverse the increase in exogenous FA levels caused by acute FA exposure, but also significantly reduce the accumulation of endogenous FA in the AD model nematode. The regulatory effects of these candidate compounds on FA homeostasis suggest their potential as anti-AD drugs.

[0055] 4. The monomeric derivative of magnolol delays the paralysis process of CL4176 nematodes. The anti-AD effect of the target compound was validated using Aβ-transgenic nematodes through multidimensional phenotypic verification. After temperature induction, CL4176 nematodes expressed human Aβ1-42 in body wall muscle cells and exhibited a rapid paralysis phenotype. The paralysis experiment method is as follows: Synchronized CL4176 nematodes were incubated to the L1 stage and then inoculated onto NGM agar plates with different treatments, and cultured at 15 °C for 36 h. Subsequently, at least 25 nematodes from each group were transferred to new 3 cm NGM agar plates coated with OP50 bacterial zones, and the temperature was raised to 25 °C to induce Aβ expression. Paralysis data were recorded every 2 h starting 24 h after temperature rise until all nematodes were paralyzed. The criterion for determining the paralysis phenotype was: when the tail of the nematode was gently plucked with a platinum wire, the nematode only retained the ability to respond to mechanical stimulation in its head and could not complete whole-body movement.

[0056] The result is as follows Figure 5 As shown, where, Figure 5 In the image, A represents a typical microscopic image of the CL4176 nematode in its normal and paralyzed states. Figure 5 In the figure, B represents the paralysis analysis of CL4176 nematodes. Treatment with derivatives 16c, 16f, compound 9, and BiM effectively delayed the paralysis time of CL4176 nematodes. Among them, derivative 16c showed the best effect, delaying the final paralysis time by 8 hours compared with untreated nematodes.

[0057] 5. The monomeric derivative of magnolol improves cognitive dysfunction in CL2355 nematodes. CL2355 nematode is an Aβ transgenic nematode whose phenotype more closely resembles the typical pathological features of Alzheimer's disease (AD). CL2355 nematodes express human Aβ1-42 in neurons, mimicking the cognitive impairment caused by abnormal Aβ aggregation. Its typical behavioral phenotype is a deficiency in benzaldehyde chemotaxis. Chemotaxis experiments are as follows: Synchronized Aβ transgenic nematodes CL2355 and the control strain CL2122 were incubated to the L1 stage and then inoculated onto NGM agar plates with different treatments. After incubation at 15 ℃ for 36 h, the temperature was increased to 25 ℃ and incubated for another 36 h to reach the L3 stage. A 6 cm NGM agar plate without OP50 was divided into two parts: a trap zone (T) and a normal zone (N). 2 μL of 0.1% benzaldehyde ethanol solution and 2 μL of 0.25 M sodium azide solution were added to the center of the T zone, and 2 μL of ethanol solution and 2 μL of 0.25 M sodium azide solution were added to the corresponding position in the N zone as controls. Subsequently, at least 25 nematodes from each group were picked and placed in the center of the agar plate, incubated at 25 ℃ for 30 min, and the number of nematodes in each quadrant was observed and recorded; the chemotactic index (CI) was calculated as [(T-N) / (T+N)]×100%.

[0058] The experimental results are as follows Figure 6 As shown, compared with the control strain CL2122 (which does not express Aβ), the chemotactic index of CL2355 nematodes was significantly reduced (p<0.001), confirming its cognitive-behavioral deficits. However, after treatment with the candidate compound, the chemotactic index of CL2355 nematodes showed varying degrees of recovery, indicating that its benzaldehyde chemotactic deficit was effectively improved. Notably, after treatment with derivative 16c, the chemotactic index of CL2355 nematodes almost returned to normal levels. This experimental result strongly supports the conclusion that the candidate compound has a neuroprotective effect on the AD model nematode.

[0059] 6. The monomeric derivative of magnolol reduces the expression level of Aβ in CL4176 nematodes. The Aβ mRNA level in the Aβ transgenic nematode CL4176 was detected using real-time quantitative PCR (RT-qPCR). The results are as follows: Figure 7 As shown, treatment with derivative 16c, compound 9, and BiM resulted in varying degrees of downregulation of Aβ mRNA levels in CL4176 nematodes, with 16c exhibiting the most significant downregulation (p<0.01). This result indicates that the aforementioned compounds can exert anti-AD effects by inhibiting Aβ mRNA transcription in transgenic nematodes, thereby reducing the expression of their toxic proteins.

[0060] 7. The monomeric derivative of magnolol reduces the level of Aβ oligomer protein in GMC101 nematodes. Following temperature induction, GMC101 expressed human Aβ1-42 in body wall muscle cells, forming Aβ oligomers. This study used Western blot to detect the protein levels of Aβ oligomers in nematodes. Results are as follows... Figure 8 As shown, no specific bands were detected in the control strain CL2122, which does not express Aβ, while Aβ oligomers such as tetramers, pentamers, and hexamers were clearly formed in GMC101 nematodes. Further comparative analysis revealed that, compared with untreated GMC101, treatment with derivatives 16c and 16f significantly reduced the protein levels of Aβ pentamers and hexamers in nematodes. This indicates that 16c and 16f can effectively inhibit Aβ oligomerization, reduce the formation of highly neurotoxic aggregates, and thus exert a neuroprotective effect.

[0061] In summary, this invention provides a series of novel monoclonal derivatives of magnolol. Activity screening results in SH-SY5Y cells showed that these derivatives effectively antagonized FA-induced cytotoxicity. In a *C. elegans* model, they significantly improved the survival rate of nematodes exposed to FA and reduced FA levels in nematodes, demonstrating a good FA detoxification effect. Furthermore, in an AD model of nematodes, these derivatives also delayed the progression of paralysis, improved cognitive dysfunction, and reduced Aβ expression and accumulation, exhibiting significant neuroprotective effects.

[0062] The present invention has been described in detail above with reference to the embodiments of the present invention. However, the present invention is not limited to the above embodiments. Within the scope of knowledge possessed by those skilled in the art, various changes can be made without departing from the spirit of the present invention.

Claims

1. A monomeric derivative of magnolol, characterized in that, It has the structural formula shown in Equation I: ； Among them, R1 and R2 are each independently selected from C. 1~6 alkyl, C 2~6 alkenyl, C 2~6 alkynyl group, C 2~6 Acyl group, , ; n represents an integer from 1 to 5, and R3 are independently selected from H and C. 1~6 alkyl, C 1~6 alkoxy, C 1~6 Halogenated alkyl groups, nitro groups, hydroxyl groups, and halogens; Alternatively, R3 may form an oxygen-doped 3- to 6-membered heterocycle with the adjacent phenyl group; R4 is selected from H or C. 1~6 Alkyl groups.

2. The honokiol monomer derivative according to claim 1, characterized in that, R1 and R2 are each independently selected from C 1~3 alkyl, C 2~4 alkenyl, C 2~4 alkynyl group, C 2~4 Acyl group, , .

3. The honokiol monomer derivative according to claim 1, characterized in that, R3 is independently selected from H and C. 1~3 alkyl, C 1~3 alkoxy, C 1~3 Halogenated alkyl groups, nitro groups, hydroxyl groups, and halogens; Alternatively, R3 can form an oxygen-doped 3- to 6-membered heterocycle with the adjacent phenyl group.

4. The monoclonal derivative of magnolol according to any one of claims 1 to 3, characterized in that, The combined magnolol monomer derivative is selected from the following structural formulas: 。 5. A method for preparing the monoclonal derivative of magnolol as described in any one of claims 1 to 4, characterized in that, Includes the following steps: The halide corresponding to compound A and R1 is obtained by nucleophilic substitution reaction; Alternatively, it can be obtained by reacting compound A with the acid anhydride corresponding to R1; Alternatively, compound A and compound B can be esterified to obtain the product. Alternatively, compound B can be reacted with a hydroxyl protecting agent first, then esterified with compound 9, and finally deprotected to obtain the product. The structural formula of compound A is as follows: ； The structural formula of compound B is as follows: 。 6. The preparation method according to claim 5, characterized in that, The esterification reaction is carried out under the conditions of EDCI and DMAP.

7. The preparation method according to claim 5, characterized in that, The hydroxyl protecting agent includes tert-butyldimethylchlorosilane.

8. The preparation method according to claim 5, characterized in that, The nucleophilic substitution reaction also includes a starting base.

9. The use of the doxycycline monomer derivative according to any one of claims 1 to 4 in the preparation of a medicament for treating methanol-induced neurocytotoxicity.

10. The use of a monoclonal derivative of magnolol in the preparation of drugs for the treatment and / or prevention of Alzheimer's disease, characterized in that, The monoclonal derivative of the ligustiol has the structural formula shown in Formula II: ； Among them, R1 and R2 are each independently selected from H and C. 1~6 alkyl, C 2~6 alkenyl, C 2~6 alkynyl group, C 2~6 Acyl group, , ; n represents an integer from 1 to 5, and R3 are independently selected from H and C. 1~6 alkyl, C 1~6 alkoxy, C 1~6 Halogenated alkyl groups, nitro groups, hydroxyl groups, and halogens; Alternatively, R3 may form an oxygen-doped 3- to 6-membered heterocycle with the adjacent phenyl group; R4 is selected from H or C. 1~6 Alkyl groups.

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