CN112194703B - Cardiac glycoside compound and synthesis method and application thereof - Google Patents
Cardiac glycoside compound and synthesis method and application thereof Download PDFInfo
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Abstract
The invention belongs to the field of medicines, and discloses a cardiac glycoside compound and a synthesis method and application thereof. The cardiac glycoside compound is a compound shown as a formula (I) or a pharmaceutically acceptable salt thereof; the cardiac glycoside compound can achieve better tumor inhibition effect and lower toxicity to normal cells. The synthesis method of the cardiac glycoside compound comprises the following steps: dissolving calotropin with solvent, adding reducing agent, reacting at room temperature under stirring, and synthesizing the cardiac glycoside compound.
Description
Technical Field
The invention belongs to the field of medicines, and particularly relates to a cardiac glycoside compound and a synthesis method and application thereof.
Background
Cardiac glycosides are drugs that act selectively on the heart to increase the force of myocardial contraction, and are also known as cardiac glycosides or cardiac glycosides. Related studies have shown that certain cardiac glycosides inhibit the growth of human tumor cells and induce apoptosis (e.g., digoxin, etc.). Many cardiac glycoside compounds have antitumor effect, and simultaneously, the cardiac glycoside compounds also have great adverse reaction on normal cells, and the safety is difficult to ensure, so the cardiac glycoside compounds become the biggest obstacle for being put into anticancer clinical application, only a few cardiac glycoside compounds can enter the clinical stage of antitumor drugs, and more research and development on cardiac glycoside antitumor drugs are needed.
Therefore, the invention hopes to provide a cardiac glycoside compound with obvious anti-tumor effect and small toxicity to normal cells, thereby promoting the development of cardiac glycoside anti-tumor drugs and providing a better choice for future tumor treatment.
Disclosure of Invention
The present invention is directed to solving at least one of the problems of the prior art described above. Therefore, the invention provides a cardiac glycoside compound which can achieve better tumor inhibition effect and lower toxicity to normal cells.
A cardiac glycoside compound is a compound shown in formula (I) or a pharmaceutically acceptable salt thereof;
the cardiac glycoside compound is named as 19-dihydrocalotoxin. The cardiac glycoside compound can be obtained by extraction and separation or artificial synthesis, wherein the source of extraction and separation can be calotropis gigantea leaves.
The synthesis method of the cardiac glycoside compound comprises the following steps:
dissolving calotropin (calotoxin) with a solvent, adding a reducing agent, reacting at room temperature under stirring, and synthesizing the cardiac glycoside compound.
Preferably, the solvent is selected from at least one of methanol, ethanol, diethylene glycol, tetrahydrofuran, or N, N-dimethylformamide.
Preferably, the reducing agent is selected from at least one of sodium borohydride, lithium aluminum hydride, palladium on carbon, or raney nickel.
The calotropin is a cardiac glycoside component, and the invention synthesizes a new cardiac glycoside compound by taking calotropin as a raw material, thereby realizing the improvement of the calotropin performance.
Preferably, the synthesis method further comprises using NH4At least one of aqueous Cl solution, dilute hydrochloric acid or dilute acetic acid.
The cardiac glycoside compounds can be used for preparing antitumor drugs.
An antitumor drug comprises the cardiac glycoside compound. Compared with the existing cardiac glycoside, the cardiac glycoside compound provided by the invention has better tumor inhibition effect and better safety, and can be used as an anti-tumor drug.
Preferably, the anti-tumor medicine also comprises pharmaceutically acceptable auxiliary materials. The pharmaceutically acceptable adjuvants include, but are not limited to, solvents, fillers, lubricants, disintegrants, buffers, cosolvents, antioxidants, bacteriostats, emulsifiers, binders or suspending agents.
Preferably, the tumor includes colon cancer, cervical cancer, liver cancer, lung cancer, breast cancer and ovarian cancer.
More preferably, the tumors include colon cancer, lung cancer and breast cancer.
The cardiac glycoside compound is used in preparing HIF-1 inhibitor.
HIF-1 (hypoxia-indicator factor-1) is widely present in various solid tumor cells and plays a leading role in the hypoxia signal transduction pathway of tumors. HIF-1 is a heterodimer consisting of an oxygen-sensitive alpha regulatory subunit and a stably expressed beta structural subunit. HIF-1 α is strictly regulated by oxygen concentration and is a key active subunit for achieving HIF-1 bioeffects. The beta subunit is expressed in a constitutive form and is not regulated and influenced by oxygen, and the function of the beta subunit is related to maintaining the structural stability of HIF-1 and causing active conformation transition by dimerization. HIF-1 alpha is the central regulator of tumor cell to regulate hypoxia microenvironment to make organism produce adaptive response to microenvironment hypoxia, and is also the upstream transcription regulating protein of relative gene of tumor angiogenesis, energy metabolism, cell proliferation, infiltration and metastasis. As a main gene transcription regulatory factor for adapting to the hypoxia crisis of an organism, HIF-1 plays a vital role in a plurality of key fields of cell proliferation and survival, angiogenesis, metabolic mode recombination, stem cell maintenance, autocrine growth factor signal path, epithelial-mesenchymal transition, infiltration, metastasis, chemoradiotherapy tolerance and the like of tumors (particularly malignant tumors), and is a key regulatory element for rapidly adapting to a hypoxic microenvironment and continuously obtaining energy to survive by tumor cells. Clinical studies have demonstrated that over 90% of solid tumor cells highly express HIF-1 α protein, whereas HIF-1 α is barely detectable in normal tissue cells. Thus, HIF-1 α is considered to be a very specific and selective anti-cancer target. Digoxin (digoxin), which is a classical cardiac glycoside component in its chemical structure, has been reported to exert an antitumor effect by inhibiting the synthesis of HIF-1 α protein.
Experiments show that the cardiac glycoside compound 19-dihydrocalotoxin has a remarkable inhibition effect on the protein expression of HIF-1 alpha, so that the cardiac glycoside compound has a prominent potential for preparing HIF-1 inhibitors.
Compared with the prior art, the invention has the following beneficial effects:
experiments show that the cardiac glycoside compound 19-dihydrocalotoxin can play an anti-tumor role by inhibiting HIF-1 expression. The cardiac glycoside compound has killing effect on various tumor cells, has especially prominent anti-tumor effect on colon cancer, lung cancer and breast cancer, and has stronger in-vivo anti-tumor effect than paclitaxel. Meanwhile, the cardiac glycoside compound has good safety and low toxicity to normal cells, so the cardiac glycoside compound has practical clinical application value and development prospect.
Drawings
FIG. 1 shows the results of the Western blotting experiment in example 3, digoxin (group D), 19-dihydrocaloxin (group 1), uschorin (group 2), caloxin (group 3), and 19-dihydrocalactin (group 4);
FIG. 2 shows the results of immunocytochemistry experiments in example 4, digoxin (group D), 19-dihydrocaloxin (group 1), uschorin (group 2), caloxin (group 3), and 19-dihydrocalactin (group 4);
FIG. 3 shows the antitumor activity of 19-dihydrocaloxin of example 7 in mice, paclitaxel (PTX group), 19-dihydrocaloxin (group 1);
FIG. 4 shows the effect of 19-dihydrocaloxin on the histomorphology of transplanted tumors and HIF-1. alpha. expression in nude mice in example 8, paclitaxel (PTX group) and 19-dihydrocaloxin (group 1).
Detailed Description
In order to make the technical solutions of the present invention more apparent to those skilled in the art, the following examples are given for illustration. It should be noted that the following examples are not intended to limit the scope of the claimed invention.
The starting materials, reagents or apparatuses used in the following examples are conventionally commercially available or can be obtained by conventionally known methods, unless otherwise specified.
Example 1
This embodiment provides a cardiac glycoside compound 19-dihydrocaloxin, which is a compound represented by formula (I) or a pharmaceutically acceptable salt thereof;
the synthesis method of the cardiac glycoside compound (19-dihydrocaloxin) comprises the following steps:
calotropin (215mg, 0.39mmol) was dissolved in a solution of methanol (20mL) pre-cooled in an ice bath, sodium borohydride solid (52mg, 1.3mmol) was added in portions, and the solution was stirred at room temperature for 2 hours. After the reaction material was completely disappeared as detected by TLC (chromatography), saturated NH was added4The reaction was quenched with aqueous Cl (6.5 mL). After recovering methanol under reduced pressure, the aqueous solution was extracted with ethyl acetate (EtOAc), and after combining the organic solvents, the mixture was washed successively with brine (5mL) and anhydrous Na2SO4Drying, filtering and recovering the organic solvent under reduced pressure. The residue was flash purified by column chromatography on silica gel (CHCl)3MeOH, 10:1) to yield 193mg of the desired product 19-dihydrocalotoxin, yield 90.0%.
Wherein the initial raw material calotoxin can be obtained by separating and purifying calotoxin from calotropis gigantea milk, and the structure of calotoxin is as follows:
example 2
Cytotoxicity of cardiac glycoside compound 19-dihydrocalotoxin on tumor cell T47D
Human ductal carcinoma of mammary gland cell T47D is cultured in DMEM complete medium, MTT experiment is adopted to detect the growth inhibition effect of the strong cardiac glycoside compound 19-dihydrocalotoxin on T47D tumor cells in example 1, and the specific experimental process is as follows:
cells in logarithmic growth phase were seeded in 96-well plates at 5X 10 per well3And (3) treating the cells with a series of drug-containing culture media with different concentrations for 24 hours after the cells are attached to the wall, setting three multiple wells, simultaneously setting a blank control well and a zero setting well, adding 10 mu L of 5mg/mL MTT solution into each well, continuously incubating for 4 hours, removing the culture medium, adding 100 mu L of DMSO into each well to dissolve generated formazan, and measuring the absorbance value at the wavelength of 570 nm. The cell growth inhibition rate was calculated according to the following formula: inhibition (%) - (blank well absorbance value-test well absorbance value)/(blank well absorbance value-zero set well absorbance value) × 100%, and then half Inhibitory Concentrations (IC) of the drugs were calculated from the inhibition under different concentration conditions50) The experimental results were expressed as mean ± standard deviation, and Paclitaxel (PTX) group and digoxin (digoxin) group were set.
The test results are shown in table 1.
TABLE 119 IC of cytotoxic and HIF-1 transcriptional repression Activity of dihydrocaloxin on T47D cells50Value (nM)
| Compound (I) | Cytotoxic Activity | HIF-1 transcriptional repression Activity |
| Paclitaxel | 356.07±26.11 | ND |
| Digoxin | 47.36±0.71 | 145.77±10.97 |
| 19-dihydrocalotoxin | 46.43±2.62 | 139.57±6.89 |
Note: ND is not determined
As shown in Table 1, paclitaxel is a typical antitumor drug with wide clinical application, but paclitaxel has poor cytotoxicity to human ductal carcinoma of mammary gland T47D, and has no effect of inhibiting HIF-1 transcription, which indicates that not all antitumor drugs have the effect of inhibiting HIF-1 transcription. The cardiac glycoside compound 19-dihydrocalotoxin prepared in example 1 has HIF-1 transcription inhibitory activity similar to that of digoxin, a classical cardiac glycoside component, and digoxin has been reported as an HIF-1 inhibitor, so the cardiac glycoside compound 19-dihydrocalotoxin can also be used as a novel HIF-1 inhibitor.
Example 3
Inhibition of HIF-1 alpha protein expression by cardiac glycoside compound 19-dihydrocalotoxin (Western blot experiment)
In order to confirm whether the inhibitory effect of the cardiac glycoside compound (19-dihydrocaloxin) on the HIF-1 transcriptional activity is caused by inhibiting the HIF-1 activity or reducing the expression of the HIF-1 protein in example 1, a Western blot experiment is adopted to detect the influence of a representative cardiac glycoside on the expression of the HIF-1 alpha protein in tumor cells under the anoxic condition. T47D cells were planted in 6-well plates, after adherence, the cells were treated with cardiac glycoside-containing media of different concentrations, and placed under hypoxic conditions for 24 hours, while blank control wells under normoxic conditions (oxygen concentration 21%) and hypoxic conditions (oxygen concentration 1%) were set. After the cell treatment is finished, extracting cell protein, performing an electrophoresis experiment and an immunoblotting experiment, and representing the expression of the HIF-1 alpha protein by comparing the gray level of protein bands in the cells under different treatment conditions.
The results are shown in FIG. 1, and digoxin (group D), 19-dihydrocaloxin (group 1), uschorin (group 2), caloxin (group 3) and 19-dihydrocalactin (group 4) all inhibited HIF-1. alpha. protein expression in T47D cells under hypoxic conditions in a dose-dependent manner. Wherein uscarin, calotoxin and 19-dihydrocalactin are all known cardiac glycoside components, and the structural formulas of uscarin and 19-dihydrocalactin are shown as follows:
example 4
Inhibition of HIF-1 alpha protein expression by cardiac glycoside 19-dihydrocalotoxin (immunocytochemistry experiment)
In order to further study the distribution of HIF-1 alpha in cancer cells and the inhibitory effect of the strong glycoside compound (19-dihydrocaloxin) on HIF-1 alpha expression in example 1, the in situ analysis of HIF-1 alpha was performed by immunocytochemistry experiments, and the specific experimental procedures and results are as follows:
place sterile coverslips in 6-well plates and then add 2X 10 to each well5And (3) treating the T47D cells with digoxin with gradient concentration, 19-dihydrocaloxin, uscarin, caloxin and 19-dihydrocalactin in the strong cardiac glycosides in example 1 after the cells are attached to the wall, culturing for 24 hours under the hypoxic condition, and setting blank control holes under the normoxic condition and the hypoxic condition. After the treatment, the coverslips were removed, washed, fixed, permeabilized, blocked, and the like, HIF-1. alpha. primary antibody was incubated overnight at 4 deg.C, followed by Alexa Fluor 555. secondary antibody, and finally cell nuclei were stained with DAPI (4', 6-diamidino-2-phenylindole), and coverslips were fixed to slides with blocking agent until they were finishedAfter full curing, the films were observed under a laser confocal fluorescence microscope (Leica TCS SP8) and photographed.
As can be seen in FIG. 2, hypoxia (oxygen concentration 1%) induces a rapid mass aggregation of HIF-1. alpha. protein and is distributed predominantly in the nucleus, as compared to normoxic conditions (oxygen concentration 21%). Digoxin (group D), 19-dihydrocaloxin (group 1), uschorin (group 2), caloxin (group 3) and 19-dihydrocalactin (group 4) were all able to dose-dependently inhibit HIF-1. alpha. protein expression in T47D cells in hypoxic culture. These results are consistent with the dual-luciferase reporter gene experiments and the western blotting experiments, and further confirm the inhibition effect of cardiac glycoside compound 19-dihydrocalotoxin on HIF-1 alpha protein expression.
Example 5
Example 1 growth inhibitory Effect of Strong cardiac glycosides (19-dihydrocalotoxin) on tumor cells and Normal cells
Human colon cancer cell HCT 116, human cervical cancer cell HeLa, human hepatoma cell HepG2, human non-small cell lung cancer cell a549 and rat cardiomyocyte H9c2 were cultured in DMEM complete medium. Human mammary epithelial cancer cell MCF-7 was cultured in MEM complete medium. Human ovarian cancer cells A2780, human triple negative breast cancer cells MDA-MB-231 and human liver cells LO2 were cultured in RPMI 1640 complete medium.
MTT (methyl thiazolyl tetrazolium) experiment is adopted to detect the growth inhibition effect of cardiac glycoside compounds (19-dihydrocaloxin) on various tumor cells, and the specific experimental flow and results are as follows:
cells in logarithmic growth phase were seeded in 96-well plates at 5X 10 per well3And (3) treating the cells with a series of drug-containing culture media with different concentrations for 24 hours after the cells are attached to the wall, setting three multiple wells, simultaneously setting a blank control well and a zero setting well, adding 10 mu L of 5mg/mL MTT solution into each well, continuously incubating for 4 hours, removing the culture medium, adding 100 mu L of DMSO into each well to dissolve generated formazan, and measuring the absorbance value at the wavelength of 570 nm. The cell growth inhibition rate was calculated according to the following formula: inhibition (%) - (blank well absorbance value-test well absorbance value)/(blank well absorbance value-zero set well absorbance value) × 100%, howeverThen calculating half Inhibitory Concentration (IC) of the drug according to the inhibition rate under different concentration conditions50) The experimental results are expressed as mean ± standard deviation. In addition to the 19-dihydrocaloxin group, this experiment was also provided with a Paclitaxel (PTX) group, a digoxin (digoxin) group, a uschorin group, a calotoxin group, and a 19-dihydrocalactin group. The test results are shown in table 2:
TABLE 219 cytotoxic Activity of dihydrocaloxin on various tumor and Normal cells (IC)50)
As shown in Table 2, the toxicity (IC) of 19-dihydrocalotoxin, a cardiac glycoside compound obtained in example 1, to various tumor cells50Values of 54.98-316.90nM) were comparable to digoxin (74.33-365.00nM) and paclitaxel (55.14-636.27nM), indicating that it exhibited excellent antitumor effects. Compared with calotoxin, the cardiac glycoside compound 19-dihydrocalotoxin prepared in the embodiment 1 has smaller toxicity to normal cells and good safety, but the 19-dihydrocalotoxin shows obviously better inhibition and killing effects on tumor cells. Compared with 19-dihydrocalactin and uscarin, the cardiac glycoside compound 19-dihydrocalatoxin prepared in the example 1 has similar toxicity to digoxin and paclitaxel on various tumor cells although the antitumor effect is weakened, and can meet the clinical antitumor requirement; but in terms of toxicity to normal cells, the toxicity of 19-dihydrocalotoxin to the LO2 normal cell line is obviously weakened, so that the medicine has better safety and pharmacy.
Example 6
In vivo toxicity study of cardiac glycoside compounds
In order to further evaluate the druggability of cardiac glycoside components and preferably select a cardiac glycoside drug with anti-tumor activity and safety, a maximum tolerated dose experiment is adopted to detect the in vivo toxicity of the cardiac glycoside drug, and the specific experimental flow is as follows: the raised 30 female BALB/c-nu nude mice of 6 weeks old were randomly divided into 5 groups of 6 mice each, and the following drugs were intraperitoneally injected into each group of nude mice: the preparation method comprises the following steps of administering the 19-dihydrocaloxin 40mg/kg, uschorin 2.5mg/kg, uschorin 5mg/kg, 19-dihydrocalactin 2.5mg/kg and 19-dihydrocalactin 5mg/kg twice a week for three weeks, and continuously monitoring the weight, spirit and living conditions of the mice.
The results of the test were: nude mice in the uscarin and 19-dihydrocalactin high and low dose groups all died within one day after the initial administration, and nude mice in the 19-dihydrocalatoxin 40mg/kg group were in good condition but reduced in body weight throughout the experiment. The results show that uscarin and 19-dihydrocalactin have strong in vivo toxicity, 19-dihydrocaloxin has no obvious in vivo toxicity, and 19-dihydrocaloxin has better druggability.
Example 7
Antitumor activity of cardiac glycoside compound 19-dihydrocalotoxin in mice
The in vivo antitumor activity of the cardiac glycoside compound is determined by a nude mouse transplantation tumor experiment, and the specific experimental process and results are as follows. 30 female BALB/c-nu nude mice of 6 weeks old were bred, and 100. mu.L of a feed containing 5X 10 amino acids was injected into the left armpit of each nude mouse6Serum-free culture medium of individual mammary epithelial cancer MCF-7 cells until the average tumor volume reaches 200mm3Thereafter, these nude mice were randomly divided into 5 groups of 6 mice each. The following drugs were administered to the nude mice by intraperitoneal injection, respectively: normal saline (blank control), PTX group (5 mg/kg paclitaxel, 10mg/kg paclitaxel), 1 group (5 mg/kg 19-dihydrocaloxin, 10mg/kg 19-dihydrocaloxin), wherein 19-dihydrocaloxin may be abbreviated as 19-dih; the administration was performed twice a week for 3 weeks, and the body weight and tumor volume of nude mice were measured before each administration. The day of experiment, the nude mice were sacrificed after measuring their body weight and tumor volume, and tumors were taken out and photographed, and the results are shown in fig. 3. According to the experimental record, the change curves of the weight (figure 3A) and the tumor volume (figure 3B) of the nude mice along with the time are drawn, the difference between the corresponding groups is counted, and the in vivo anti-tumor effect of the 19-dihydrocaloxin is analyzed.
The experimental result shows that in the whole experimental period, the paclitaxel PTX is 5mg/kg, the paclitaxel PTX is 10mg/kg, the 19-dihydrocaloxin is 5mg/kg, the 19-dihydrocaloxin is 10mg/kg and the nude mice of the blank control group do not die, the average body weight of the nude mice of the four administration groups and the blank control group is basically maintained between 18g and 20g, and the 19-dihydrocaloxin is the same as the paclitaxel and has no obvious in vivo toxicity. By analyzing the tumor volumes of the groups in the experimental process (fig. 3C), it can be seen that both 19-dihydrocaloxin (i.e., 19-dih) and paclitaxel can inhibit tumor growth dose-dependently, and the tumor inhibition effect of the same dose of 19-dihydrocaloxin is stronger than that of paclitaxel, which indicates that 19-dihydrocaloxin has stronger in vivo anti-tumor activity than paclitaxel.
Example 8
Histomorphometry and HIF-1 alpha immunohistochemical analysis of nude mice transplantable tumors
After the nude mouse transplantation tumor experiment of example 7 was completed, the effects of 19-dihydrocalotoxin (group 1) and paclitaxel (group PTX) on tumor tissue morphology and HIF-1 α protein expression were analyzed by H & E staining and immunohistochemical experiments, and the specific experimental procedures were as follows: the nude mouse transplantation tumor is taken out and placed in 10% neutral formalin solution for fixation for 12 hours, cut into slices with the thickness of 5 microns after paraffin embedding, respectively carry out H & E staining and immunohistochemistry experiments according to standard operation procedures after dewaxing and hydration, and finally carry out observation and photographing by using a phase contrast microscope.
The experimental results are shown in fig. 4, and it can be seen from H & E staining that the cytoplasm and nucleus in the blank group are normal in morphology, plump in structure and tightly arranged, while 19-dihydrocalotoxin (group 1) and paclitaxel (PTX group) can induce tumor cell necrosis in a dose-dependent manner, specifically, as shown by cell membrane disruption, cell boundary disappearance, cell nucleus shrinkage, cytoplasm and cell and staining deepening, and even cytolysis. And immunohistochemical experiments show that HIF-1 alpha is highly expressed in blank group tumors, while 19-dihydrocaloxin can inhibit the expression of HIF-1 alpha in tumor tissues in a dose-dependent manner, but paclitaxel has no obvious influence on the expression of HIF-1 alpha. These results explain to some extent the in vivo anti-tumor mechanism of 19-dihydrocalotoxin.
Claims (8)
1. A cardiac glycoside compound is characterized by being represented by the formula (A)
) A compound shown in the specification or a pharmaceutically acceptable salt thereof;
（
）。
2. the method of synthesizing cardiac glycosides of claim 1, comprising the steps of:
dissolving calotropin with solvent, adding reducing agent, reacting at room temperature under stirring to synthesize the cardiac glycoside compound;
the solvent is selected from at least one of methanol, ethanol, diethylene glycol, tetrahydrofuran or N, N-dimethylformamide;
the reducing agent is selected from at least one of sodium borohydride, lithium aluminum hydride, palladium carbon or Raney nickel.
3. The method of claim 2, further comprising using NH4At least one of aqueous Cl solution, dilute hydrochloric acid or dilute acetic acid.
4. The cardiac glycoside compound of claim 1, for use in the preparation of an anti-tumor medicament.
5. An antitumor agent comprising the cardiac glycoside compound according to claim 1.
6. The antitumor drug as claimed in claim 5, further comprising pharmaceutically acceptable excipients.
7. The antitumor agent as claimed in claim 5, wherein the tumor includes colon cancer, lung cancer and breast cancer.
8. The cardiac glycoside compound of claim 1, for use in the preparation of a HIF-1 inhibitor.
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| CN1711099A (en) * | 2002-10-09 | 2005-12-21 | 优尼拜尔斯金股份有限公司 | Extract with anti-tumor and anti-poisonous activity |
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| CN1711099A (en) * | 2002-10-09 | 2005-12-21 | 优尼拜尔斯金股份有限公司 | Extract with anti-tumor and anti-poisonous activity |
Non-Patent Citations (3)
| Title |
|---|
| Antiproliferative cardenolides from the aerial parts of Pergularia tomentosa;Hosseini, Seyed Hamzeh;;《Journal of Natural Products》;20190110;第82卷(第1期);74-79 * |
| Biochemical studies on ghalakinoside, a possible antitumor agent from Pergularia tomentosa;Al-Said, Mansour S.;;《Journal of Ethnopharmacology》;19891231;第27卷(第1-2期);235-240 * |
| Cardenolides from Pergularia tomentosa Display Cytotoxic Activity Resulting from Their Potent Inhibition of Na+/K+-ATPase;Piacente, Sonia;;《J. Nat. Prod.》;20091231;第72卷;1087–1091 * |
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