CN112010931B - curcumin-4-O-acetyl-Arg-Gly-Asp-Ser strontium salt, and synthesis, activity and application thereof - Google Patents

curcumin-4-O-acetyl-Arg-Gly-Asp-Ser strontium salt, and synthesis, activity and application thereof Download PDF

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CN112010931B
CN112010931B CN201910464571.3A CN201910464571A CN112010931B CN 112010931 B CN112010931 B CN 112010931B CN 201910464571 A CN201910464571 A CN 201910464571A CN 112010931 B CN112010931 B CN 112010931B
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赵明
张筱宜
彭师奇
李辉
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Abstract

The invention discloses curcumin-4-OCH 2 CO-Arg-Gly-Asp-Ser strontium, discloses a preparation method thereof, discloses the anti-osteoporosis activity thereof, and thus the invention discloses the application thereof in preparing anti-osteoporosis medicaments.
Figure DDA0002079052480000011

Description

curcumin-4-O-acetyl-Arg-Gly-Asp-Ser strontium salt, and synthesis, activity and application thereof
Technical Field
The invention relates to curcumin-4-OCH 2 CO-Arg-Gly-Asp-Ser strontium, relates to a preparation method thereof, and relates to the anti-osteoporosis activity thereof. The invention thus relates to its use in the preparation of an anti-osteoporosis medicamentThe use of (1). The invention belongs to the field of biological medicine.
Technical Field
The world health organization predicts that by the year 2050, the population will reach 20 billion. This means that population aging is a significant global problem. Osteoporosis is one of the diseases afflicting the elderly. Considering population base, the threat of osteoporosis to the health of the elderly in China is particularly serious. Curcumin is a natural product extracted from the rhizome of plant curcuma longa and has wide pharmacological activity. Such as anti-tumor, anti-thrombotic and anti-inflammatory. However, curcumin has low bioavailability and poor water solubility. Various curcumin derivatives are reported in documents for improving the bioavailability and water solubility of curcumin. Clinically, the strontium ranelate is used for treating and preventing the osteoporosis of postmenopausal women, and the pharmacophore is strontium ions. Due to the poor solubility, the clinical dose of strontium ranelate is large. The side effect of the strontium ranelate is great due to the large clinical dose. The inventors have been working to develop strontium salts with good solubility, low dosage and low side effects. After three years of exploration, the inventor finds that curcumin-4-OCH 2 The strontium CO-Arg-Gly-Asp-Ser has the three characteristics. Based on this finding, the inventors have proposed the present invention.
Disclosure of Invention
The first aspect of the present invention is to provide curcumin-4-OCH of the formula 2 CO-Arg-Gly-Asp-Ser strontium.
Figure BDA0002079052460000011
The second content of the invention is to provide curcumin-4-OCH 2 The method for synthesizing the strontium CO-Arg-Gly-Asp-Ser comprises the following steps:
(1) synthesizing 3-methoxy-4- (benzyl acetate oxy) benzaldehyde;
(2) synthesizing 6- (4-hydroxy-3-methoxyphenyl) -5, 6-hexene-2, 4-dione;
(3) synthesizing 1- (4-hydroxy-3-methoxyphenyl) -7- (4-oxyacetobenzoyl-3-methoxyphenyl) -1, 6-heptadiene-3, 5-diketone;
(4) synthesizing 1- (4-hydroxy-3-methoxyphenyl) -7- (4-oxyacetoacetoxy-3-methoxyphenyl) -1, 6-heptadiene-3, 5-diketone;
(5) synthesis of curcumin-4-OCH 2 CO-Arg-Gly-Asp(OBzl)-Ser-OBzl；
(6) Synthesis of curcumin-4-OCH 2 CO-Arg-Gly-Asp-Ser；
(7) Synthesis of curcumin-4-OCH 2 CO-Arg-Gly-Asp-Ser strontium.
The third content of the invention is to evaluate curcumin-4-OCH 2 The anti-osteoporosis effect of the strontium CO-Arg-Gly-Asp-Ser.
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FIG. 1 curcumin-4-OCH 2 A synthetic route of CO-Arg-Gly-Asp-Ser strontium. i) K 2 CO 3 ,BrCH 2 COOCH 2 C 5 H 5 Anhydrous tetrahydrofuran at 60 ℃ for 48 hours; ii) acetylacetone, B 2 O 3 ,(nBuO) 3 B,nBu-NH 3 Anhydrous ethyl acetate, at 60-80 ℃ for 4 h; iii) B 2 O 3 ,B 2 O 3 ,(nBuO) 3 B, anhydrous ethyl acetate at 60-80 ℃ for 4 h; iv) aqueous NaOH (2M), MeOH; v) 1-hydroxybenzotriazole, dicyclohexylcarbodiimide, N-methylmorpholine, anhydrous tetrahydrofuran; vi) Sr (OH) 2 ,MeOH；vii)Pd/C,H 2 MeOH, MeOH; viii) hydrogen chloride in ethyl acetate (4M).
Detailed Description
To further illustrate the invention, a series of examples are given below. These examples are purely illustrative and are intended to be a detailed description of the invention only and should not be taken as limiting the invention.
EXAMPLE 1 preparation of 3-methoxy-4- (benzyloxy acetate) benzaldehyde (1)
Dissolving 15.2g (100mmol) of vanillin in 100mL of anhydrous tetrahydrofuran, adding 6.9g (50mmol) of anhydrous potassium carbonate, stirring at room temperature for 2h, adding 15mL (76mmol) of benzyl bromoacetate after the solution turns from light yellow clear to milky turbid, and stirring at 60 ℃ for 48 h. The reaction mixture was filtered, the filtrate was concentrated under reduced pressure, and the residue was dissolved in 100mL of ethyl acetate. The obtained solution is treated with 5% KHSO 4 Washing with an aqueous solution (30 mL. times.3) and a saturated aqueous NaCl solution (30 mL. times.3), and washing with anhydrous Na 2 SO 4 Drying for 12hFiltration and concentration of the filtrate under reduced pressure gave a residue which was taken up in anhydrous ether to precipitate 27.6g (92%) of the title compound as colorless crystals. ESI-MS (M/e) 301[ M + H] + 。
EXAMPLE 2 preparation of 6- (4-hydroxy-3-methoxyphenyl) -5, 6-hexene-2, 4-dione (2)
9.9mL (97.0mmol) of acetylacetone was dispersed in 50mL of anhydrous ethyl acetate, and 4.6g (66.7mmol) of boric anhydride was added thereto, followed by stirring at 60 ℃ for 1 hour. Thereafter, 5.06g (33.3mmol) of vanillin and 9mL (33.5mmol) of tri-n-butyl borate were added successively, and stirred at 80 ℃ for 0.5 h. Thereafter, 34mL of a solution of n-butylamine in anhydrous ethyl acetate (1/10, v/v) was added thereto, and the mixture was stirred at 80 ℃ for 2 hours. The temperature is reduced to 60 ℃, 34mL of diluted hydrochloric acid (1M) is added, the mixture is stirred for 0.5h, and the mixture is cooled to the room temperature. Filtering, and adding 5% KHSO into the filtrate 4 Washing with an aqueous solution (30 mL. times.3) and a saturated aqueous NaCl solution (30 mL. times.3), and washing with anhydrous Na 2 SO 4 Drying for 12h, filtration, concentration of the filtrate under reduced pressure and purification of the residue by column chromatography on silica gel gave 3.1g (40%) of the title compound as a pale yellow powder. ESI-MS (M/e):235[ M + H] + 。
EXAMPLE 3 preparation of 1- (4-hydroxy-3-methoxyphenyl) -7- (4-oxoacetylbenzyloxy-3-methoxyphenyl) -1, 6-heptadiene-3, 5-dione (3)
5g (21.4mmol)6- (4-hydroxy-3-methoxyphenyl) -5, 6-hexene-2, 4-dione (2),3g (42.8mmol) boron anhydride and 30mL anhydrous ethyl acetate were suspended with sonication. The suspension is stirred at 60 ℃ for 1h, 6.4g (21.4mmol) of 3-methoxy-4- (benzyloxy acetate) benzaldehyde and 5.7mL (21.2mmol) of tri-n-butyl borate are added, stirring is carried out at 80 ℃ for 0.5h, 21mL of a solution of n-butylamine in anhydrous ethyl acetate (1/10, v/v) are added and stirring is carried out for 2 h. The temperature is reduced to 60 ℃, 42.7mL of diluted hydrochloric acid (1M) is added, the mixture is stirred for 0.5h, and the mixture is cooled to the room temperature. Filtering, and adding 5% KHSO into the filtrate 4 Washing with an aqueous solution (30 mL. times.3) and a saturated aqueous NaCl solution (30 mL. times.3), and washing with anhydrous Na 2 SO 4 Drying for 12h, filtration, concentration of the filtrate under reduced pressure and purification of the residue by column chromatography on silica gel gave 4.9g (45%) of the title compound as a dark yellow powder. ESI-MS (M/e):517[ M + H] + 。
EXAMPLE 4 preparation of 1- (4-hydroxy-3-methoxyphenyl) -7- (4-oxoacetoacetoxy-3-methoxyphenyl) -1, 6-heptadiene-3, 5-dione (4)
200mg (0.387mmol) of 1- (4-hydroxy-3-methoxyphenyl) -7- (4-oxyacetobenzyl esterThe 3-methoxyphenyl) -1, 6-heptadiene-3, 5-dione (3) was dissolved in 10mL of methanol, and 1mL of aqueous solution of NaOH (2M) was added thereto at 0 ℃ to adjust the pH of the reaction mixture to 14, followed by stirring for 2 hours. The pH of the reaction mixture was adjusted to 7 with dilute hydrochloric acid (2M) at 0 ℃. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in 3mL of distilled water, the pH was adjusted to 2 with dilute hydrochloric acid (2M), the resulting aqueous solution was extracted with ethyl acetate (30 mL. times.3) and washed with saturated aqueous NaCl solution (30 mL. times.3) and anhydrous Na 2 SO 4 Drying for 12h, filtration, concentration of the filtrate under reduced pressure and purification of the residue by column chromatography on silica gel gave 135mg (82%) of the title compound as a dark yellow powder. ESI-MS (M/e) 427[ M + H ]] + ；
1 H-NMR(300MHz,DMSO-d 6 ):δ/ppm＝16.31(s,1H),12.989(s,1H),9.660(s,1H),7.570(d,J＝15.9Hz,2H),7.378(s,1H),7.330(s,1H),7.223(d,J＝8.1Hz,1H),7.164(d,J＝7.5Hz,1H),6.921-6.817(m,3H),6.769(d,J＝15.9Hz,1H),6.096(s,1H),4.742(s,2H),3.854(s,3H)。
EXAMPLE 5 preparation of Boc-Arg (NO) 2 )-Gly-OBzl
5g (14.3mmol) of Boc-Arg (NO) 2 ) And 2.1g (15.5mmol) of 1-hydroxybenzotriazole were dissolved in 80mL of anhydrous tetrahydrofuran, and 3.2g (17.1mmol) of dicyclohexylcarbodiimide was added to the solution at 0 ℃ and stirred for 0.5 h. Thereafter, 3.9g (14.3mmol) of Gly-OBzl was added thereto, the pH was adjusted to 9 with N-methylmorpholine, and the mixture was stirred at room temperature for 4 hours. Filtering, concentrating the filtrate under reduced pressure, dissolving the residue with ethyl acetate, sequentially dissolving the ethyl acetate solution with saturated NaHCO 3 Aqueous solution (30 mL. times.3), 5% KHSO 4 Aqueous solution (30 mL. times.3) and saturated aqueous NaCl solution (30 mL. times.3), anhydrous Na 2 SO 4 Drying for 12h, filtration, concentration of the filtrate under reduced pressure gave a solid which was recrystallised from dichloromethane to give 7.9g (82.1%) of the title compound as colourless crystals. ESI-MS (M/e) 467[ M + H] + 。
EXAMPLE 6 preparation of Boc-Arg-Gly
4g (8.56mmol) of Boc-Arg (NO) 2 ) -Gly-OBzl was dissolved in 100mL of methanol and 400mg of palladium on carbon was added. Pumping out air by a vacuum circulating water pump, filling hydrogen, repeating for 3 times, and stirring for 48h under the condition of keeping the hydrogen filled. Filtration and concentration of the filtrate under reduced pressure gave 2.2g (80.1%) of the title compound as a colorless solid. ESI-MS (M/e):332[ M + H] + 。
EXAMPLE 7 preparation of Boc-Asp (OBzl) -Ser-OBzl
The procedure of example 5 was followed from 5g (15.48mmol) Boc-Asp (OBzl) and 3.6g (17.02mmol) Ser-OBzl to give 7.0g (88.3%) of the title compound as a yellow solid. ESI-MS (m/e): 501[ M + H [ ]] + 。
EXAMPLE 8 preparation of Asp (OBzl) -Ser-OBzl
5g (9.65mmol) of Boc-Asp (OBzl) -Ser-OBzl are dissolved in 60mL of a solution of hydrogen chloride in ethyl acetate (4M) and stirred at 0 ℃ for 5 h. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in 10mL of anhydrous ethyl acetate and then concentrated under reduced pressure, and the residue was dissolved in 10mL of anhydrous ethyl acetate again. This operation was repeated 3 times. The residue was dispersed in 10mL of anhydrous ether, allowed to stand, and ether was discarded to give 3.91g (97%) of the title compound as a pale yellow solid. ESI-MS (M/e) 401[ M + H [, M + H ]] + 。
EXAMPLE 9 preparation of Boc-Arg-Gly-Asp (OBzl) -Ser-OBzl
From 3.2g (9.67mmol) Boc-Arg-Gly and 4.84g (11.60mmol) Asp (OBzl) -Ser-OBzl 2.0g (30%) of the title compound was obtained as colorless powder by the method of example 5. ESI-MS (M/e):714[ M + H] + 。
EXAMPLE 10 preparation of Arg-Gly-Asp (OBzl) -Ser-OBzl
From 500mg (0.70mmol) Boc-Arg-Gly-Asp (OBzl) -Ser-OBzl 417mg (97%) of the title compound was obtained as a light yellow solid by the method of example 8. ESI-MS (M/e) 614[ M + H] + 。
EXAMPLE 11 preparation of curcumin-4-OCH 2 CO-Arg-Gly-Asp(OBzl)-Ser-OBzl(5)
350mg (0.812mmol) of 1- (4-hydroxy-3-methoxyphenyl) -7- (4-oxoacetoacetoxy-3-methoxyphenyl) -1, 6-heptadiene-3, 5-dione (4) and 109mg (0.812mmol) of 1-hydroxybenzotriazole are dissolved in 50mL of anhydrous tetrahydrofuran. To the solution was added 200mg (0.974mmol) dicyclohexylcarbodiimide at 0 ℃ and stirred for 0.5 h. Then, 600mg (0.974mmol) of Arg-Gly-Asp (OBzl) -Ser-OBzl was added thereto, the pH was adjusted to 9 with N-methylmorpholine, and the mixture was stirred at room temperature for 4 hours. Filtration, concentration of the filtrate under reduced pressure and dissolution of the residue with dichloromethane. The dichloromethane solution is sequentially treated with saturated NaHCO 3 Aqueous solution (30 mL. times.3), 5% KHSO 4 Aqueous solution (30 mL. times.3) and saturated aqueous NaCl solution (30 mL. times.3), anhydrous Na 2 SO 4 Drying for 12h, filtration and concentration of the filtrate under reduced pressure gave a solid which was purified by silica gel column chromatography to give 120mg (14%) of the title compound as a dark yellow powder. ESI-MS (M/e):1024[ M + H] + ； 1 H-NMR(300MHz,DMSO-d 6 ):δ/ppm＝9.738(s,1H),8.446(m,1H),8.345–8.310(m,2H),8.213(d,J＝7.2Hz,1H),7.679(d,J＝7.2Hz,1H),7.569(d,J＝15.9Hz,1H),7.386–7.339(m,12H),7.254–7.147(m,3H),6.975–6.702(m,5H),6.098(s,1H),5.170–5.070(m,4H),4.83–4.75(m,1H),4.632(s,2H),4.383–4.359(m,2H),4.126(m,1H),3.853(s,3H),3.835(s,3H),3.784–3.636(m,5H),3.126–3.085(m,2H),2.808–2.535(m,2H),1.744–1.492(m,4H)。
EXAMPLE 12 preparation of curcumin-4-OCH 2 CO-Arg-Gly-Asp-Ser strontium (6)
Mixing 100mg (0.1mmol) curcumin-4-OCH 2 CO-Arg-Gly-Asp (OBzl) -Ser-OBzl (5) was dissolved in 10mL of methanol. Dissolving 26.8mg (0.1mmol) strontium hydroxide octahydrate in 10mL distilled water, mixing the two solutions at 0 deg.C, stirring for 2h, filtering to obtain red solid C 18 Column purification gave 30mg (34%) of the title compound. FT-MS (M/e) 926.34277[ M-H] - (926.3)；Mp＞245.6℃；
Figure BDA0002079052460000051
IR＝3194,3077,2967,2881,1660,1567,1510,1416,1254,1201,1176,1131,1031,837,800cm -1 。
Experimental example 1 evaluation of curcumin-4-OCH 2 Anti-osteoporosis activity of strontium CO-Arg-Gly-Asp-Ser
Female ICR mice (25. + -.2 g) were used as mice in the surgical and sham groups. Mice in the operation group were injected intraperitoneally with a 5% chloral hydrate physiological saline solution (0.1mL/10 g). Wiping the lower abdomen of a mouse with iodophor and benzalkonium chloride in sequence, cutting off the epidermis layer of the lower abdomen, cutting off the muscle layer along the albuginea, cutting off the abdominal cavity, finding out the uterus under the bladder, finding out two fallopian tubes along the uterus, finding out ovaries which are in the shape of cauliflower and are wrapped by fat at the blind ends of the two fallopian tubes, ligating the fallopian tubes at a position far away from the uterus, removing the two ovaries, dropping a drop of penicillin solution at the ligation position, dropping a drop of penicillin solution before and after suturing the muscle layer after putting the ligation position back into the abdominal cavity, and sequentially smearing the iodophor and the iodophor at the wound after suturing the epidermis layer. The application of penicillin, benzalkonium chloride and iodophor can prevent wound infection. Placing the mouse in a mouse cage, and keeping the temperature for 3-5 h to awaken the mouse.
Sham-operated mice were injected intraperitoneally with 5% chloral hydrate in physiological saline (0.1mL/10 g). Wiping the lower abdomen of a mouse by iodophor and benzalkonium chloride in sequence, cutting off the epidermal layer of the lower abdomen, cutting off the muscle layer along the albuginea, cutting off the abdominal cavity, finding out the uterus under the bladder, finding out two fallopian tubes along the uterus, finding out ovaries which are in the shape of cauliflower and are wrapped by fat at the blind ends of the two fallopian tubes, not ligating the fallopian tubes and not removing the ovaries, putting the ovaries back to the abdominal cavity, dripping a drop of penicillin solution before and after the muscle layer is sutured, and smearing the iodophor and the benzalkonium chloride in sequence at the wound after the epidermal layer is sutured. Placing the mouse in a mouse cage, and keeping the temperature for 3-5 h to awaken the mouse.
The postoperative recovery lasts for seven days. The model groups on day eight were randomly grouped. Administration of curcumin-4-OCH to mice or mice by intragastric administration once a day 2 Suspension of CO-Arg-Gly-Asp-Ser strontium (6) and 5 per thousand CMCNa (dosage is 50.13 mu mol/kg/day), or suspension of strontium ranelate and 5 per thousand CMCNa (dosage is 501.3 mu mol/kg/day) or 5 per thousand CMCNa solution (dosage is 0.1mL/10 g/day). After 28 days of continuous gavage, the mice were anesthetized with ether, sacrificed, and bilateral femurs were harvested, muscle tissues were removed, and the dissected length was measured with a vernier caliper, and the bone dry weight, bone ash weight, and bone and mineral content were measured according to the following methods.
1) Degreasing, namely preparing degreasing solution of which the concentration is 2/1 trichloromethane/methanol, and soaking the left femur of the mouse in the degreasing solution for 3 hours twice each time. The defatting solution was volatilized in a fume hood.
2) And (3) measuring the dry weight of the bone, namely putting the femur into an oven to be dried for 6h at the temperature of 120 ℃, cooling to room temperature, and then weighing the dry weight of the femur.
3) Measuring the weight of the bone ash, weighing the weight of the crucible (m) 1 ) Placing the femur with measured dry weight in a small crucible, calcining at 800 deg.C in a muffle furnace for 8h, cooling to room temperature, and weighing total weight (m) of femur ash and crucible 2 ) M is 2 -m 1 The gray weight of the femur was calculated.
4) And (3) measuring the Bone Mineral Content (BMC), namely calculating the ratio of the bone ash weight to the femur dry weight to obtain the bone mineral content. The data are shown in Table 1. The bone mineral content (0.575 + -0.016) in mice treated with compound 6 at 50.13 μmol/kg/day for 28 days of continuous treatment was significantly greater than that in mice treated with 5% o CMCNa at 0.1mL/10 g/day for 28 days of continuous treatment (0.549 + -0.020, p <0.01), comparable to that in mice treated with strontium ranelate at 501.3 μmol/kg/day for 28 days of continuous treatment (0.576 + -0.008, p > 0.05). It can be seen that compound 6 not only has anti-osteoporosis effect at 50.13 μmol/kg/day dose, but also restores bone mineral density to the level before ovariectomy in mice. The compound 6 still has the excellent anti-osteoporosis effect under the dosage of only the positive drug strontium ranelate 1/10, which indicates that the invention has outstanding technical effect.
TABLE 1 Effect of Compound 6 on femur Dry weight, Ash weight and bone mineral content in castrated mice
Figure BDA0002079052460000061
a) P <0.01 to CMCNa group; b) p <0.01 for CMCNa, p >0.05 for sham surgery group, and p >0.05 for strontium ranelate group; n is 12.

Claims (3)

1. curcumin-4-OCH 2 CO-Arg-Gly-Asp-Ser strontium,
Figure FDA0002079052450000011
2. curcumin-4-OCH of claim 1 2 The preparation method of the strontium CO-Arg-Gly-Asp-Ser comprises the following seven steps:
(1) preparing 3-methoxy-4- (benzyl acetate-oxy) benzaldehyde;
(2) preparing 6- (4-hydroxy-3-methoxyphenyl) -5, 6-hexene-2, 4-dione;
(3) preparing 1- (4-hydroxy-3-methoxyphenyl) -7- (4-oxyacetobenzoyl-3-methoxyphenyl) -1, 6-heptadiene-3, 5-dione;
(4) preparing 1- (4-hydroxy-3-methoxyphenyl) -7- (4-oxyacetoacetoxy-3-methoxyphenyl) -1, 6-heptadiene-3, 5-dione;
(5) preparation of curcumin-4-OCH 2 CO-Arg-Gly-Asp(OBzl)-Ser-OBzl；
(6) Preparation of curcumin-4-OCH 2 CO-Arg-Gly-Asp-Ser；
(7) Preparation of curcumin-4-OCH 2 CO-Arg-Gly-Asp-Ser strontium.
3. curcumin-4-OCH of claim 1 2 Application of CO-Arg-Gly-Asp-Ser strontium in preparing anti-osteoporosis medicine.
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