CN115960069A - Mixed source terpenes, preparation method thereof, pharmaceutical composition thereof and application thereof - Google Patents
Mixed source terpenes, preparation method thereof, pharmaceutical composition thereof and application thereof Download PDFInfo
- Publication number
- CN115960069A CN115960069A CN202111169421.3A CN202111169421A CN115960069A CN 115960069 A CN115960069 A CN 115960069A CN 202111169421 A CN202111169421 A CN 202111169421A CN 115960069 A CN115960069 A CN 115960069A
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- Prior art keywords
- compound
- nephropathy
- compounds
- pharmaceutically acceptable
- acute
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- 239000008194 pharmaceutical composition Substances 0.000 title claims description 10
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- 150000001875 compounds Chemical class 0.000 claims abstract description 71
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Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention belongs to the field of natural medicines and medicinal chemistry, and relates to a mixed source terpene, a preparation method thereof, a medicinal composition thereof and application thereof. In particular to the application in the aspect of acute and chronic kidney diseases. The in vitro activity evaluation shows that the compound shows excellent kidney cell protection effect in the test of the oxidative damage of the renal tubular epithelial cells caused by hydrogen peroxide and cisplatin, and has application prospect in the aspect of resisting acute and chronic nephrosis.
Description
Technical Field
The invention belongs to the field of natural medicines and medicinal chemistry, and relates to a mixed source terpene, a preparation method thereof, a medicinal composition thereof and application thereof. The invention specifically discloses application of the mixed source terpene in treating acute and chronic nephrosis.
Background
In recent years, kidney diseases have been receiving increasing attention as the level of medical care has increased and aging has accelerated. Renal diseases are generally classified into acute renal injury and chronic renal disease. Acute renal injury is often caused by nephrotoxic drugs, sepsis due to bacterial infection, and ischemia-reperfusion due to trauma, and if not treated promptly, it rapidly progresses to acute renal failure with poor prognosis. Chronic kidney disease is generally classified into primary and secondary chronic kidney disease. The primary chronic nephropathy mainly refers to various immune glomerulonephritis and the like, including IgA nephritis, focal segmental glomerulosclerosis, membranous nephropathy and the like; the secondary chronic nephropathy mainly comprises diabetic nephropathy, hypertensive nephropathy, lupus nephritis, purpura nephritis, etc. Besides genetic factors, the factors causing nephritis also include physical, chemical and biological factors, which cause pathological structural change and dysfunction of kidney, and are clinically characterized by high glomerular filtration rate, hematuria, proteinuria, edema, accumulation of uremic toxin substances in blood, hypertension and the like. At present, no effective treatment medicine is available for acute kidney injury or chronic kidney disease in clinic. Nephropathy can be well treated and controlled in an early stage, and the progress can be delayed. In contrast, kidney function is further impaired, causing kidney failure and even progression to uremia. Once kidney failure occurs, electrolyte disorder, high potassium, severe metabolic acidosis and even general edema occur, so that the kidney failure is extremely harmful to human bodies. Chronic kidney disease can cause hypertension, thereby inducing the onset of cardiovascular disease or increasing the mortality rate of patients with existing cardiovascular disease. Glomerulonephritis causes massive proteinuria or loss of other nutrients, which can also cause malnutrition, and the accumulation of uremic substances in the blood can further exacerbate the progression of other organ diseases.
Disclosure of Invention
Guava is a plant of genus guava of family Myrtaceae, mainly distributed in south China, and is a fruit tree and medicinal plant. The guava mixed source terpenoids G-1 and G-2 are two new skeleton mixed source terpenoids separated from guava leaves. Biological activity screening shows that guava mixed source terpenes G-1 and G-2 have certain activity of resisting acute nephritis. The invention takes guava mixed source terpenoids G-1 and G-2 as lead compounds, discovers a batch of mixed source terpenoids with the effect of resisting acute and chronic nephrosis by carrying out structural modification on a plurality of sites and systematically summarizing structure-activity relationship, and further completes the invention through verification of pharmacological experiments.
The invention discloses a compound of a general formula I, which has obvious protective effect on oxidative stress injury of renal tubular epithelial cells in vitro and injury caused by chemotherapeutic drugs through pharmacological experiments. Therefore, the compound of the general formula I can be used for preventing and/or treating acute kidney injury caused by chemotherapeutic drugs (such as cisplatin), bacterial lipopolysaccharide, ischemia reperfusion and other various nephrotoxic drugs; also includes chronic kidney diseases such as IgA nephritis, henoch Schonlein purpura nephritis, membranous nephropathy, lupus nephritis, diabetic nephropathy, hypertensive nephropathy and various kinds of glomerulonephritis. The invention relates to a mixed source terpenoid shown as a general formula I or a pharmaceutically acceptable salt thereof:
R 1 、R 2 independently selected from H, CH 3 、CH 2 CH 3 、CH 2 CH 2 CH 3 、CH(CH 3 ) 2 、CH 2 CH 2 CH 2 CH 3 、 CH 2 CH(CH 3 ) 2 、CH(CH 3 )CH 2 CH 3 A tert-butyl group;
R 3 、R 4 independently selected from formyl, benzoyl, carboxyl, hydroxymethyl,
Wherein formula I excludes the following compounds:
the structure and the number of partial compounds of the invention are as follows:
a pharmaceutical composition comprising, as an active ingredient, a compound described in G-1 to 10 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or excipient.
The compound G-1-10 or the pharmaceutically acceptable salt thereof can be applied to the preparation of medicines for preventing and/or treating acute and chronic nephrosis.
The acute kidney disease is selected from chemotherapy drugs, nephrotoxic drugs, bacterial lipopolysaccharide or acute kidney injury caused by ischemia reperfusion injury; the chronic nephropathy is selected from IgA nephropathy, purpura nephritis, membranous nephropathy, lupus nephritis, diabetic nephropathy, hypertensive nephropathy or glomerulonephritis.
The compounds of the present invention represented by formula I can be prepared by the following method:
wherein G-1 and G-2 are reaction intermediates, and the reaction conditions (a) are reactant methyl iodide, catalyst potassium carbonate and solvent acetone at 50 ℃; the reaction condition (b) is oxidant DDQ, mixed solvent tert-butyl alcohol-tetrahydrofuran-water, 0 ℃; the reaction condition (c) is a reducing agent NaBH 4 Tetrahydrofuran, solvent, 0 ℃; the reaction condition (d) is that reactant N-methyl piperazine, catalyst acetic acid and solvent tetrahydrofuran are at 0 ℃.
Ia includes G-4 and the like.
Ib includes compounds such as G-6.
Ic includes compounds such as G-8.
Id includes compounds such as G-10, etc.
IIa includes compounds such as G-3.
IIb includes compounds such as G-5.
IIc includes compounds such as G-7.
IId includes compounds such as G-9.
The intermediates G-1 and G-2 can be prepared according to the literature (org. Lett.2019,21,8700-8704, the synthesis method is as follows:
wherein (1) to (3) are reaction conditions: (1) nitrobenzene, aluminum chloride and benzoyl chloride are carried out for 24 hours at 65 ℃; (2) DMF, POCl 3 12h; (3) paraformaldehyde and luprene, and the temperature is 80 ℃ for 5 hours.
In another aspect, the invention relates to pharmaceutical compositions comprising as active ingredient a compound of the invention. The pharmaceutical compositions are prepared according to methods well known in the art. The compounds of the invention may be formulated into any dosage form suitable for human or animal use by combining them with one or more pharmaceutically acceptable solid or liquid excipients and/or adjuvants. The compounds of the invention are generally present in the pharmaceutical compositions in an amount of from 0.1 to 95% by weight.
The compound of the invention or the pharmaceutical composition containing the same can be administrated in a unit dosage form, and the administration route can be intestinal tract or parenteral tract, such as oral administration, intravenous injection, intramuscular injection, subcutaneous injection, nasal cavity, oral mucosa, eyes, lungs, respiratory tract, skin, vagina, rectum and the like.
The dosage form for administration may be a liquid dosage form, a solid dosage form, or a semi-solid dosage form. The liquid dosage forms can be solution (including true solution and colloidal solution), emulsion (including o/w type, w/o type and multiple emulsion), suspension, injection (including water injection, powder injection and infusion), eye drop, nose drop, lotion, liniment, etc.; the solid dosage form can be tablet (including common tablet, enteric coated tablet, buccal tablet, dispersible tablet, chewable tablet, effervescent tablet, orally disintegrating tablet), capsule (including hard capsule, soft capsule, enteric coated capsule), granule, powder, pellet, dripping pill, suppository, pellicle, patch, aerosol (powder), spray, etc.; semisolid dosage forms can be ointments, gels, pastes, and the like.
The compound can be prepared into common preparations, sustained-release preparations, controlled-release preparations, targeting preparations and various microparticle drug delivery systems.
For tableting the compounds of the invention, a wide variety of excipients well known in the art may be employed, including diluents, binders, wetting agents, disintegrants, lubricants, glidants. The diluent can be starch, dextrin, sucrose, glucose, lactose, mannose, sorbitol, xylitol, microcrystalline cellulose, calcium sulfate, calcium hydrogen phosphate, calcium carbonate, etc.; the humectant can be water, ethanol, isopropanol, etc.; the binder can be starch slurry, dextrin, syrup, mel, glucose solution, microcrystalline cellulose, acacia slurry, gelatin slurry, sodium carboxymethylcellulose, methylcellulose, hydroxypropyl methylcellulose, ethyl cellulose, acrylic resin, carbomer, polyvinylpyrrolidone, polyethylene glycol, etc.; the disintegrant may be dry starch, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, crosslinked polyvinylpyrrolidone, crosslinked sodium carboxymethylcellulose, sodium carboxymethyl starch, sodium bicarbonate and citric acid, polyoxyethylene sorbitol fatty acid ester, sodium dodecyl sulfate, etc.; the lubricant and glidant may be talc, silicon dioxide, stearate, tartaric acid, liquid paraffin, polyethylene glycol, etc.
The tablets may be further formulated as coated tablets, such as sugar-coated tablets, film-coated tablets, enteric-coated tablets, or double-layered and multi-layered tablets.
To encapsulate the administration units, the active ingredient of the compounds of the invention can be mixed with diluents and glidants and the mixture can be placed directly into hard or soft capsules. Or the effective component of the compound of the invention can be prepared into granules or pellets with diluent, adhesive and disintegrating agent, and then placed into hard capsules or soft capsules. The various diluents, binders, wetting agents, disintegrants, glidants used to prepare tablets of the compounds of the present invention may also be used to prepare capsules of the compounds of the present invention.
For preparing the compound of the present invention into injection, water, ethanol, isopropanol, propylene glycol or their mixture can be used as solvent, and appropriate amount of solubilizer, cosolvent, pH regulator, and osmotic pressure regulator commonly used in the art can be added. The solubilizer or cosolvent may be poloxamer, lecithin, hydroxypropyl-beta-cyclodextrin, etc. The pH regulator can be phosphate, acetate, hydrochloric acid, sodium hydroxide, etc.; the osmotic pressure regulator can be sodium chloride, mannitol, glucose, phosphate, acetate, etc. For example, in the preparation of lyophilized powder for injection, mannitol and glucose can also be added as proppant.
In addition, colorants, preservatives, flavors, or other additives may also be added to the pharmaceutical preparation, if desired.
For the purpose of administration and enhancing the therapeutic effect, the drug or pharmaceutical composition of the present invention can be administered by any known administration method.
The dosage of the pharmaceutical composition of the compound of the present invention to be administered may vary widely depending on the nature and severity of the disease to be prevented or treated, the individual condition of the patient or animal, the route and dosage form of administration, and the like. Generally, a suitable daily dosage range of the compounds of the invention is from 0.001 to 150mg/kg body weight, preferably from 0.1 to 100 mg/kg body weight, more preferably from 1 to 60mg/kg body weight, most preferably from 2 to 30mg/kg body weight. The above-described dosage may be administered in one dosage unit or divided into several dosage units, depending on the clinical experience of the physician and the dosage regimen including the use of other therapeutic means.
The compounds or compositions of the present invention may be administered alone or in combination with other therapeutic or symptomatic agents. When the compound of the present invention has a synergistic effect with other therapeutic agents, its dosage should be adjusted according to the actual circumstances.
The compounds shown in part of the general formula I of the invention are subjected to pharmacological experiments related to kidney protection. Among the many mechanisms causing acute and chronic kidney injury, oxidative stress is an important one, and excessive production of intracellular free radicals or reduction of the ability to scavenge free radicals destroys the oxidative balance, which in turn causes lipid peroxidation, mitochondrial dysfunction, activation of apoptotic pathways, etc., and damages cells.
The in vitro hydrogen peroxide is used for constructing an oxidative damage model, which is very classic, has the advantages of easy operation, strong repeatability and the like, and is widely used. Cisplatin is an effective anticancer drug, but it shows strong nephrotoxicity, and researchers in recent years find that a major mechanism of acute kidney injury caused by cisplatin is oxidative stress, and a method for constructing an oxidative injury model by cisplatin is gradually accepted, so in the research, the compounds of the general formula I are screened by constructing the oxidative injury model by hydrogen peroxide and cisplatin.
The inventor finds that the compound of the general formula I provided by the invention shows excellent kidney cell protection effect in a test of hydrogen peroxide and cisplatin causing oxidative damage of renal tubular epithelial cells.
Pharmacological experiments show that the compound shown in the general formula I has good protection effect on kidney injury caused by oxidative stress, and can be used for preparing medicines for preventing and/or treating the acute and chronic kidney injury.
Preferred renal diseases are selected from the group consisting of acute renal injury caused by chemotherapeutic agents (e.g., cisplatin), bacterial lipopolysaccharide, ischemia reperfusion, and other nephrotoxic drugs; also includes chronic kidney diseases such as IgA nephritis, henoch Schonlein purpura nephritis, membranous nephropathy, lupus nephritis, diabetic nephropathy, hypertensive nephropathy, and various kinds of glomerulonephritis.
The beneficial technical effects are as follows: at present, no effective treatment medicine is available for acute kidney injury or chronic kidney disease in clinic. Nephropathy can be well treated and controlled in early stage, and the progress can be delayed. On the contrary, the kidney function is further impaired, thereby causing kidney failure and even uremia, which is extremely harmful to the human body. The guava mixed source terpenes G-1 and G-2 are two new skeleton mixed source terpenoids separated from guava leaves. Biological activity screening shows that guava mixed source terpenes G-1 and G-2 have certain activity of resisting acute nephritis. The invention takes guava mixed source terpenoids G-1 and G-2 as lead compounds, discovers a batch of mixed source terpenoids with the effect of resisting acute and chronic nephrosis by carrying out structural modification on a plurality of sites and systematically summarizing structure-activity relationship, and passes the verification of pharmacological experiments, thereby completing the invention.
Detailed Description
EXAMPLE 1 preparation (G-3)
Compound G-2 (1000mg, 1eq) was dissolved in 20ml acetone and K was added 2 CO 3 (580mg, 2eq), CH was added dropwise 3 I (521. Mu.l, 4 eq), heating to 50 ℃ and starting the reaction. After 10 hours of reaction, K is added 2 CO 3 (580 mg，2eq)，CH 3 I (521 μ l,4 eq), and after further reaction for 6h, the reaction was stopped, the reaction mixture was cooled to room temperature, 500ml of ethyl acetate was poured into the reaction mixture, and the ethyl acetate was washed twice with water (500 ml × 2) and once with 500ml of saturated brine. Drying over anhydrous magnesium sulfate, filtering, and spin-drying ethyl acetate to obtain a crude product, PE: EA =4, scraper 1 to obtain white crystal G-3 857.3mg with a yield of 80.9%.
1 H NMR(400MHz，Chloroform-d)δ10.40(s,1H),7.96–7.85(m,2H),7.64– 7.52(m,1H),7.46(dd,J＝8.2,6.9Hz,2H),5.17–5.13(m,1H),5.09–5.01(m,1H), 3.70(s,3H),3.67(s,3H),3.04(dd,J＝17.0,5.2Hz,1H),2.70–2.58(m,1H),2.44– 2.28(m,1H),2.26–2.07(m,3H),1.78(dd,J＝13.0,4.4Hz,1H),1.68–1.61(m，3H)， 1.58(s，1H),1.36(dd，J＝13.8，10.7Hz，1H)，1.20(s,3H)，1.06(d,J＝4.4Hz，6H).
13 C NMR(101MHz，CDCl 3 )δ195.0,188.2,160.4,159.7,158.6,143.1,138.2, 136.5,133.7,129.7,128.7,123.5,120.1,119.1,114.1,111.7,83.0,63.7,61.4,42.9, 41.6,38.4,37.8,34.7,30.4,30.3,24.5,24.0，20.5,17.3.
ESI-MS(m/z):503.3[M+H] + .
EXAMPLE 2 preparation (G-4)
Compound G-1 (1000mg, 1eq) was dissolved in 20ml acetone and K was added 2 CO 3 (580mg, 2eq), CH was added dropwise 3 I (521. Mu.l, 4 eq), heating to 50 ℃ and starting the reaction. After 10 hours of reaction, K is added 2 CO 3 (580 mg，2eq)，CH 3 I (521 μ l,4 eq), and after further reaction for 6h, the reaction was stopped, the reaction mixture was cooled to room temperature, 500ml of ethyl acetate was poured into the reaction mixture, and the ethyl acetate was washed twice with water (500 ml × 2) and once with 500ml of saturated brine. Drying over anhydrous magnesium sulfate, filtering, and spin-drying ethyl acetate to obtain a crude product, wherein EA =4 is used as a scraper for 1, and white crystals G-4 866.2mg are obtained with the yield of 81.8%.
1 H NMR(400MHz,Chloroform-d)δ10.28(s,1H),7.86–7.79(m,2H),7.60– 7.51(m,1H),7.48–7.38(m,2H),5.02–4.93(m,2H),4.59(ddd,J＝15.9,10.0,3.4 Hz,1H),3.93(s,3H),3.79(s，3H)，3.11(dd,J＝16.9，5.2Hz，1H)，2.24–2.13(m,1H), 2.17–2.08(m,3H),2.11–1.98(m,1H),1.83(dd,J＝12.8,10.5Hz,1H),1.79–1.68 (m,2H),1.57(s,2H),1.31–1.20(m,2H),1.02(s,3H),0.94(d,J＝17.4Hz,6H).
13 C NMR(101MHz,CDCl 3 )δ194.2,187.6,162.0,160.1,158.1,142.9,138.0, 136.5,133.5,129.3，128.7，123.4，119.9,119.5,115.5，112.7，83.4，64.7，62.7，42.6, 41.5,38.2,37.8,35.0，30.2，30.2，24.5，23.3，20.4，17.3.
ESI-MS(m/z):503.3[M+H] + .
EXAMPLE 3 preparation (G-5)
Mixing KH with water 2 PO 4 (270mg, 10eq) was dissolved in 2ml of water, and Compound G-3 (100mg, 1eq), 2-methyl-2-butene (830. Mu.l, 50 eq), naClO were added 2 (179mg, 10eq) in 6ml THF-tert-butanol-water mixed solvent, stirring at 0 deg.C for reaction, after 6hAdding water into the reaction solution to quench and react, and stopping the reaction. 50ml of ethyl acetate was poured into the reaction mixture, and then ethyl acetate was washed twice with water (50 ml. Times.2) and once with 50ml of saturated brine. The crude product is obtained by drying the anhydrous magnesium sulfate, filtering and spin-drying ethyl acetate, and the crude product is developed by a thin layer chromatography PE: EA = 2.
1 H NMR(400MHz,Chloroform-d)δ7.93–7.84(m,2H),7.61–7.52(m,1H), 7.45(dd,J＝8.4,7.1Hz,2H),5.29(s,1H),5.20–5.06(m,2H),5.04(ddd,J＝11.9,4.6, 1.6Hz，1H),3.68(d,J＝1.0Hz,6H),3.06(dd,J＝17.0,5.2Hz，1H),2.60(d,J＝14.2 Hz,1H),2.35(ddd,J＝14.6,8.0,2.0Hz,1H),2.24–2.08(m,3H),1.94–1.74(m,3H), 1.63(d,J＝1.4Hz,3H),1.40–1.23(m,2H),1.21(s,3H)，1.21–1.12(m,1H),1.06(s, 6H).
13 C NMR(101MHz,CDCl 3 )δ194.8,166.5,157.9,157.2,154.5,143.4,138.0, 136.4,133.7,129.7,128.7,123.5,119.9,119.7,112.1,110.2,84.1,63.6,61.7,53.6,43.1, 41.6,38.4,37.7,34.9,30.4,30.2,24.5,24.0,20.4,17.3.
ESI-MS(m/z):519.3[M+H] + .
EXAMPLE 4 preparation (G-6)
KH is prepared by mixing 2 PO 4 (270mg, 10eq) was dissolved in 2ml of water, and Compound G-4 (100mg, 1eq), 2-methyl-2-butene (830. Mu.l, 50 eq), naClO 2 (179mg, 10eq) was dissolved in 6ml of a THF-tert-butanol-water mixed solvent, the reaction was stirred at 0 ℃ and quenched with water after 6 hours, and the reaction was stopped. 50ml of ethyl acetate was poured into the reaction mixture, and then ethyl acetate was washed twice with water (50 ml. Times.2) and once with 50ml of saturated brine. Drying over anhydrous magnesium sulfate, filtering, and spin-drying ethyl acetate to obtain a crude product, which is developed by using a thin-layer chromatography PE: EA = 2.
1 H NMR(400MHz,Chloroform-d)δ7.82(d,J＝7.7Hz,2H),7.54(t,J＝7.3Hz, 1H),7.41(t,J＝7.6Hz,2H),5.01–4.92(m,2H),4.66–4.55(m,1H),3.93(s,3H), 3.77(s,3H),3.09(dd,J＝16.9,5.1Hz,1H),2.24–2.14(m,1H),2.12(s,1H),2.09(s, 2H),2.05(d,J＝9.5Hz,1H),1.82(t,J＝11.6Hz,1H),1.77–1.68(m,2H),1.58(s, 3H),1.25(t,J＝12.0Hz,1H),1.12(dt,J＝22.4,11.7Hz,1H),1.09(s,1H),1.00(s, 3H),0.94(d,J＝16.8Hz,6H).
13 C NMR(101MHz,CDCl 3 )δ194.4,168.6,158.3,155.8,155.1,142.7,138.0, 136.4,133.4,129.3,128.6,123.3,120.0,119.1,112.5,111.6,82.6,64.2，62.0,42.6，41.5, 38.2,37.8,35.0,30.3,30.2，24.5,23.8,20.2,17.3.
ESI-MS(m/z):519.3[M+H] + .
EXAMPLE 5 preparation (G-7)
Compound G-3 (100mg, 1eq) and 16mg NaBH 4 (1695 mg, 2eq) was dissolved in 5ml THF, and the reaction was stirred at 0 deg.C for 6 hours, and then quenched with water to stop the reaction. 50ml of ethyl acetate was poured into the reaction mixture, and then ethyl acetate was washed twice with water (50 ml. Times.2) and once with 50ml of saturated brine. Anhydrous magnesium sulfate is dried, filtered, ethyl acetate is spin-dried to obtain a crude product, and the crude product is developed by using a thin layer chromatography PE: EA = 4.
1 H NMR(400MHz,Chloroform-d)δ7.94–7.87(m,2H),7.61–7.52(m,1H), 7.50–7.41(m,2H),5.30(s,1H),5.22–5.00(m,3H),4.76–4.64(m,2H),3.65(d,J＝ 5.8Hz,6H),3.06(dd,J＝16.9,5.2Hz,1H),2.60(dt,J＝14.4,1.9Hz,1H),2.38(dd,J ＝14.5,9.9Hz,1H),2.25–2.07(m,3H),1.90–1.81(m,3H),1.78(dd,J＝13.0,4.5Hz, 2H),1.63(t,J＝0.9Hz,3H),1.45–1.30(m,2H),1.25(s,1H),1.18(s,5H),1.06(d,J ＝6.6Hz,6H).
13 C NMR(101MHz,CDCl 3 )δ195.6,155.4,154.9,154.9,143.1,138.3,136.6, 133.5,129.7,128.6,123.4,120.0,119.3,117.8,112.0,82.1,63.8,61.8,55.7,43.2,41.6, 38.4,37.9,35.1,30.5,30.3,24.4,24.0,20.6,17.3.
ESI-MS(m/z):527.3[M+Na] + .
EXAMPLE 6 preparation (G-8)
Compound G-4 (100mg, 1eq) and 16mg NaBH 4 (1695 mg, 2eq) was dissolved in 5ml THF, and the reaction was stirred at 0 deg.C for 6 hours, and then quenched with water to stop the reaction. 50ml of ethyl acetate was poured into the reaction mixture, and then ethyl acetate was washed twice with water (50 ml. Times.2) and once with 50ml of saturated brine. Anhydrous magnesium sulfate is dried, filtered, ethyl acetate is dried in a rotary manner to obtain a crude product, the crude product is developed by using a thin layer chromatography PE: EA = 4.
1 H NMR(400MHz,Chloroform-d)δ7.88–7.79(m,2H),7.57–7.49(m,1H), 7.41(t,J＝7.6Hz,2H),4.96(dd,J＝13.8,6.7Hz,2H),4.71(s,2H),3.88(s,3H),3.73 (s,3H),3.07(dd,J＝16.8,5.2Hz,1H),2.25–2.08(m,2H),2.08(d,J＝8.1Hz,1H), 2.08–2.04(m,1H),2.04(d,J＝2.2Hz,1H),1.83(t,J＝11.6Hz,1H),1.58(s,3H), 0.97(d,J＝5.3Hz,6H),0.93(s,3H).
13 C NMR(101MHz,CDCl 3 )δ195.5,158.2,155.9,152.5,142.3,138.4,136.5, 133.2,129.4,128.5,123.3,120.5,118.7,118.6,111.9,81.5,63.6,61.7,55.6,42.7,41.5, 38.2,37.9,35.2,30.4,30.3,24.6,24.1,20.1,17.3.
ESI-MS(m/z):527.3[M+Na] +
EXAMPLE 7 preparation (G-9)
Dissolving a compound G-3 (100mg, 1eq) and N-methylpiperazine (44 mu l,2 eq) in 5ml THF, stirring for reaction at 0 ℃, dropwise adding AcOH (23 mu l,2 eq) for 6h, heating to 20 ℃ for continuous reaction, adding water into the reaction solution for quenching reaction after 5h,the reaction was stopped. 50ml of ethyl acetate was poured into the reaction mixture, and then ethyl acetate was washed twice with water (50 ml. Times.2) and once with 50ml of saturated brine. Drying with anhydrous magnesium sulfate, filtering, spin-drying ethyl acetate to obtain crude product, and subjecting the crude product to thin layer chromatography CH 2 Cl 2 :CH 3 OH =9, 1 was spread and scraped to obtain white crystals G-9.4mg with a yield of 80.7%.
1 H NMR(400MHz,Chloroform-d)δ7.96–7.89(m,2H),7.64–7.54(m,1H), 7.50(dd,J＝8.3,7.0Hz,2H),5.18(dd,J＝15.7,1.7Hz,1H),5.02(dd,J＝12.1,4.3Hz, 1H),4.93(ddd,J＝15.9,10.6,2.5Hz,1H),4.30(s,2H),3.62(d,J＝16.1Hz,5H),3.61 (s,4H),3.05(dd,J＝16.9,5.2Hz,1H),2.84(s,3H),2.57(d,J＝14.8Hz,1H),2.39(dd, J＝14.9,10.6Hz,1H),2.16(dtd,J＝23.6,12.4,7.3Hz,3H),1.88–1.73(m,3H),1.61 (d,J＝1.3Hz,3H),1.14(s，3H),1.07(s,3H),1.01(s,3H).
13 C NMR(101MHz,CDCl 3 )δ195.0,158.7,156.9,155.5,143.6,138.0,136.6, 134.0,129.8,129.0,123.3,119.3,118.3,112.4,102.8,83.8,62.7,61.5,50.2,49.0,43.2, 42.9,41.4,38.4,37.8,35.0,30.4,30.3,24.4,24.0,20.4,17.3.
ESI-MS(m/z):587.4[M+H] + .
EXAMPLE 8 preparation (G-10)
Dissolving the compound G-4 (100mg, 1eq) and N-methylpiperazine (44 mu l,2 eq) in 5ml THF, stirring for reaction at 0 ℃, dropwise adding AcOH (23 mu l,2 eq) for 6h, heating to 20 ℃ for continuous reaction, adding water into the reaction solution for quenching reaction after 5h, and stopping the reaction. 50ml of ethyl acetate was poured into the reaction mixture, and then ethyl acetate was washed twice with water (50 ml. Times.2) and once with 50ml of saturated brine. Drying with anhydrous magnesium sulfate, filtering, spin-drying ethyl acetate to obtain crude product, and subjecting the crude product to thin layer chromatography CH 2 Cl 2 :CH 3 OH =9, 1 was developed and scraped to obtain white crystals G-10.8mg, with a yield of 82.7%.
1 H NMR(400MHz,Chloroform-d)δ7.88–7.79(m,2H),7.56(t,J＝7.3Hz,1H), 7.45(t,J＝7.6Hz,2H),5.07–4.99(m,1H),4.95(d,J＝15.8Hz,1H),4.34–4.19(m, 1H),3.82(s,2H),3.71(s,2H),3.07–2.97(m,1H),2.86(s,2H),2.26–2.10(m,1H), 2.09(s,2H),2.06(d,J＝7.0Hz,1H),1.83(t,J＝11.5Hz,1H),1.77–1.67(m,2H), 1.57(s,3H),1.25(s,1H),0.97(d,J＝10.8Hz,4H),0.96(s,2H),0.91(s,2H).
13 C NMR(101MHz,CDCl 3 )δ195.2,159.3,156.2,155.8,142.8,138.1,136.3, 133.7,129.4,128.9,123.4，119.8，117.1，111.1,103.8,82.4，62.5，61.1，50.2，48.0,43.3, 42.7,41.4,38.1,37.7,34.9,30.5,30.4,24.7,24.5,19.9,17.2.
ESI-MS(m/z):587.4[M+H] + .
Pharmacological experiments:
experimental example 1: protective effect of compounds G-1-10 on hydrogen peroxide damaged HK2 cells in vitro
The method comprises the following steps: collecting HK2 cells (renal tubular epithelial cells) with a monolayer at logarithmic growth phase, discarding the stock culture solution, adding 10% FBS and 5% bovine serum in DMEM complete culture solution, gently blowing with a pipette to completely disperse the cells at 10% 4 Each 100. Mu.l of the suspension was inoculated into a 96-well plate and cultured overnight for the experiment. The experiment is divided into a blank group, a model group and an additive group. Blank group was given complete medium and model group was hydrogen peroxide (H) 2 O 2 ) The final concentration is 500 mu M, the administration group is that various test compounds are simultaneously administered for modeling, the cells are acted for 24 hours, then 20 mu l of 5mg/ml MTT is added, formazan crystals are formed after 4 hours, 150 mu l of dimethyl sulfoxide (DMSO) is added to dissolve the crystals, and the absorbance value is measured by a microplate reader at the wavelength of 570nm, which represents the number of the living cells.
Compounds G-1 to 10 pairs of H 2 O 2 The results of the in vitro HK2 cytoprotective screening of the lesions are shown in Table 1, H 2 O 2 Can obviously reduce the survival rate of HK2 cells, and H is treated in 10 mu mol/L G-1 to 10 compounds 2 O 2 The compounds with certain protective effect on the injured HK2 cells are G-1, 2, 3, 4, 8, 9 and 10.
# p < 0.001vs blank control group, # p < 0.05, # p < 0.01vs model control group
Experimental example 2: in vitro HK2 cell protection effect of compounds G-1-10 on cisplatin damage
The method comprises the following steps: collecting HK2 cells (renal tubular epithelial cells) with a monolayer at logarithmic growth phase, discarding the stock culture solution, adding 10% FBS and 5% bovine serum in DMEM complete culture solution, gently blowing with a pipette to completely disperse the cells at 10% 4 Each 100. Mu.l of the suspension was inoculated into a 96-well plate and cultured overnight for the experiment. The experiment is divided into a blank group, a model group and an additive group. The blank group is given with complete culture medium, the model group is given with Cisplatin (Cisplatin) with the final concentration of 150 mu M, the administration group is used for model building and simultaneously given with various tested compounds, cells are acted for 24h, then 20 mu l of 5mg/ml MTT is added, formazan crystals are formed after 4h, 150 mu l of DMSO is added for dissolving the crystals, and the absorbance value is measured by a microplate reader at the wavelength of 570nm, thereby representing the number of the surviving cells.
The screening results of the protective action of the compounds G-1 to 10 on the HK2 cells damaged by the cisplatin in vitro are shown in the table 2, the survival rate of the HK2 cells can be obviously reduced by the cisplatin, and in the compounds of No. 10 mu mol/l G-1 to No. 10, the compounds having a certain protective action on the HK2 cells damaged by the cisplatin are G-3, 4, 6 and 10.
TABLE 2 Effect of Compounds G1-10 on cisplatin oxidative Damage (means. + -. SD, n = 3)
The blank control group with # p < 0.001vs, the model control group with p < 0.05, and the model control group with p < 0.01vs
Experimental example 3: in vitro HK2 cell protection effect on hydrogen peroxide injury under multiple concentrations of 8 compounds
The method comprises the following steps: logarithm taking birthLong-term confluent monolayer of HK2 cells (renal tubular epithelial cells), discarding the stock culture, adding 10% (wt) of FBS and 5% of bovine serum in DMEM complete culture, gently blowing with a pipette to completely disperse the cells at 10% 4 The cells were inoculated in a 96-well plate at a volume of 100. Mu.l and cultured overnight for the experiment. The experiment is divided into a blank group, a model group and an additive group with different concentrations. Blank group was given complete medium and model group was H 2 O 2 The final concentration is 500 mu M, the administration sets with different concentrations are used for modeling, meanwhile, various test compounds are administered according to the final concentrations of 1, 5 and 10 mu mol/l of the test compounds, the cells are acted for 24h, then 20 mu l of 5mg/ml MTT is added, formazan crystals are formed after 4h, 150 mu l of DMSO is added for dissolving the crystals, and the absorbance value is measured by a microplate reader at the wavelength of 570nm, so that the number of the viable cells is represented.
To H under different concentrations of 8 compounds 2 O 2 Results of the in vitro HK2 cytoprotective screening of lesions are shown in Table 3, H 2 O 2 Can obviously reduce the survival rate of HK2 cells, and can obviously reduce the H in tested compounds with different concentrations 2 O 2 The compounds with remarkable protective effect on the injured HK2 cells are G-1, 2, 4, 8, 9 and 10, and have certain dose dependence.
Table 3 effect of different concentrations of compound G1, 2, 3, 4, 6, 8, 9, 10 on hydrogen peroxide oxidative damage (means ± SD, n = 3)
# p < 0.001vs blank control group, # p < 0.05, # p < 0.01vs model control group
Experimental example 4: in-vitro HK2 cell protection effect on cisplatin damage under multiple concentrations of 8 compounds
The method comprises the following steps: collecting HK2 cells (renal tubular epithelial cells) with a monolayer at logarithmic growth phase, discarding the stock culture solution, adding 10% FBS and 5% bovine serum in DMEM complete culture solution, gently blowing with a pipette to completely disperse the cells at 10% 4 Each 100. Mu.l of the suspension was inoculated into a 96-well plate and cultured overnight for the experiment. The experiment is divided into a blank group, a model group and an additive group. Blank spaceThe complete culture medium is given to the model group, the final concentration of cisplatin is 150 mu M, the administration groups with different concentrations are used for adding cisplatin and simultaneously giving various tested compounds with the final concentrations of the tested compounds of 1, 5 and 10 mu mol/l, cells act for 24h, then 20 mu l of 5mg/ml MTT is added, formazan crystals are formed after 4h, 150 mu l of DMSO is added for dissolving the crystals, and the absorbance value is measured by a microplate reader at the wavelength of 570nm to indicate the number of the viable cells.
The screening results of 7 in vitro HK2 cell protection effects on the damage of cisplatin are shown in Table 4, the survival rate of HK2 cells can be obviously reduced by the cisplatin, and among tested compounds with different concentrations, compounds with certain protection effects on the HK2 cells damaged by the cisplatin are G-3, 4, 8 and 9.
Table 4 effect of different concentrations of compound G1, 2, 3, 4, 6, 8, 9, 10 on cisplatin oxidative damage (means ± SD, n = 3)
# p < 0.001vs blank control, p < 0.05, p < 0.01vs model control.
Claims (5)
1. A class of mixed source terpenoids represented by the general formula I or pharmaceutically acceptable salts thereof:
R 1 、R 2 independently selected from H, CH 3 、CH 2 CH 3 、CH 2 CH 2 CH 3 、CH(CH 3 ) 2 、CH 2 CH 2 CH 2 CH 3 、CH 2 CH(CH 3 ) 2 、CH(CH 3 )CH 2 CH 3 A tert-butyl group;
R 3 、R 4 independently selected from formyl, benzoyl, carboxyl, hydroxymethyl,
Wherein formula I excludes the following compounds:
2. the compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein said compound is selected from the group consisting of:
3. a pharmaceutical composition comprising the compound of claim 1 or 2 or a pharmaceutically acceptable salt thereof as an active ingredient and a pharmaceutically acceptable carrier or excipient.
4. Use of a compound according to claim 1 or 2 or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the prevention and/or treatment of acute or chronic kidney disease.
5. The use according to claim 4, wherein the acute kidney disease is selected from the group consisting of acute kidney injury caused by chemotherapeutic agents, nephrotoxic agents, bacterial lipopolysaccharide, or ischemia reperfusion injury; the chronic nephropathy is selected from IgA nephropathy, purpura nephritis, membranous nephropathy, lupus nephritis, diabetic nephropathy, hypertensive nephropathy or glomerulonephritis.
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| BYEOL RYU等: "Meroterpenoids from the leaves of Psidium guajava (guava) cultivated in Korea using MS/MS-based molecular networking", 《PHYTOCHEMISTRY》, pages 1 - 12 * |
| JIWU HUANG等: "Psiguamers A–C, three cytotoxic meroterpenoids bearing a methylated benzoylphloroglucinol framework from Psidium guajava and total synthesis of 1 and 2", 《CHINESE CHEMICAL LETTERS》, pages 1721 * |
| LIRONG JIANG等: "Antitumor effect of guava leaves on lung cancer: A network pharmacology study", 《ARABIAN JOURNAL OF CHEMISTRY》, pages 7773 * |
| 刘晓聪等: "番石榴的化学成分及其抗肿瘤与抗真菌活性", 《中国中药杂志》, pages 3877 - 3885 * |
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