CN113967212B - Disproportionated rosin compound and preparation method and application thereof - Google Patents
Disproportionated rosin compound and preparation method and application thereof Download PDFInfo
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- CN113967212B CN113967212B CN202111207488.1A CN202111207488A CN113967212B CN 113967212 B CN113967212 B CN 113967212B CN 202111207488 A CN202111207488 A CN 202111207488A CN 113967212 B CN113967212 B CN 113967212B
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- disproportionated rosin
- vascular
- rosin compound
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- compound
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- A—HUMAN NECESSITIES
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Abstract
The invention belongs to the technical field of compounds, and discloses a disproportionated rosin compound, a preparation method and application thereof, wherein the preparation method of the disproportionated rosin compound comprises the following steps: adding a catalytic amount of N, N-dimethylformamide into an anhydrous dichloromethane solution of dehydroabietic acid, dropwise adding oxalyl chloride under ice bath conditions, and reacting at room temperature; after the reaction is completed, the solvent is removed under reduced pressure under the protection of nitrogen, and anhydrous dichloromethane is slowly added dropwise; under the protection of nitrogen, piperazine and triethylamine are slowly added into a flask, stirred at room temperature and monitored by TLC; after the reaction is finished, the solvent is removed under reduced pressure, the mixture is extracted, washed by 10 percent of hydrochloric acid solution, saturated sodium bicarbonate and saturated saline solution, dried by anhydrous magnesium sulfate or anhydrous sodium sulfate and subjected to column chromatography, and the compound Z28 is obtained. The disproportionated rosin compound Z28 provided by the invention can be used for developing and producing a novel medicine with multiple targets, and is expected to become a novel way for treating vascular diseases such as hypertension, coronary heart disease and the like.
Description
Technical Field
The invention belongs to the technical field of compounds, and particularly relates to a disproportionated rosin compound, and a preparation method and application thereof.
Background
At present, it is estimated that 15% to 20% of patients with hypertension cannot be fully controlled by combining two antihypertensive drugs, three or more different antihypertensive drugs are needed to realize blood pressure control, the target point is single, and the antihypertensive drug has stronger toxic and side effects and larger damage to target organs. In recent years, the search for new active ingredients or lead compounds to develop new drugs has been a hotspot for global attention and research; the new generation of low-toxicity multi-target antihypertensive drugs are sought, and meanwhile, target organs can be effectively protected, so that the development and production of new vascular dilating drugs are expected to become a new way for treating vascular diseases such as hypertension, coronary heart disease and the like.
Through the above analysis, the problems and defects existing in the prior art are as follows: the existing method for realizing blood pressure control by using three or more than three different antihypertensive drugs has single target point, stronger toxic and side effects and larger damage to target organs.
The difficulty and meaning for solving the problems and the defects are as follows: vascular endothelium regulates normal intravascular homeostasis, is located in the vessel wall between the lumen and smooth muscle cells, and endothelial cell layers are capable of conducting blood signals, sensing mechanical forces within the lumen, and generating a variety of different factors. Vascular endothelium produces the most potent vasodilators such as EDRF, prostacyclin and endothelial-derived hyperpolarization factors. The most important vasodilating substance in endothelial cells is EDRF, which has been identified as Nitric Oxide (NO). Endothelial-derived NO is thought to regulate a variety of activities from neural function to vascular activity as a pleiotropic biological mediator. NO has been identified as a neurotransmitter in the peripheral and central nervous systems. It accounts for many autonomic and cardiovascular responses, as well as gastrointestinal and genitourinary tracts, such as blood regulating flow and blood pressure, inhibiting urethral relaxation in the gastrointestinal motility, the micturition reflex. In particular, in vascular smooth muscle cells, NO-mediated activation of soluble guanylate cyclase catalyzes the formation of a second messenger cGMP, leading to aortic vasodilation. NO inhibits smooth muscle cell contraction, migration and proliferation, endothelin generation, platelet aggregation and adhesion of leukocytes into the endothelium in addition to vasodilation function, and then prevents atherosclerosis. Healthy and primary hypertensive patients can be treated with L-arginine to cause rapid decline in systolic and diastolic blood pressure. Z28 has vascular protective and vasodilatory effects through NO production. However, the current antihypertensive drugs have only antihypertensive effects.
Disclosure of Invention
Aiming at the problems existing in the prior art, the invention provides a disproportionated rosin compound, and a preparation method and application thereof.
The invention is realized in this way, a disproportionated rosin compound is used in preparing the multi-target medicine for treating vascular diseases including hypertension and coronary heart disease.
Drug concentration in vitro vascular perfusion model: after stabilization of the vascular ring, 1X 10 -6 Adding mol/L PE into vascular ring nutrient solution with complete vascular endothelium or various blocking agents, and treating 1×10 -6 After the shrinkage of the mol/L PE had been smoothed, Z28 was added at a final concentration of 0.3125, 0.625, 1.25, 2.5, 5, 10, 20. Mu.M.
The drug concentration in human umbilical vein endothelial cell experiments was 0.25, 0.5, 1 μm Z28.
The invention further aims to provide a disproportionated rosin compound, which has a chemical structural formula as follows:
further, the disproportionated rosin compound is named as:
(1R, 4aS,10 aR) -7-isopropyl-1,4a-dimethyl-1,2,3, 4a,9, 10, 10 a-octahydrohenthren-1-yl) (piperazin-1-yl) methyl; abbreviated as Z28.
Further, the disproportionated rosin isThe molecular formula of the compound is C 24 H 36 N 2 O, molecular weight 368.57.
Another object of the present invention is to provide a method for preparing a disproportionated rosin compound using the disproportionated rosin compound, the method comprising the steps of:
step one, adding anhydrous dichloromethane solution of dehydroabietic acid into catalytic amount of N, N-dimethylformamide, dropwise adding oxalyl chloride under ice bath condition, reacting at room temperature after adding, and monitoring by TLC;
step two, after the reaction is completed, the solvent is removed under reduced pressure under the protection of nitrogen, and anhydrous dichloromethane is slowly added dropwise; under the protection of nitrogen, piperazine and triethylamine are slowly added into a flask, stirred at room temperature and monitored by TLC;
and thirdly, after the reaction is finished, removing the solvent under reduced pressure, extracting, washing with 10% hydrochloric acid solution, saturated sodium bicarbonate and saturated saline solution, drying with anhydrous magnesium sulfate or anhydrous sodium sulfate, and performing column chromatography to obtain the compound Z28.
Further, in the first step, the room temperature reaction time is 2h.
In the second step, the reaction time is 12-24 hours.
It is another object of the present invention to provide the use of said disproportionated rosin in the activation of PI3K/Akt/NO/cGMP/PKG channels.
The invention also aims to provide an application of the disproportionated rosin compound in blocking potassium-calcium channels.
It is another object of the present invention to provide the use of said disproportionated rosin in multi-target vasodilation and anti-inflammatory action against vascular adhesion factors ICAM-1 and VCAM-1.
The invention also aims to provide an application of the disproportionated rosin compound in preparing medicines for treating vascular diseases including hypertension and coronary heart disease.
By combining all the technical schemes, the invention has the advantages and positive effects that: the disproportionated rosin compound Z28 provided by the invention is a novel compound (dehydroabietic acid derivative), activates PI3K/Akt/NO/cGMP/PKG channels, blocks potassium calcium channels, has multi-target vasodilation characteristics and has anti-inflammatory effects of inhibiting vascular adhesion factors ICAM-1 and VCAM-1. The vasomotor effect of phenylephrine pre-contraction is stronger than nifedipine, so that the development of a novel medicine with multiple targets is expected to become a novel way for treating vascular diseases such as hypertension, coronary heart disease and the like.
Drawings
In order to more clearly illustrate the technical solutions of the embodiments of the present invention, the drawings that are needed in the embodiments of the present invention will be briefly described below, and it is obvious that the drawings described below are only some embodiments of the present invention, and other drawings may be obtained according to these drawings without inventive effort for a person skilled in the art.
FIG. 1 is a flow chart of a preparation method of disproportionated rosin compounds provided by the embodiment of the invention.
FIG. 2 is a schematic diagram of nuclear magnetic hydrogen spectrum of the compound Z28 provided by the embodiment of the invention.
FIG. 3 is a schematic diagram of nuclear magnetic carbon spectrum of the compound Z28 provided by the embodiment of the invention.
Fig. 4 is a graph showing the effect of Z28 on endothelial integrity (V), endothelial-removed (-Endo) rat thoracic aortic annulus (n=6), P < 0.001vs. V (endothelial integrity), provided by the examples of the present invention.
Fig. 5 is a graph showing the effect of L-NAME, ODQ on Z28-induced vasodilation (n=6) with P < 0.001vs. v (endothelial integrity) provided in the examples of the present invention.
Fig. 6 is a graph showing the effect of WT, KT5823 on Z28-induced vasodilation (n=6), P < 0.01, P < 0.001vs v (endothelial integrity), provided by examples of the present invention.
FIG. 7 (a) and FIG. 7 (b) are TEA, gli, 4-AP, baCl provided by an embodiment of the invention 2 The effect on Z28-induced vasodilation is schematically shown (n=6), < P < 0.01, < P < 0.001vs. v (endothelial integrity).
Fig. 8 is a graph showing the effect of Indo on Z28-induced vasodilation (n=6), P < 0.01, P < 0.001vs (endothelial integrity), provided in the examples of the present invention.
Fig. 9 is a schematic diagram showing the effect of Prop, atro on Z28-induced vasodilation (n=6), P < 0.001vs. v (endothelial integrity), provided in the examples of the present invention.
Fig. 10 is a graph showing the effect of Dilt on Z28-induced vasodilation (n=6) with P < 0.001vs. v (endothelial integrity) provided by the examples of the present invention.
FIG. 11 is a graph showing the effect of Z28 on TNF- α stimulated HUVEC cell vascular adhesion factor provided by the examples of the present invention.
Detailed Description
The present invention will be described in further detail with reference to the following examples in order to make the objects, technical solutions and advantages of the present invention more apparent. It should be understood that the specific embodiments described herein are for purposes of illustration only and are not intended to limit the scope of the invention.
Aiming at the problems existing in the prior art, the invention provides a disproportionated rosin compound, a preparation method and application thereof, and the invention is described in detail below with reference to the accompanying drawings.
The invention provides an application of disproportionated rosin compounds in preparing multi-target medicaments for treating vascular diseases including hypertension and coronary heart disease.
As shown in fig. 1, the preparation method of the disproportionated rosin compound provided by the embodiment of the invention comprises the following steps:
s101, adding anhydrous dichloromethane solution of dehydroabietic acid into catalytic amount of N, N-dimethylformamide, dropwise adding oxalyl chloride under ice bath condition, reacting at room temperature for 2h after adding, and monitoring by TLC;
s102, after the reaction is completed, removing the solvent under reduced pressure under the protection of nitrogen, and slowly and dropwise adding anhydrous dichloromethane; under the protection of nitrogen, piperazine and triethylamine are slowly added into a flask, stirred at room temperature, reacted for 12 to 24 hours, and TLC monitors the reaction;
and S103, after the reaction is finished, removing the solvent under reduced pressure, extracting, washing with 10% hydrochloric acid solution, saturated sodium bicarbonate and saturated saline solution, drying with anhydrous magnesium sulfate or anhydrous sodium sulfate, and performing column chromatography to obtain the compound Z28.
The technical scheme of the invention is further described below by combining the embodiments.
Examples: design, synthesis and study of vasodilation and anti-inflammatory effects of dehydroabietic acid derivative (Z28)
The disproportionated rosin compound provided by the embodiment of the invention has the chemical structural formula:
the disproportionated rosin compound provided by the embodiment of the invention is named as follows:
((1R，4aS，10aR)-7-isopropyl-1，4a-dimethyl-1，2，3，4，4a，9，10，10a-octahydrophenanthren-1-yl)(piperazin-1-yl)methanone
abbreviated as Z28; the molecular formula is: c (C) 24 H 36 N 2 O; molecular weight: 368.57
The invention discloses a preparation method of disproportionated rosin compounds, which comprises the following specific preparation steps:
adding a catalytic amount of N, N-dimethylformamide into an anhydrous dichloromethane solution of dehydroabietic acid, dropwise adding oxalyl chloride under ice bath conditions, reacting at room temperature for 2h after the addition, and monitoring by TLC; after the reaction is completed, the solvent is removed under reduced pressure under the protection of nitrogen, and then anhydrous dichloromethane is slowly and dropwise added; under the protection of nitrogen, piperazine and triethylamine are slowly added into a flask, stirred at room temperature, reacted for 12-24 hours, TLC monitors the reaction, the solvent is removed under reduced pressure after the reaction is finished, extraction is carried out, 10% hydrochloric acid solution, saturated sodium bicarbonate and saturated saline solution are used for washing, anhydrous magnesium sulfate or anhydrous sodium sulfate are used for drying, and the compound Z28 is obtained through column chromatography.
Example 2: verifying blood pressure lowering effect and vascular anti-inflammatory effect of the synthesized novel compound
2.1 preparation of isolated thoracic aortic Ring
The observed healthy male SD rats are sacrificed by cervical dislocation, the thoracic aorta is taken out by rapidly opening the thoracic cavity, and Krebs is put inIn solution (4 ℃ C. Contains 95% O) 2 And 5% CO 2 Mixed gas), connective tissue and adipose tissue around the blood vessel are removed, and blood in the blood vessel is washed clean, and cut into a vascular ring of about 3-4 mm. In endothelial injury experiments, the inner wall of the thoracic aortic annulus of the isolated rat needs to be gently scraped back and forth with a toothpick to remove endothelial cells. The vascular ring is connected to the tension transducer by a miniature hook and a thin steel wire and hung in the bath. The bath comprises the following components: by passing through 95% O 2 And 5% CO 2 Mixing the gases; 6mL of Krebs solution at 37℃and pH 7.40.
2.2 detection of vascular Activity
When detecting vascular endothelial injury or endothelial integrity, 1×10 is used -6 Pre-shrinking mol/L Phenylephrine (PE) and adding 1×10 after balancing shrinkage curve -6 mol/L Acetylcholine (Ach) relaxation. If acetylcholine (1X 10) -6 mol/L) postphenylephrine (1X 10) -6 mol/L) the pre-contracted vascular ring relaxation amplitude is less than 10% of the pre-contraction, the endothelial removal can be considered; if acetylcholine (1X 10) -6 The vasodilation amplitude of the vascular ring reaches more than 80% after mol/L), and the endothelium can be considered to be perfect.
2.3 in vitro rat thoracic aortic vascular ring tension determination
The isolated rat thoracic aortic ring passes through the vascular ring by two tiny hooks and is stably suspended in the bath, so that the upper end of the isolated rat thoracic aortic ring is connected with a tension transducer, and the tension change of the thoracic aortic ring is recorded by BL-420S and a computer biological signal acquisition and analysis instrument. The tension of the vascular ring in each bath was stepped from 0.25g to 1.0g and allowed to stabilize for 60min. The vascular ring was then activated with 60mmol/L KCl to stimulate maximum absorption of the vascular ring, followed by 1X 10 -6 The maximum contraction amplitude (100%) induced by mol/L PE is shown as the relaxation rate, and the experiment reflects the change of the vascular tension, namely the ratio of the vascular tension amplitude after adding the medicine to the maximum contraction amplitude induced by PE.
2.4 Effect of Z28 on endothelial integrity and endothelial removal vasodilatory Effect
After stabilization of the vascular ring, 1X 10 -6 The mol/L PE is added simultaneouslyWhole vascular endothelium and vascular ring nutrient solution with endothelium removed. After the shrinkage was smoothed, Z28 was added at a final concentration of 0.3125, 0.625, 1.25, 2.5, 5, 10, 20. Mu.M. Of the two groups, each group consists of 1×10 -6 The difference in the percent change in maximum diastolic rate was calculated and compared for a 100% range of shrinkage caused by mol/L PE, and the drug concentration-diastolic effect curve was again determined.
2.5 Effect of L-NAME on Z28-induced vasodilation Effect
After stabilization of the vascular ring, 1X 10 is used -4 Pretreatment with mol/L NO synthase inhibitor L-NAME for 20 min, 1X 10 was added -6 mol/L PE. After the shrinkage was stabilized, Z28 was added at a final concentration of 0.3125 to 20. Mu.M, the corresponding vascular tension was recorded and the change value was calculated.
2.6 Influence of ODQ on Z28-induced vasodilation Effect
After stabilization of the vascular ring, 1X 10 is used -5 Pretreatment with guanylate cyclase-specific inhibitor ODQ for 20 min at mol/L, 1X 10 was added -6 And after the shrinkage is stabilized, adding Z28 with the final concentration of 0.3125-20 mu M, recording the corresponding vascular tension and calculating the change value.
2.7 Effect of diltiazem on Z28-induced vasodilation
Selecting Krebs solution, stabilizing blood vessel ring, and treating with 1×10 -5 Pre-treating diltiazem serving as a mol/L L-type calcium channel blocker for 20 minutes, and adding 1X 10 -6 After the shrinkage of the mol/L PE became smooth, Z28 was added at a final concentration of 0.3125 to 20. Mu.M, and the tension of the blood vessel was recorded and the change value was calculated.
2.8 Effect of Wortmannin (WT) on Z28-induced vasodilation effects
After vascular ring stabilization, akt Wortmannin (WT) blocker 1X 10 -7 Pretreatment for 20 minutes at mol/L and addition of 1X 10 -6 mol/L PE. After the shrinkage has stabilized, Z28 is added cumulatively at a final concentration in the range of 0.3125 to 20. Mu.M, the corresponding vascular tension is recorded and the change is recorded.
2.9 Effect of Potassium channel on Z28-induced vasodilation Effect
After stabilization of the vascular ring, K is sensitive to ATP + Channel blockers (K) ATP ) Glibenclamide (Gli) 1×10 -5 mol/L, nonselective Ca 2+ Activated K + Channel blockers (K) ca )TEA 1×10 -3 mol/L, voltage sensitive K + Channel (K) V ) Inhibitor 4-AP 1X 10 -4 mol/L, inward rectifying type K + Channel (K) IR ) Inhibitor BaCl 2 1×10 -4 Pretreatment for 20 minutes at mol/L, adding 1X 10 -6 After the shrinkage of the mol/L PE was stabilized, Z28 was added cumulatively at a final concentration in the range of 0.3125 to 20. Mu.M. The corresponding vascular tension is recorded and the change value is calculated.
2.10 Effect of indomethacin on Z28-induced vasodilatory Effect
After stabilization of the vascular ring, the cyclooxygenase inhibitor Indomethacin (Indomethacin, indo) was used at 1×10 -5 Pretreatment was performed for 20 minutes at mol/L, and 1X 10 was added -6 mol/L PE, and wait until the shrinkage reaches a steady value. Z28 was added at a final concentration of 0.3125 to 20. Mu.M, the corresponding vascular tension was recorded and the change was calculated.
2.11 Effect of atropine and propranolol on Z28-induced vasodilation Effect
After stabilization of the vascular ring, the concentration was 1X 10, respectively -6 The mol/L muscarinic receptor blocker atropine (Atro) and the concentration is 1×10 -6 After pretreatment of the mol/L nonselective beta-adrenergic receptor blocker propranolol (Prop) for 20 minutes, 1X 10 is added -6 After the shrinkage of the mol/L PE is stable, adding Z28 with the final concentration range of 0.3125-20 mu M in an accumulated way, recording the corresponding vascular tension and calculating the change value. An equal volume of Krebs solution was added to the control group.
2.12 Western Blot detection of protein level changes
The arterial loop was homogenized with buffer. Adding sodium fluoride (NaF, 1M) and sodium orthovanadate (Na) into protein-containing extract (Ripa, elpis Biotech, korea) 3 VO 4 0.2M). After homogenization, centrifugation was carried out at 13000 rpm for 10 minutes at 4 ℃. Rat aortic cycloprotein (20 μg) was treated with 10% sodium dodecyl sulfatePolyacrylamide gel electrophoresis (SDS-PAGE) electrophoresis transfer nitrocellulose membranes (Bio-Rad Laboratories, hercules, calif., USA). The membranes were blocked with 5% nonfat milk powder (Becton Dickinson, le Pont-De-Claix, france) 0.05% Tween 20-TBS for 1 hour, and then with vascular adhesion factors ICAM-1, VCAM-1 and beta-actin (Santa Cruz Biotechnology, santa Cruz, calif., USA). The antibody was finally diluted 1:1000 overnight at 4 ℃. Rinse with 0.05% Tween 20-TBS. Secondary antibodies were added for 1 hour. Membranes were washed several times with 0.05% tween 20. Then the procedure was performed using enhanced chemiluminescence detection (Amersham Lab, buckingham Hire, england). This protein expression level was detected by analyzing the signal captured on nitrocellulose membranes (Millipore, MA, USA) using a Chemi-Doc image analyzer (Bio-Rad Laboratories, hertfordshire, UK).
The compound Z28 (novel compound) is a derivative of dehydroabietic acid.
The results of phenylephrine pre-systolic vasodilation are shown in table 1.
TABLE 1 results of phenylephrine pre-systolic vasodilation
The nuclear magnetic hydrogen spectrum of the compound Z28 is shown in FIG. 2.
The Z28 NMR data are as follows; the yield was 60%; m.p.280-282 deg.c; 1 H-NMR(300MHz，CDCl 3 )：δ7.15(d，J＝8.1Hz，1H，Ar-H)，7.00(d，J＝8.4Hz，1H，Ar-H)，6.90(s，1H，Ar-H)，3.94-3.84(m，4H，-CH 2 -)，3.09(s，4H，-CH 2 -)，2.97-2.78(m，3H)，2.28(d，J＝10.5Hz，2H)，1.89-1.56(m，5H)，1.58-1.41(m，3H)，1.34(s，3H，-CH 3 )，1.25(s，3H，-CH 3 )，1.24(d，J＝3.5Hz，3H，-CH 3 )，1.21(s，3H，-CH 3 ). 13 C-NMR(75MHz，CDCl 3 )：δ177.36，146.69，145.77，134.90，127.11，124.09，123.86，46.79，45.42，44.30，43.87，37.60，37.40，35.61，33.44，30.50，25.41，23.97，22.13，18.77，18.69.
the nuclear magnetic carbon spectrum of the compound Z28 is shown in FIG. 3.
The results in Table 1 show that the dehydroabietic acid derivatives were synthesized in this experiment, the structures of the compounds were confirmed by 1H-NMR and 13C-NMR, and the vasodilation of the compounds was selected, wherein compound Z28 showed the highest vasodilation activity, and the maximum rate of relaxation (Emax) at 100. Mu.M was 95.4.+ -. 2.3%.
3.1 Effect of Z28 on endothelial integrity and endothelial removal vascular ring tension
In endothelial intact vascular ring, Z28 (0.3125-20. Mu. Mol/L) concentration-dependently relaxes PE (1X 10) - 6 mol/L) pre-contracted rat thoracic aortic annulus, while the vasodilation effect of Z28 was significantly inhibited (P < 0.001) after endothelial removal (see FIG. 4). Indicating that the vasodilatory effect of Z28 on blood vessels is endothelial dependent.
3.2 Effect of L-NAME and ODQ on Z28-induced vasodilation
The NO-cGMP signaling pathway in endothelial cells plays an important role in regulating endothelial-dependent vasodilation, and the guanylate cyclase inhibitor ODQ (1×10) -5 mol/L) and NO synthase inhibitor L-NAME (1×10) - 4 mol/L) pretreatment significantly inhibited the diastolic effect of Z28 (P < 0.001) (see FIG. 5). Z28 is shown to act through the NO/sGC/cGMP signaling pathway to relax blood vessels.
3.3 Effect of Akt and PKG signalling pathways on Z28-induced vasodilation effects
To investigate whether Z28-induced vasodilation was associated with non-calcium dependent Akt and PKG signaling pathways, endothelial intact vascular rings were challenged with the Akt inhibitor wortmannin (WT, 1 x 10) -7 mol/L) and PKG inhibitors KT5823 (KT 5823, 1X 10) -6 mol/L) of the composition, the pretreatment significantly inhibits Z28-induced vasodilation (P < 0.001) (see FIG. 6). Indicating that Z28 is exerted by activating PI3K/Akt/NO/cGMP/PKG signaling pathwayVasodilation.
3.4 Effect of Potassium channel on Z28-induced vasodilation Effect
To determine K + Whether the channel is involved in Z28-induced vasodilation, ATP-sensitive K for endothelial intact blood vessels + Channel (K) ATP ) The blocker glibenclamide (Gli, 1×10) -5 mol/L) pretreatment does not inhibit the Z28-induced vasodilation effect, but rather the selective Ca 2+ Activated K + Channel (K) Ca ) Inhibitors (TEA, 1X 10) -3 mol/L), voltage-sensitive K + Channel (K) V ) Inhibitors (4-AP, 1X 10) -4 mol/L), inward rectifying type K + Channel (K) IR ) Inhibitors (BaCl) 2 ，1×10 -4 mol/L) significantly attenuated the diastolic effect of Z28 (P < 0.05) (see FIGS. 7 (a) and (b)). Description K Ca 、K V 、K IR Activation may be involved in Z28-induced vasodilation responses.
3.5 Effect of cyclooxygenase inhibitors on Z28-induced vasodilation Effect
To determine PGI 2 Whether or not it is involved in Z28-induced vasodilation, cyclooxygenase inhibitor indomethacin (Indo, 1×10) -5 mol/L) pretreatment can inhibit Z28 vasodilation (see FIG. 8), illustrating PGI 2 The cAMP signaling pathway is involved in Z28-induced vasodilation.
3.6 Effect of muscarinic and adrenergic receptor inhibitors on Z28-induced vasodilatory Effect
To determine the effect of the autonomic nervous system on the vasodilating effect of Z28, endothelial intact blood vessels were treated with the non-selective beta-adrenergic receptor inhibitor propranolol (Prop, 1 x 10 -6 mol/L) and the muscarinic receptor inhibitor atropine (Atro, 1X 10) -6 mol/L) pretreatment significantly inhibited the diastolic effect of Z28 (P < 0.001) (see FIG. 9). It is stated that Z28-induced vasodilation is associated with the autonomic nervous system.
3.7 L-type Ca 2+ Effect of channel blockers on Z28-induced vasodilation
As shown in fig. 10, with the complete vascular ring,with L-type Ca 2+ Channel blocker diltiazem (Dilt, 1×10) - 5 mol/L) and observing the experimental results. The experimental result shows that the diltiazem Zhuo Mingxian blocks the vasodilation effect induced by Z28, which indicates that the vasodilation effect is related to L-type calcium ion channels.
3.8 Anti-inflammatory action of Z28 in HUVECs
To assess whether Z28 has anti-inflammatory effects, TNF- α treatment increases the expression of cell adhesion molecules such as ICAM-1 and VCAM-1. Interestingly, the concentration-dependent attenuation of TNF- α mediated cell adhesion molecule expression by Z28 pretreatment was observed by Western blotting. The low concentration of Z28 had no significant inhibitory effect on the increase in blood vessel adhesion factor expression in HUVEC cells caused by TNF- α, but the medium and high concentrations of Z28 significantly inhibited the blood vessel adhesion factor expression as shown in FIG. 11.
Z28 is a novel compound (dehydroabietic acid derivative), activates PI3K/Akt/NO/cGMP/PKG channels, blocks potassium-calcium channels, has multi-target vasodilating properties and inhibits the anti-inflammatory effects of vascular adhesion factors ICAM-1, VCAM-1. The vasomotor effect of phenylephrine pre-contraction is stronger than nifedipine, so that the development of a novel medicine with multiple targets is expected to become a novel way for treating vascular diseases such as hypertension, coronary heart disease and the like.
In the description of the present invention, unless otherwise indicated, the meaning of "a plurality" is two or more; the terms "upper," "lower," "left," "right," "inner," "outer," "front," "rear," "head," "tail," and the like are used as an orientation or positional relationship based on that shown in the drawings, merely to facilitate description of the invention and to simplify the description, and do not indicate or imply that the devices or elements referred to must have a particular orientation, be constructed and operated in a particular orientation, and therefore should not be construed as limiting the invention. Furthermore, the terms "first," "second," "third," and the like are used for descriptive purposes only and are not to be construed as indicating or implying relative importance.
The foregoing is merely illustrative of specific embodiments of the present invention, and the scope of the invention is not limited thereto, but any modifications, equivalents, improvements and alternatives falling within the spirit and principles of the present invention will be apparent to those skilled in the art within the scope of the present invention.
Claims (6)
1. Application of disproportionated rosin compounds in preparing multi-target medicines for treating vascular diseases including hypertension and coronary heart disease;
the chemical structural formula of the disproportionated rosin compound is as follows:
the disproportionated rosin compound is named as follows:
(1R, 4aS,10 aR) -7-isopropyl-1,4a-dimethyl-1,2,3, 4a,9, 10, 10 a-octahydrohenthren-1-yl) (piperazin-1-yl) methyl; abbreviated as Z28;
the dosage of the disproportionated rosin compound is as follows:
drug concentration in vitro vascular perfusion model: after stabilization of the vascular ring, 1X 10 -6 Adding mol/L PE into vascular ring nutrient solution with complete vascular endothelium or various blocking agents, and treating 1×10 -6 After the shrinkage of the mol/L PE is stabilized, adding Z28 with the final concentration of 0.3125, 0.625, 1.25, 2.5, 5, 10 and 20 mu M in an accumulated way;
the drug concentration in human umbilical vein endothelial cell experiments was 0.25, 0.5, 1 μm Z28.
2. The use according to claim 1, wherein the disproportionated rosin has the formula C 24 H 36 N 2 O。
3. A method for producing a disproportionated rosin compound for use according to any one of claims 1 to 2, characterized in that the method for producing a disproportionated rosin compound comprises the steps of:
step one, adding anhydrous dichloromethane solution of dehydroabietic acid into catalytic amount of N, N-dimethylformamide, dropwise adding oxalyl chloride under ice bath condition, reacting at room temperature after adding, and monitoring by TLC;
step two, after the reaction is completed, the solvent is removed under reduced pressure under the protection of nitrogen, and anhydrous dichloromethane is slowly added dropwise; under the protection of nitrogen, piperazine and triethylamine are slowly added into a flask, stirred at room temperature and monitored by TLC;
and thirdly, after the reaction is finished, removing the solvent under reduced pressure, extracting, washing with 10% hydrochloric acid solution, saturated sodium bicarbonate and saturated saline solution, drying with anhydrous magnesium sulfate or anhydrous sodium sulfate, and performing column chromatography to obtain the compound Z28.
4. A method for producing disproportionated rosin compound according to claim 3, wherein in the first step, the room temperature reaction time is 2 hours.
5. The method for producing disproportionated rosin compound according to claim 3, wherein in the second step, the reaction time is 12 to 24 hours.
6. Use of disproportionated rosin compound according to any one of claims 1-2 for the preparation of an anti-inflammatory medicament for multi-target vasodilation and inhibition of vascular adhesion factors ICAM-1 and VCAM-1.
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