A forskolin ring-expanded derivative and its preparation method and application

Abstract

The invention belongs to the technical field of medicinal chemistry and pharmacology, and discloses a forskolin ring expansion derivative and a preparation method and application thereof. The forskolin ring expansion derivative has a chemical structure shown in formula (I), wherein forskolin and potassium hydroxide react in methanol to obtain a forskolin rearrangement product 1, then the forskolin rearrangement product 1 reacts with a Dess-Martin oxidant and pyridine in dichloromethane to obtain a forskolin rearrangement product 2, then the forskolin rearrangement product 2 reacts with meta-chloroperbenzoic acid and sodium bicarbonate in dichloromethane to obtain a forskolin rearrangement ring expansion product 3, and finally the forskolin rearrangement ring expansion product 3 reacts with an aryl iodide in anhydrous dichloroethane under the catalysis of anhydrous silver acetate, anhydrous copper acetate and palladium acetate to obtain a forskolin ring expansion derivative 4. The forskolin ring expansion derivative obtained by the invention has strong anti-inflammatory activity and can be used to prepare anti-inflammatory drugs.

Description

Technical Field

[0001] The invention belongs to the technical field of pharmaceutical chemistry and pharmacology, and specifically relates to a forskolin ring-expanded derivative and a preparation method and application thereof. Background Art

[0002] In recent years, Hergenrother, PJ and others have developed a new synthesis strategy: Complexity-to-Diversity Strategy (CtD) (Furiassi, L.; Tonogai, EJ; Hergenrother, PJ Limonin as a Starting Point for the Construction of Compounds with High Scaffold Diversity. Angew. Chem. Int. Ed. 2021, 60, 16119-16128; Morrison. KC; Hergenrother, PJ Natural Products as Starting Points for the Synthesis of Complex and Diverse Compounds, Nat. Prod. Rep. 2014, 31, 6-14). This strategy uses complex and abundant natural products such as pleuromutilin, gibberellins, and adrenosterone as starting materials, and reshapes the skeleton structure of natural products through various ring deformation reactions (Ring-Distortion Reactions) such as ring breakage, ring rearrangement, ring fusion, ring contraction, and ring expansion to obtain complex and diverse natural product analogs for drug screening.

[0003] Forskolin is a diterpenoid compound with important medicinal value in anti-cancer, anti-asthma, anti-hypertension and positive inotropic effects. In addition, forskolin can also interact with certain other proteins, such as glucose transporters and ion channels. The results of pharmacodynamic studies have shown that forskolin can effectively promote the differentiation of neurons and the growth of neurites in the central and peripheral nervous systems, thereby having an important impact on the cardiovascular and cerebrovascular systems, respiratory systems and tumors, and has pharmacological effects such as cardiotonic, anti-asthmatic, anti-tumor, anti-thrombotic and lowering intraocular pressure. It is now clinically used for the treatment of cardiovascular and cerebrovascular diseases, tumors and common diseases of the elderly, with obvious pharmacological effects and broad prospects for clinical application. Forskolin has a chemical structure with three cyclic ring systems of A, B and C and 8 stereochemical centers, and is a high-yield natural product, making it very suitable as a starting material for ring deformation reactions. Summary of the invention

[0004] The purpose of the present invention is to provide a forskolin ring-expanded derivative and a preparation method and application thereof, and to chemically transform forskolin and obtain a forskolin ring-expanded derivative with a novel structure by adopting a complexity to diversity strategy (CtD strategy), so as to further develop its pharmaceutical use.

[0005] The present invention provides a forskolin ring-expanded derivative, which has a structure shown in general formula (I):

[0006]

[0007] Wherein, R1 represents one of phenyl, p-chlorophenyl, p-methoxyphenyl, p-trifluoromethoxyphenyl, p-tert-butylphenyl, p-nitrophenyl and p-cyanophenyl.

[0008] Furthermore, the forskolin ring-expanded derivative has a structure as shown in any one of Formulae 4a to 4d:

[0009]

[0010] in,

[0011] When R1 is phenyl, the forskolin ring-expanded derivative is a compound with a structure shown in Formula 4a;

[0012] When R1 is p-chlorophenyl, the forskolin ring-expanded derivative is a compound with a structure shown in Formula 4b;

[0013] When R1 is p-methoxyphenyl, the forskolin ring-expanded derivative is a compound with a structure shown in Formula 4c;

[0014] When R1 is p-trifluoromethoxyphenyl, the forskolin ring-expanded derivative is a compound having a structure shown in Formula 4d;

[0015] The present invention also provides a preparation method of a forskolin ring-expanded derivative, comprising the following steps: reacting forskolin with potassium hydroxide in methanol to obtain a forskolin rearrangement product 1, then reacting the forskolin rearrangement product 1 with a Dess-Martin oxidant and pyridine in dichloromethane to obtain a forskolin rearrangement product 2, then reacting the forskolin rearrangement product 2 with meta-chloroperbenzoic acid and sodium bicarbonate in dichloromethane to obtain a forskolin rearrangement ring-expanded product 3, and finally reacting the forskolin rearrangement ring-expanded product 3 with an aryl iodide in anhydrous dichloroethane under the catalysis of anhydrous silver acetate, anhydrous copper acetate and palladium acetate to obtain a forskolin ring-expanded derivative 4.

[0016] Wherein, the reaction formula of the reaction is:

[0017]

[0018] Wherein, R1 represents one of phenyl, p-chlorophenyl, p-methoxyphenyl, p-trifluoromethoxyphenyl, p-tert-butylphenyl, p-nitrophenyl and p-cyanophenyl.

[0019] Specifically, the preparation method comprises the following steps:

[0020] (1) dissolving potassium hydroxide in methanol, adding forskolin to react to obtain a first reaction solution, cooling the first reaction solution, concentrating under reduced pressure, diluting with an organic solvent, washing with water, washing with saturated brine, drying over anhydrous MgSO4, drying under reduced pressure, and then flash column chromatography to obtain a white solid forskolin rearrangement product 1, wherein the molar ratio of forskolin to potassium hydroxide is 1:13;

[0021] (2) dissolving the forskolin skeleton rearrangement product 1 in dichloromethane, adding a Dess-Martin periodinane and pyridine to react to obtain a second reaction solution, diluting the second reaction solution with an organic solvent, adding a saturated sodium bicarbonate aqueous solution and a saturated sodium thiosulfate aqueous solution, filtering, washing the organic phase with water and saturated brine in sequence, drying over anhydrous MgSO4, concentrating under reduced pressure, and then flash column chromatography to obtain a white solid forskolin rearrangement product 2, wherein the molar ratio of the forskolin rearrangement product 1, the Dess-Martin periodinane, and the pyridine is 1:2.5:2;

[0022] (3) dissolving the forskolin rearrangement product 2 in dichloromethane, adding sodium bicarbonate and meta-chloroperbenzoic acid to react to obtain a third reaction solution, diluting the third reaction solution with an organic solvent, adding a 10% sodium sulfite aqueous solution, filtering, washing the organic phase with water, washing with saturated brine, drying over anhydrous MgSO4, concentrating under reduced pressure, and then flash column chromatography to obtain a white solid forskolin ring expansion product 3, wherein the molar ratio of the forskolin rearrangement product 2, sodium bicarbonate, and meta-chloroperbenzoic acid is 1:1:1.5;

[0023] (4) dissolving the forskolin rearrangement ring-expanding product 3 in anhydrous dichloroethane, and sequentially adding anhydrous silver acetate, anhydrous copper acetate, palladium acetate and aryl iodide to react to obtain a fourth reaction solution, cooling the fourth reaction solution, diluting it with an organic solvent, filtering it, concentrating the filtrate under reduced pressure, and then flash column chromatography to obtain a white solid forskolin ring-expanding derivative 4, wherein the molar ratio of the forskolin ring-expanding product 3, anhydrous silver acetate, anhydrous copper acetate, palladium acetate and aryl iodide is 1:1.2:2:0.05:2;

[0024] Wherein, the aryl iodide is one of iodobenzene, p-chloroiodobenzene, p-methoxyiodobenzene, p-trifluoromethoxyiodobenzene, p-tert-butyliodobenzene, p-nitroiodobenzene and p-cyaniodobenzene.

[0025] Furthermore, in step (1) of the above preparation method, the reaction temperature is 65° C. and the reaction time is 4 h.

[0026] Furthermore, in step (2) of the above preparation method, the reaction temperature is 25° C. and the reaction time is 12 h.

[0027] Furthermore, in step (3) of the above preparation method, the reaction temperature is 25° C. and the reaction time is 24 h.

[0028] Furthermore, in step (4) of the above preparation method, the reaction temperature is 70° C. and the reaction time is 12 h.

[0029] Furthermore, in the above preparation method, the organic solvent is at least one of methanol, dichloromethane, dichloroethane and ethyl acetate.

[0030] The present invention also provides the use of the forskolin ring-expanded derivative in the preparation of anti-inflammatory drugs.

[0031] Compared with the prior art, the present application provides a class of forskolin ring-expanded derivatives and preparation methods and applications thereof. Such compounds have novel structures and excellent anti-inflammatory activity and can be used in the preparation of anti-inflammatory drugs. BRIEF DESCRIPTION OF THE DRAWINGS

[0032] In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings required for use in the embodiments or the description of the prior art are briefly introduced below.

[0033] Figure 1 The NMR of the forskolin rearrangement product (2) provided in Example 2 of the present invention 1 H spectrum;

[0034] Figure 2 The NMR of the forskolin rearrangement product (2) provided in Example 2 of the present invention 13 C spectrum;

[0035] Figure 3 The NMR of the forskolin ring expansion product (3) provided in Example 3 of the present invention 1 H spectrum;

[0036] Figure 4 The NMR of the forskolin ring expansion product (3) provided in Example 3 of the present invention 13 C spectrum;

[0037] Figure 5 The NMR of the forskolin ring-expanded derivative (4a) provided in Example 4 of the present invention is 1 H spectrum;

[0038] Figure 6The nuclear magnetic resonance of the forskolin ring-expanded derivative (4a) provided in Example 4 of the present invention 13 C spectrum. DETAILED DESCRIPTION

[0039] The technical solutions in the embodiments of the present invention are described clearly and completely below. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of them. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0040] Example 1

[0041] 730 mg (13.0 mmol) of potassium hydroxide was dissolved in methanol (10 ml), and then 410 mg (1.0 mmol) of forskolin was added and reacted at 65° C. for 4 hours. The reaction solution was concentrated under reduced pressure, diluted with ethyl acetate (10 ml), and then washed with water and saturated brine in sequence, dried over anhydrous MgSO4, and concentrated under reduced pressure. 336 mg of white solid was obtained by flash column chromatography (petroleum ether: ethyl acetate = 2:1), i.e., forskolin rearrangement product 1 (yield 91%).

[0042] 1 H NMR(400MHz,Methanol-d4)δ6.06(dd,J=17.5,10.9Hz,1H,H-14),5.16(dd,J=17.5,1.2Hz,1H,H-15),5.04(dd,J=10 .9,1.2Hz,1H,H-15),4.16(dd,J=11.0,5.2Hz,1H,H-1),4.01(dd,J=4.1,1.7Hz,1H,H-6),3.64(d,J=1.6Hz,1H,H-7), 3.19(d,J=14.4Hz,1H,H-12),1.90(d,J=14.3Hz,1H,H-12),1.79–1.68(m,1H),1.65(d,J=4.1Hz,1H,H-5),1.64–1.60 (m,1H),1.52(s,3H,CH3),1.48(s,3H,CH3),1.47(s,3H,CH3),1.34–1.28(m,2H),1.26(s,3H,CH3),0.98(s,3H,CH3). 13C NMR(100MHz,MeOD)δ143.89,111.35,106.48,91.76,90.54,88.51,88.44,71.18,64 .92,47.66,45.98,44.38,40.55,33.31,30.00,28.38,26.45,24.95,23.14,13.44.

[0043] Example 2

[0044] 368 mg (1.0 mmol) of forskolin rearrangement product 1 was dissolved in dichloromethane (10 ml), and 183 μL (2.0 mmol) of pyridine and 1.06 g (2.5 mmol) of Dess-Martin periodinane were added, and the mixture was reacted at 25° C. for 12 hours. Ethyl acetate (10 ml), saturated sodium bicarbonate aqueous solution, and saturated sodium thiosulfate aqueous solution were added to the reaction solution, and the mixture was filtered. The organic phase was washed with water and saturated brine in sequence, dried over anhydrous MgSO4, and concentrated under reduced pressure. Then, 243 mg of a white solid, i.e., forskolin rearrangement product 2 (yield 67%), was obtained by flash column chromatography (petroleum ether: ethyl acetate = 8:1).

[0045] 1 H NMR(400MHz,Chloroform-d)δ5.91(dd,J=17.4,10.7Hz,1H,H-15),5.18(d,J=17.4Hz,1H,H-16),5.12( d,J=10.7Hz,1H,H-16),4.64(s,1H,H-6),4.39(d,J=2.5Hz,1H,H-7),2.82(d,J=18.2Hz,1H,H-13),2.6 4–2.59(m,1H,6-OH),2.59–2.49(m,2H),2.47(d,J=2.7Hz,1H,H-5),2.46(d,J=18.1Hz,1H,H-13),1.82 –1.71(m,2H),1.78(s,3H,CH3),1.42(s,3H,CH3),1.35(s,3H,CH3),1.26(s,3H,CH3),1.19(s,3H,CH3). 13 C NMR (100MHz, CDCl3) δ215.04,206.38,169.58,142.13,113.97,87.88,83.12,79.16,65.19,53. 88,47.89,46.17,38.32,35.63,32.66,30.39,27.69,26.03,21.07,20.75.HRMS(ESI):m / zcalcd for C 20 H28 O6Na:387.1778; found:387.1788[M+Na] + .

[0046] Example 3

[0047] 364 mg (1.0 mmol) of forskolin rearrangement product 2 was dissolved in dichloromethane (10 ml), and 84 mg (1.0 mmol) of sodium bicarbonate and 259 mg (1.5 mmol) of m-chloroperbenzoic acid were added, and the mixture was reacted at 25° C. for 24 hours. The reaction solution was diluted with dichloromethane (10 ml), and a 10% aqueous sodium sulfite solution was added, and the mixture was filtered. The organic phase was washed with water and saturated brine in sequence, dried over anhydrous MgSO4, and concentrated under reduced pressure. 171 mg of a white solid was obtained by flash column chromatography (ethyl acetate: petroleum ether = 5:1), i.e., forskolin rearrangement ring expansion product 3 (yield 45%).

[0048] 1 H NMR(400MHz,Chloroform-d)δ5.91(dd,J=17.4,10.7Hz,1H,H-15),5.21(d,J=17.0Hz,1H,H-16),5.20(d,J=11.0Hz,1H,H-16),4.54(dd,J =11.2,1.5Hz,1H,H-6),4.10(dd,J=10.7,1.5Hz,1H,H-7),3.93(d,J=10.8Hz,1H,OH),3.46(d,J=11.1Hz,1H,H-5),3.05(d,J=19.0Hz,1H, H-13),2.84(ddd,J=17.6,8.8,1.9Hz,1H,H-2),2.71(ddd,J=17.6,11.4,1.9Hz,1H,H-2),2.52(d,J=19.0Hz,1H,H-13),2.04(ddd,J=15.0 ,11.3,1.9Hz,1H,H-3),1.70(s,3H,CH3),1.56(s,3H,CH3),1.55–1.50(m,1H,H-3),1.47(s,3H,CH3),1.18(s,3H,CH3),1.17(s,3H,CH3). 13 C NMR (100MHz, CDCl3) δ218.9,171.9,170.1,140.8,115.6,82.2,80.8,80.7,80.1, 76.7,52.4,46.0,36.3,33.1,31.7,31.5,29.3,25.6,24.1,20.7.HRMS(ESI):m / z calcd for C 20H 28 O7Na:403.1733; found:403.1731[M+Na] + .

[0049] Example 4

[0050] 380 mg (1.0 mmol) of the forskolin ring-enlargement product 3 was dissolved in anhydrous dichloroethane (10 ml), and 200 mg (1.2 mmol) of anhydrous silver acetate, 363 mg (2.0 mmol) of anhydrous copper acetate, 12 mg (0.05 mmol) of palladium acetate, and 408 mg (2.0 mmol) of iodobenzene were added in sequence, and the mixture was reacted at 70° C. for 12 hours. After the reaction solution was cooled, ethyl acetate (10 ml) was added for dilution, and the mixture was filtered. The filtrate was washed with water and saturated brine in sequence, dried over anhydrous MgSO4, and concentrated under reduced pressure. 305 mg of a white solid, i.e., the forskolin ring-enlargement derivative 4a (yield 67%), was obtained by flash column chromatography (petroleum ether: ethyl acetate = 8:1).

[0051] 1 H NMR(400MHz,)δ7.44–7.30(m,5H,ArH),6.58(d,J=16.1Hz,1H,H-16),6.33(d,J=16.1Hz,1H,

[0052] H-15), 4.58 (dd, J=11.2, 2.0Hz, 1H, H-6), 4.13 (dd, J=10.3, 1.9Hz, 1H, H-7), 3.89 (d, J=10. 6Hz,1H,OH),3.30(d,J=11.1Hz,1H,H-5),3.11(d,J=18.9Hz,1H,H-13),2.72–2.56(m,2H,H -2),2.63(d,J=19.0Hz,1H,H-13),1.90(dd,J=10.0,4.7Hz,1H,H-3),1.72(s,3H,CH3),1.6 3(s,3H,CH3),1.61(s,3H,CH3),1.55–1.46(m,1H,H-3),1.25(s,3H,CH3),1.18(s,3H,CH3). 13 C NMR (100MHz, CDCl3) δ218.9,171.9,169.8,135.4,132.2,130.7,128.9,128.3,126.8,82.1,81. 4,80.5,80.0,76.6,54.1,47.8,36.9,33.5,31.9,29.7,28.8,25.3,23.8,20.7.HRMS(ESI):m / z calcd for C26 H 32 O7Na:479.2046; found:479.2041[M+Na] + .

[0053] Embodiments 5 to 7

[0054] According to the method of Example 4 above, iodobenzene was replaced by p-chloroiodobenzene, p-methoxyiodobenzene, or p-trifluoromethoxyiodobenzene to prepare Example compounds 4b to 4d.

[0055] The physicochemical data of compounds 4b to 4d are listed below: 4b: Yield 76%. 1 H NMR(400MHz,Chloroform-d)δ7.34(q,J=8.6Hz,4H,ArH),6.51(d,J=16.2Hz,1H,H-16),6.28(d,J=16.2Hz,1H,H-15),4.59(dd,J=1 1.0,1.7Hz,1H,H-6),4.16(dd,J=10.6,1.7Hz,1H,H-7),3.99(d,J=10.5Hz,1H,OH),3.28(d,J=11.1Hz,1H,H-5),3.13(d,J=19.0Hz, 1H,H-13),2.75(ddd,J=16.9,10.2,2.1Hz,1H,H-2),2.68–2.57(m,1H,H-2),2.62(d,J=18.8Hz,1H,H-13),1.91(ddd,J=15.1,10.1 ,1.8Hz,1H,H-3),1.73(s,3H,CH3),1.63(s,3H,CH3),1.61(s,3H,CH3),1.60–1.53(m,1H,H-3),1.20(s,3H,CH3),1.19(s,3H,CH3). 13 C NMR (100MHz, CDCl3) δ219.1,172.0,169.8,134.0,133.9,132.8,129.6,129.0,128.1,82.4,81.0, 80.4,80.1,76.8,54.2,47.7,37.2,33.6,32.1,32.0,28.6,25.6,23.6,20.7.HRMS(ESI):m / zcalcd for C 26 H 31 O7NaCl:513.1656; found:513.1658[M+Na] + .

[0056] 4c: Yield 54%. 11H NMR (400 MHz, ) δ 7.36 (d, J = 8.6 Hz, 2H, ArH), 7.04–6.81 (m, 2H, ArH), 6.53 (d, J = 16.1 Hz, 1H, H-16), 6.17 (d, J = 16.1 Hz, 1H, H-15), 4.58 (dd, J = 11.1, 1.9 Hz, 1H, H-6), 4.15–4.10 (m, 1H, H-7), 3.92 (d, J = 10.5 Hz, 1H, OH), 3.81 (s, 3H, OCH3), 3.34 (d, J = 11.1 Hz, 1H, H-5), 3.10 (d, J = 18.9 Hz, 1H, H-13), 2.75–2.67 (m, 1H, H-2), 2.65–2.55 (m, 1H, H-2), 2.61 (d, J = 19.1 Hz, 1H, H-13), 1.91 (dd, J = 14.6, 10.5 Hz, 1H, H-3), 1.73 (s, 3H, CH3), 1.63 (s, 3H, CH3), 1.61 (s, 3H, CH3), 1.59–1.52 (m, 1H, H-3), 1.25 (s, 3H, CH3), 1.19 (s, 3H, CH3), 1.18 (s, 3H, CH3). 13 13C NMR (100 MHz, CDCl3) δ 219.3, 171.9, 169.8, 159.7, 130.3, 130.0, 128.1, 128.1, 114.3, 82.2, 81.2, 80.5, 80.1, 76.7, 55.3, 54.0, 48.0, 37.0, 33.5, 31.9, 31.9, 28.6, 25.4, 23.8, 20.7. HRMS (ESI): m / z calcd for C 27 1 34 21H38O8Na: 509.2151; found: 509.2155 [M+Na] + .

[0057] 4d: Yield 73%. 1H NMR(400MHz,Chloroform-d)δ7.48(d,J=8.7Hz,2H,ArH),7.25–7.14(m,2H,ArH),6.56(d,J=16.2Hz,1H,H-16),6.30(d,J=16.1Hz,1H,H- 15),4.61(dd,J=11.1,1.6Hz,1H,H-6),4.18(dd,J=10.6,1.6Hz,1H,H-7),4.03(d,J=10.6Hz,1H,OH),3.31(d,J=11.1Hz,1H,H-5),3.17(d ,J=19.0Hz,1H,H-13),2.77(ddd,J=16.9,10.3,1.9Hz,1H,H-2),2.69–2.60(m,1H,H-2),2.64(d,J=19.0Hz,1H,H-13),1.92(ddd,J=15.2 ,10.0,1.9Hz,1H,H-3),1.75(s,3H,CH3),1.65(s,3H,CH3),1.64(s,3H,CH3),1.62–1.56(m,1H,H-3),1.22(s,3H,CH3),1.21(s,3H,CH3). 13 C NMR (100MHz, CDCl3) δ219.1,172.0,169.8,149.0,134.2,133.3,129.3,128.2,121.3,82.4,81. 0,80.4,80.1,76.9,54.2,47.7,37.2,33.6,32.1,32.0,28.7,25.6,23.5,20.7.HRMS(ESI):m / z calcd for C 27 H 31 O8 NaF3:563.1869; found:563.1874[M+Na] + .

[0058] In order to better understand the essence of the present invention, the pharmacological experimental results of the inhibitory effect of the forskolin ring expansion derivatives provided by the present invention on the NO release of RAW264.7 cells induced by LPS are used below to illustrate its new use in the field of anti-inflammatory drug research. The pharmacological examples provide partial activity data of representative compounds. It must be noted that the pharmacological examples of the present invention are used to illustrate the present invention rather than to limit the present invention. Simple improvements made to the present invention according to the essence of the present invention all fall within the scope of protection claimed by the present invention.

[0059] Drug Example 1: Inhibitory activity of compounds 4a-4d, forskolin and dexamethasone on LPS-induced NO release in RAW 264.7 macrophages

[0060] RAW 264.7 macrophages were cultured at 1×10 5 The cells were inoculated at a density of 100 μg / mL on a 96-well plate and incubated in a 37°C, 5% CO2 incubator for 24 hours. This experiment set up a control group, an LPS-induced group, a positive control dexamethasone (DEX) group, and an experimental group. The positive control group and the experimental group were added with 0.2, 1.0, 5.0, and 25.0 μM of the test compound 4a-4d or DEX to be tested to the treated RAW 264.7 macrophages. After 4 hours of placement, 10 μL of culture medium was added to the control group, and LPS (1.0 μg / mL) was added to the other groups to induce the cells. The cells were incubated for 24 hours, centrifuged, and the supernatant of the cells was collected. The release of NO was determined by a nitric oxide kit, and the IC was calculated using Graphpad5 software. 50 The MTT assay was used to detect the effects of the compounds at 20 μM on the growth of RAW 264.7 macrophages.

[0061] Table 1 Inhibitory activity of compounds 4a-4d, forskolin and dexamethasone on LPS-induced NO release in RAW 264.7 macrophages

[0062] Compound <![CDATA[IC 50 (μM)]]> Cell survival rate / % 4a 2.2 99.55±3.14 4b 4.8 99.36±1.31 4c 7.2 98.04±3.16 4d 6.1 98.76±1.24 Forskolin 25.1 100.33±1.88 DEX 8.6 99.27±2.43

[0063] As shown in Table 1, the forskolin ring-expanded derivatives provided by the present invention have important biological activities. The inhibitory activity test of LPS-induced NO release in RAW 264.7 macrophages shows that the forskolin ring-expanded derivatives of the structure shown in formula (1) have good inhibitory activity on LPS-induced NO release in RAW 264.7 macrophages. The inhibitory effects of compounds 4a-4d in the examples are significantly better than those of the positive control drugs dexamethasone and forskolin, and they have no obvious cytotoxicity, and may be developed into new anti-inflammatory drugs.

[0064] The above is only a preferred embodiment of the present invention. It should be pointed out that for ordinary technicians in this technical field, several improvements and modifications can be made without departing from the principle of the present invention. These improvements and modifications should also be regarded as the scope of protection of the present invention.

Claims

1. A forskolin ring-expanded derivative, characterized in that: The structure of the forskolin ring expansion derivative is shown in the following formula: Wherein, R1 represents one of phenyl, p-chlorophenyl, p-methoxyphenyl, p-trifluoromethoxyphenyl, p-tert-butylphenyl, p-nitrophenyl and p-cyanophenyl.

2. A forskolin ring-expanded derivative according to claim 1, characterized in that: The forskolin ring-expanded derivative has a structure as shown in any one of Formulae 4a to 4d:

3. A method for preparing the forskolin ring-expanded derivative according to claim 1, characterized in that: The reaction formula of the preparation method is shown below: The preparation method comprises the following steps: S1. Potassium hydroxide is dissolved in methanol, and forskolin is added to react to obtain a first reaction solution, the first reaction solution is cooled, concentrated under reduced pressure, diluted with an organic solvent, washed with water, washed with saturated brine, dried over anhydrous MgSO4, dried under reduced pressure, and then flash column chromatography to obtain a white solid forskolin rearrangement product 1, wherein the molar ratio of forskolin to potassium hydroxide is 1:13; S2. Dissolve the forskolin rearrangement product 1 in dichloromethane, add Dess-Martin periodinane and pyridine to react to obtain a second reaction solution, dilute the second reaction solution with an organic solvent, add saturated sodium bicarbonate aqueous solution and saturated sodium thiosulfate aqueous solution, filter, wash the organic phase with water and saturated brine in sequence, dry over anhydrous MgSO4, concentrate under reduced pressure, and then obtain a white solid forskolin rearrangement product 2 by flash column chromatography, wherein the molar ratio of forskolin rearrangement product 1, Dess-Martin periodinane and pyridine is 1:2.5:2; S3. Dissolve the forskolin rearrangement product 2 in dichloromethane, add sodium bicarbonate and meta-chloroperbenzoic acid to react to obtain a third reaction solution, dilute the third reaction solution with an organic solvent, add a 10% sodium sulfite aqueous solution, filter, wash the organic phase with water, wash with saturated brine, dry with anhydrous MgSO4, concentrate under reduced pressure, and then flash column chromatography to obtain a white solid forskolin ring expansion product 3, wherein the molar ratio of the forskolin rearrangement product 2, sodium bicarbonate, and meta-chloroperbenzoic acid is 1:1:1.5; S4. dissolving the forskolin ring-expansion product 3 in anhydrous dichloroethane, and sequentially adding anhydrous silver acetate, anhydrous copper acetate, palladium acetate and aryl iodide to react to obtain a fourth reaction solution, cooling the fourth reaction solution, diluting it with an organic solvent, filtering it, concentrating the filtrate under reduced pressure, and then flash column chromatography to obtain a white solid forskolin ring-expansion derivative 4, wherein the molar ratio of the forskolin rearrangement ring-expansion product 3, anhydrous silver acetate, anhydrous copper acetate, palladium acetate and aryl iodide is 1:1.2:2:0.05:2; Wherein, the aryl iodide is one of iodobenzene, p-chloroiodobenzene, p-methoxyiodobenzene, p-trifluoromethoxyiodobenzene, p-tert-butyliodobenzene, p-nitroiodobenzene and p-cyaniodobenzene.

4. The preparation method according to claim 3, characterized in that: In step S1, the reaction temperature is 65° C. and the reaction time is 4 h.

5. The preparation method according to claim 3, characterized in that: In step S2, the reaction temperature is 25° C. and the reaction time is 12 h.

6. The preparation method according to claim 3, characterized in that: In step S3, the reaction temperature is 25° C. and the reaction time is 24 h.

7. The preparation method according to claim 3, characterized in that: In step S4, the reaction temperature is 70° C. and the reaction time is 12 h.

8. The preparation method according to claim 3, characterized in that: The organic solvent is at least one of methanol, dichloromethane, dichloroethane and ethyl acetate.

9. Use of the forskolin ring-expanded derivative according to claim 1 in the preparation of anti-inflammatory drugs.

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