CN108623607B - 5,5, 6-polycyclic tetramic acid-containing macrocyclic lactam compound and preparation method and application thereof - Google Patents
5,5, 6-polycyclic tetramic acid-containing macrocyclic lactam compound and preparation method and application thereof Download PDFInfo
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Abstract
5,5, 6-polycyclic tetramic acid-containing macrolactam compounds, a preparation method and application thereof. The 5,5, 6-polycyclic tetramic acid-containing macrocyclic lactam compound can be used as a tumor cell proliferation inhibitor or a tumor cell killing agent or an aspergillus fumigatus growth inhibitor.
Description
Technical Field
The invention relates to a5, 5, 6-polycyclic tetramic acid-containing macrocyclic lactam compound, a preparation method and application thereof.
Background
Chinese resident nutritional and chronic disease status report (2015) indicates that the death rate of chronic diseases of residents in the country in 2012 is 533/10 ten thousand, accounting for 86.6% of the total deaths. Cardiovascular and cerebrovascular diseases, cancer and chronic respiratory diseases are main causes of death, accounting for 79.4 percent of the total death, wherein the cancer death rate is 144.3/10 ten thousand (the first five are lung cancer, liver cancer, gastric cancer, esophagus cancer and colorectal cancer respectively). A report (2016,66: 115) in 2016 for Clinicians shows that Cancer has become the first cause of death in China, the morbidity and mortality rate are continuously increased, 429.2 ten thousand new tumor cases and 281.4 ten thousand death cases are predicted in 2015, almost 22% of new Cancer cases and 27% of Cancer death cases are predicted in China all over the world. Cancer has become a very important public health problem, and the large population base of China also makes the data of Chinese people have great significance for the prevention and control of cancer in the world.
With the continuous development of science and technology and medical level, people explore various methods for treating tumors, which are mainly divided into surgery, chemotherapy, radiotherapy, multidisciplinary comprehensive treatment of traditional Chinese medicine intervention and the like. Among them, chemotherapy is one of the important means for treating cancer patients. Chemotherapy is a treatment mode of killing tumor cells, inhibiting the growth and reproduction of the tumor cells and promoting the differentiation of the tumor cells by using chemical drugs, almost all the chemotherapeutic drugs can cause liver function damage, mild patients can have abnormal liver functions, patients can have discomfort in liver regions, and even toxic hepatitis can be caused; some chemotherapy drugs can cause damage to renal function to cause lumbago, renal discomfort and the like at large dose, and due to poor selectivity of the chemotherapy drugs, normal cells and immune cells are greatly killed while tumor cells are killed by the chemotherapy drugs, so that side effects and toxic effects are great. Therefore, the research and development of a safe and efficient anti-tumor drug are urgently needed, normal cells for maintaining life are not damaged when specific tumor cells in a patient body are effectively killed, and the survival rate and the survival quality of the patient are greatly improved.
5,5, 6-Polycyclic tetramic acid-containing macrocyclic lactams (PTMs) were first isolated in 1972 from Streptomyces phaeochromogenes var. ikarunensis Sakai (Jomon K, Kuroda Y, Ajisaka M, Sakai H.A new antigen, ikarugamycin. J. Antibiot.1972,25: 271-280) and have novel structural features including: 1 unusual tetraamminic acid residue, a multiple cyclic structure and a macrolactam nucleus. Not only are challenging structures conferred, PTMs also exhibit a number of potentially potent activities, especially antifungal activities (Sugawara T, Chiao YF, Kaneda Y, Ando T, Adachi t.afa 05200 from Streptomyces species, and pharmaceuticals and fungicides conjugation it jpn.kokai tokyo Koho, JP 10310584a 19981124.Hashidoko Y, Tahara S, Nakayama t.xanthobaccin antibodies pct int. app. (2000), WO 2000020418a 120000413). In addition, PTMs have been reported to have antitumor activity (Bae MA, Yamada K, Uemura D, Seu JH, Kim YH.Aburatobalactam C, a novel apoptosis-inducing substance produced by marine Streptomyces sp.SCRC A-20.J.Microbiol.Biotechnol.1998,8(5): 455-) 460). For this reason, chemists, biologists, and pharmacologists never stopped exploring such compounds.
Disclosure of Invention
The inventor of the invention is dedicated to the development of 5,5, 6-polycyclic medicaments containing tetramic acid macrocyclic lactam compounds, and on one hand, the compounds are found to have antitumor activity and better selectivity. On the other hand, the compounds are found to have good inhibitory activity on the growth of aspergillus fumigatus.
The present invention provides a compound of formula I, a pharmaceutically acceptable salt or prodrug thereof,
preferably, the compound of formula I is a compound of formula I',
in the formula I and the formula I',
R1selected from-H, -OH, ═ O or R1' O-, wherein R1' is alkyl; r2Selected from-H, -OH or R2' O-, wherein R2' is alkyl;
R3、R4together form-O-; or, R4Is H, R3Is selected from-H, -OH, R 'O-or R' COO-, wherein R 'and R' are each independently alkyl;
R5、R6together form-O-or a single bond; or, R5、R6Each independently selected from-H or-OH;
R7、R8together form-O-or a single bond; or, R7Is H, R8Selected from alkyl or alkenyl;
R9is an alkyl group;
R10、R11together form-O-or a single bond; or, R10、R11Each independently selected from-H or-OH;
R12、R13each independently selected from-H or alkyl;
alternatively, the alkyl is C1～C20Branched or straight-chain alkyl, or is C1～C16Branched or straight-chain alkyl, or is C1～C8Branched or straight-chain alkyl, or is C1～C4Branched or straight chain alkyl; the alkenyl is C2～C20A branched or linear alkenyl group, or is C2～C16A branched or linear alkenyl group, or is C2～C8A branched or linear alkenyl group, or is C2～C4Branched or straight chain alkenyl.
Alternatively, the compound of formula I, a pharmaceutically acceptable salt or prodrug thereof, described above is a compound of formula II, a pharmaceutically acceptable salt or prodrug thereof,
preferably, the compound of formula II is a compound of formula II',
in the formula II and the formula II',
R1is selected from-OH or ═ O; r2Is selected from-H or-OH; r3Is selected from-H, -OH or R 'COO-, wherein R' is alkyl, and the alkyl is C1～C20Branched or straight-chain alkyl, or is C1～C16Branched or straight-chain alkyl, or is C1～C8Branched or straight chain alkyl.
Alternatively, the compound of formula I, a pharmaceutically acceptable salt or prodrug thereof, described above, is selected from the group consisting of the following compounds, pharmaceutically acceptable salts or prodrugs thereof,
alternatively, the compound of formula I, a pharmaceutically acceptable salt or prodrug thereof, wherein the pharmaceutically acceptable salt is a salt of the compound of formula I with: hydrochloric acid; sulfuric acid; phosphoric acid; formic acid; acetic acid; propionic acid; lactic acid; citric acid; tartaric acid; succinic acid; fumaric acid; maleic acid; mandelic acid; malic acid; camphorsulfonic acid; the pharmaceutically acceptable prodrug comprises a prodrug formed by combining the compound shown in the formula I and a pharmaceutically acceptable carrier; optionally, the pharmaceutically acceptable carrier comprises: phosphoric acid triglyceride, polyethylene glycol ester, polyethylene glycol amide, polyethylene glycol ether.
The invention also provides a preparation method of the compound shown in the formula I, the pharmaceutically acceptable salt or the prodrug thereof, wherein the method comprises the following steps:
culturing actinomycetes A. cyanogeneus WH1-2216-6 by fermentation, and separating and purifying the fermentation liquor obtained by the fermentation culture to obtain a product; optionally, the product of separation and purification is used as a raw material to carry out semi-synthesis reaction to prepare,
optionally, the fermentation culture comprises: culturing actinomycetes A. cyanogeneus WH1-2216-6 in seed culture medium, inoculating into fermentation culture medium, culturing, and fermenting to obtain fermentation product;
optionally, the seed medium comprises: a carbon source, a nitrogen source and an aqueous solution containing sodium chloride; optionally, the seed medium comprises: peptone, glycerol, soybean meal, soluble starch, calcium carbonate and seawater; optionally, the seed culture medium is 15 parts by weight of peptone, 15 parts by weight of glycerol, 5 parts by weight of soybean meal, 15 parts by weight of soluble starch, 2 parts by weight of calcium carbonate and 1000 parts by weight of aged seawater, and the pH is 7.8;
optionally, the fermentation medium comprises: soluble starch, glycerol, peptone, calcium carbonate, macroporous adsorption resin and aged seawater; optionally, the fermentation medium comprises 20 parts by weight of soluble starch, 20 parts by weight of glycerol, 20 parts by weight of peptone, 2 parts by weight of calcium carbonate, 50 parts by weight of XAD-16 macroporous adsorption resin and 1000 parts by weight of aged seawater, and the pH value is 7.5;
optionally, the separating and purifying comprises: extracting the fermentation liquor by using an organic solvent, concentrating an organic phase, adding an acidic solution, extracting by using the organic solvent, removing the organic phase, adding alkali into a water phase to adjust the pH value, extracting by using the organic solvent, concentrating the organic phase to obtain an alkaloid part, performing gradient elution and separation on the obtained alkaloid part by using reduced pressure silica gel column chromatography, and performing reverse phase silica gel column chromatography, gel column chromatography and high performance liquid semi-preparative separation on the eluted component; optionally, each organic solvent for extraction is independently selected from ethyl acetate, dichloromethane, chloroform, petroleum ether; optionally, the acidic solution is selected from hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid; optionally the base is selected from ammonia, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate; optionally, the eluent for the reduced pressure silica gel chromatographic column is selected from petroleum ether, dichloromethane, methanol, dichloromethane-methanol mixed solution, and water; optionally, the eluent for gel column chromatography is selected from methanol, dichloromethane-methanol mixture; optionally, the eluent for the high performance liquid semi-preparation is a methanol-trifluoroacetic acid mixed solution;
alternatively, the step of semi-synthesis reaction using the isolated and purified product as a raw material comprises: epoxidation reaction, dihydroxylation reaction, hydration reaction, NH-and OH-methylation reaction, OH-acylation reaction, oxidation reaction, carbonyl O-reduction reaction or combination reaction of the two reactions in the structure of the separated and purified product;
alternatively, the compound of formula I is a compound 1-6;
alternatively, the preparation method of the compounds 1 to 6 comprises the following steps: culturing actinomyces dissimilis WH1-2216-6 in a seed culture medium, inoculating the actinomyces dissimilis WH1-2216-6 into a fermentation culture medium, culturing and fermenting in a shaking table to obtain a fermented product, extracting the fermented product with ethyl acetate, concentrating an organic phase to obtain a crude extract, adding an HCl solution into the crude extract, extracting with dichloromethane, adjusting a water phase to pH 8.0 with ammonia water, extracting with dichloromethane, concentrating an organic phase to obtain an alkaloid part, separating the obtained alkaloid part with reduced pressure silica gel column chromatography, and performing gradient elution with petroleum ether, dichloromethane and dichloromethane-methanol (v/v, 100:1, 50:1, 25:1, 15:1, 10:1, 5:1, 4:1, 2:1, 1:1, 0:1) as solvents in sequence: wherein the dichloromethane-methanol eluent contains dichloromethane and methanol with the ratio of 5:1(v/v), the elution component is separated by reverse phase silica gel column chromatography, and is eluted by methanol-1.5 thousandth trifluoroacetic acid aqueous solution with the ratio of 70:30(v/v), and the compound 6 is obtained; separating the dichloromethane-methanol eluent with methanol of 4:1(v/v) by Sephadex LH20 gel column chromatography, eluting with methanol, separating the obtained fraction by high performance liquid semipreparative chromatography, and eluting with methanol-1.5 ‰ trifluoroacetic acid water solution of 75:25(v/v) to obtain compound 1-5.
The invention also provides a pharmaceutical composition, which comprises at least one of the compound shown in the formula I, the pharmaceutically acceptable salt or the prodrug thereof and pharmaceutically acceptable auxiliary materials. The pharmaceutically acceptable excipient may be an excipient conventional in the art, and optionally, the excipient is selected from diluents, fillers, binders, wetting agents, absorption promoters, surfactants, adsorption carriers or lubricants.
Optionally, the dosage form of the pharmaceutical composition comprises a solid preparation and a liquid preparation; optionally, the dosage form of the pharmaceutical composition comprises an oral preparation, an injection preparation and a transdermal preparation; optionally, the pharmaceutical composition may be in the form of tablets, capsules, powders, granules, lozenges, suppositories, oral liquids, sterile parenteral suspensions, ampoules; optionally, the injection comprises a freeze-dried powder injection. The medicaments of the dosage forms can be prepared according to the conventional method in the field of pharmacy.
The invention also provides the compound of the formula I, the pharmaceutically acceptable salt or prodrug thereof, or the application of the pharmaceutical composition in preparing antitumor drugs; optionally, the anti-tumor drug is a tumor cell proliferation inhibitor or a tumor cell killing agent; optionally, the anti-tumor drugs do not comprise anti-human lung adenocarcinoma cell A549 drugs, anti-human liver cancer cell HepG2 drugs, anti-human breast cancer cell MCF-7 drugs and anti-human leukemia cell P-388 drugs; optionally, the anti-tumor drug is a drug for resisting human colon cancer cells HCT-116, a drug for resisting human peripheral blood leukemia T cells Jurkat, a drug for resisting human pancreatic cancer cells PANC-1, a drug for resisting human pancreatic cancer cells BXPC-3 or a drug for resisting human chronic myelogenous leukemia cells K562.
The invention also provides the compound of the formula I, the pharmaceutically acceptable salt or the prodrug thereof, or the application of the pharmaceutical composition in preparing the aspergillus fumigatus growth inhibitor or the aspergillus fumigatus resisting medicine.
The invention also provides application of the compound shown in the formula I, the pharmaceutically acceptable salt or the prodrug thereof in serving as a low molecular biological probe for inhibiting cell proliferation or inhibiting the growth of aspergillus fumigatus. Optionally, the low molecular biological probe can also comprise a pharmaceutically acceptable carrier, excipient or auxiliary material; the carrier, excipient or auxiliary material can be the carrier, excipient or auxiliary material conventionally used by the low molecular biological probe.
The invention also provides a low molecular biological probe kit, which comprises the low molecular biological probe and an optional biocompatible medium; optionally, the biocompatible medium is selected from one or more of methanol, water, dimethyl sulfoxide.
The strain used for preparing the compound of the formula I is actinoallothecus cyanovireus WH1-2216-6, the strain has a collection number: CCTCC M209277, date of deposit: 11/28/2009, deposit location: wuhan, Wuhan university, China center for type culture Collection. Details of this actinomycete strain WH1-2216-6 have been reported in the literature (Fu P, Wang S, Hong K, Li X, Liu P, Wang Y, Zhu W.Cytoxic bipyridines from the marine-derived activated actinomycete cyanogenes WH1-2216-6.J.Nat.prod.2011,74,1751-. This application does not relate to biological preservation.
The method for producing the compound of the present invention by fermenting a microorganism can employ any other microorganism capable of producing the compound of the present invention, as long as the microorganism capable of producing the compound of the present invention can be used as a producing bacterium for producing the compound of the present invention.
The compound has good anti-tumor activity, obvious inhibition effect on tumor cell proliferation, weak inhibition effect on normal cell growth and good selectivity.
On the other hand, the compound has good inhibition effect on the growth of aspergillus fumigatus, and has important guiding significance on the development of aspergillus fumigatus growth inhibitors.
Detailed Description
The present invention is illustrated below by examples, but the scope of the present invention is not limited to the following examples.
[ PREPARATION EXAMPLES ]
(1) Preparation of Compounds 1-6
Fermentation culture: culturing actinomycetes A. cyanogeneus WH1-2216-6 in a seed culture medium for 5 days, inoculating into 150mL fermentation culture medium, performing shake culture, and fermenting for 12 days to obtain a fermentation liquid; wherein, the seed culture medium: 15g of peptone, 15g of glycerol, 5g of soybean meal, 15g of soluble starch, 2g of calcium carbonate, 7.8 of pH value and 1L of aged seawater; fermentation medium: 20g of soluble starch, 20g of glycerol, 20g of peptone, 2g of calcium carbonate, 50g of XAD-16 macroporous adsorption resin and 7.5 g of aged seawater 1L, pH.
Separation and purification: extracting the fermentation liquor with equal volume of ethyl acetate for three times, combining ethyl acetate extraction liquid, concentrating to obtain a crude extract, adding 50mL of 3% HCl solution into each gram of crude extract, stirring, standing, extracting with equal volume of dichloromethane for three times, adjusting the pH value of an aqueous phase to 8.0 with ammonia water, extracting with dichloromethane, concentrating an organic phase to obtain 35.0g of an alkaloid part, separating the alkaloid part by using a reduced pressure silica gel column chromatography, and performing gradient elution by using petroleum ether, dichloromethane and dichloromethane-methanol (v/v, 100:1, 50:1, 25:1, 15:1, 10:1, 5:1, 4:1, 2:1, 1:1, 0:1) as solvents in sequence: wherein the dichloromethane-methanol eluent contains dichloromethane and methanol with the ratio of 5:1(v/v), the elution components are separated by reverse phase silica gel column chromatography, and eluted by methanol-1.5 thousandth trifluoroacetic acid water solution with the ratio of 70:30(v/v), so as to obtain a compound 6(9.5 mg); separating the dichloromethane-methanol eluent with methanol 4:1(v/v) by Sephadex LH20 gel column chromatography, eluting with methanol, separating the obtained fraction by high performance liquid semipreparative chromatography, and eluting with methanol-1.5 ‰ trifluoroacetic acid water solution 75:25(v/v) to obtain compound 1(15.0mg, retention time t/v)R9.7min), 2(24.0mg, retention time tR14.4min), 3(8.2mg, retention time tR16.2min), 4(25.0mg, retention time tR19.2min), 5(5.0mg, retention time tR 26.4min)。
Compound 1, light red amorphous powder, HRESIMS: 527.2747[ M + H]+(calcd for C29H39N2O7,527.2752)；[α]D 21+20(c 0.15,CH3OH)；UV(CH3OH)λmax(logε)210(3.99),326(3.55)nm；CD(c 0.05,CH3OH)λmax(Δε)221(+3.2),249(-3.8),328(+1.7)nm；IR(KBr)νmax 3589,3570,3535,3483,3402,3205,2915,2846,1655,1637,1509,1474,1024,889cm-1；1H and13the C NMR data are shown in Table 1.
Compound 2, light red amorphous powder, ESIMS: 513.3554[ M + H]+(calcd for C29H41N2O6,513.29)；[α]D 21+21(c 0.15,CH3OH)；UV(CH3OH)λmax(logε)212(4.29),314(3.99)nm；CD(c 0.05,CH3OH)λmax(Δε)221(+10.7),249(-15.0),328(+5.2)nm；IR(KBr)νmax 3676,3650,3630,3621,3569,3402,1655,1638,1596,1561,1509,1459,1033,845cm-1；1H and13the C NMR data are shown in Table 1.
Compound 3, light red amorphous powder, ESIMS: 497.3828[ M + H]+(calcd for C29H41N2O5,497.29)；[α]D 21+26(c 0.15,CH3OH)；UV(CH3OH)λmax(logε)212(4.04),320(3.73)nm；CD(c 0.05,CH3OH)λmax(Δε)221(+9.6),249(-12.7),328(+4.6)nm；IR(KBr)νmax 3753,3713,3692,3589,3402,2366,1701,1654,1596,1509,1459,1022,799cm-1；1H and13the C NMR data are shown in Table 1.
Compound 4, light red amorphous powder, ESIMS: 511.3254[ M + H]+(calcd for C29H39N2O6,511.27)；[α]D 21+15(c 0.15,CH3OH)；UV(CH3OH)λmax(logε)206(4.05),316(3.63)nm；CD(c 0.05,CH3OH)λmax(Δε)221(+14.4),249(-12.7),328(+3.3)nm；IR(KBr)νmax 3752,3736,3713,3670,3630,3621,3589,3569,3401,1655,1638,1544,1509,1459,1022,792cm-1；1H and13the C NMR data are shown in Table 2.
Compound 5, light red amorphous powder, ESIMS: 495.3551[ M + H]+(calcd for C29H39N2O5,495.28)；[α]D 21+13(c 0.15,CH3OH)；UV(CH3OH)λmax(logε)206(3.81),320(3.29)nm；CD(c 0.05,CH3OH)λmax(Δε)221(+4.4),249(-4.8),328(+1.4)nm；IR(KBr)νmax 3735,3651,3649,3630,3621,3589,3446,3402,2953,2360,1647,1558,1541,1508,1457,1385,1207,1033,806cm-1；1H and13the C NMR data are shown in Table 2.
Compound 6, pale red amorphous powder, ESIMS:533.3[ M + Na [ ]]+(calcd for C29H38N2O6Na,533.27)，509.2[M-H]-(calcd for C29H37N2O6,509.2)；[α]D 21+14(c 0.15,CH3OH)；UV(CH3OH)λmax(logε)219(3.9),322(3.7)nm；IR(KBr)νmax 3667,3645,3629,3618,3588,3572,3403,1651,1644,1600,1561,1509,1459,1103,921cm-1；1H and13the C NMR data are shown in Table 2.
TABLE 1 preparation of compounds 1, 2 and 31H and13c NMR data
Note: nuclear magnetic resonance hydrogen spectrum of compound (1H NMR) and carbon Spectroscopy (13C NMR) at 500MHz and 125MHz magnetic field frequencies, respectively, in deuterated dimethyl sulfoxide (DMSO-d)6) As solvent Tetramethylsilane (TMS) was scan recorded as an internal standard.
[ test example 1 ] antitumor Activity test
1. Experimental sample and experimental method
Preparing a solution of a sample to be detected: the test samples were compounds 1-5 isolated and prepared as described above in example 1. Accurately weighing a proper amount of sample, and preparing a solution with a required concentration by using methanol for activity test.
Cell lines and subculture of cells: the activity test adopts 5 tumor cell lines, specifically human colon cancer cell line HCT-116 cells, human peripheral blood leukemia T cell Jurkat cells, human pancreatic cancer cell line PANC-1, BXPC-3 cells, human chronic myelogenous leukemia cell line K562 cells, and 1 human normal liver cell line L-02 cells. Wherein the human peripheral blood leukemia T cell Jurkat cell, the human pancreatic cancer cell line BXPC-3 and the human normal liver cell line L-02 fine cell
TABLE 2 preparation of compounds 4,5, 61H and13c NMR data
Note: nuclear magnetic resonance hydrogen spectrum of compound (1H NMR) and carbon Spectroscopy (13C NMR) at 500MHz and 125MHz magnetic field frequencies, respectively, in deuterated dimethyl sulfoxide (DMSO-d)6) As solvent Tetramethylsilane (TMS) was scan recorded as an internal standard.
Testing the cell line by adopting an MTT model; testing a human colon cancer cell line HCT-116, a human pancreatic cancer cell line PANC-1 cell line and a human chronic myelogenous leukemia cell line K562 by adopting an SRB model; each cell was subcultured in RPMI-1640 medium containing 10% FBS at 37 ℃ in an incubator containing 5% carbon dioxide.
MTT method: in mitochondria of living cells, dehydrogenase can metabolize and reduce yellow 3- (4, 5-dimethylthiazole) -2, 5-diphenyl tetrazole bromide into blue-purple formazan which is insoluble in water, and the amount of formazan can be determined by measuring the absorption degree of the formazan by an enzyme labeling instrument. Since the amount of formazan is proportional to the number of living cells, the number of living cells can be determined from the degree of absorption, and the ability of the drug to inhibit or kill tumor cells can be known. In activity test, test cell line in logarithmic growth phase is prepared into density of 3 × 10/ml with fresh RPMI-1640 medium4The cell suspension of each cell was inoculated into a 96-well plate at 100. mu.L per well, and after culturing at 37 ℃ for 24 hours, 100. mu.L of sample solutions of different concentrations were added to each well, and the culture was continued for 72 hours. Then, 20. mu.L of IPMI-1640 solution containing MTT (5mg/L) was added thereto, and after further culturing for 4 hours, the culture was slowly poured out, 150. mu.L of DMSO was further added thereto to dissolve formazan, and the absorbance at 540nm was measured. The inhibition of cell proliferation (IR%) at each concentration was calculated according to the following formula: IR% ((OD))Blank control-ODSample (I))/ODBlank controlX 100%. Determining IC50。
SRB method: according to the cell growth rate, tumor cells (medium: RPMI-1640 medium containing 10% newborn Fetal Bovine Serum (FBS); cells) in logarithmic growth phase were culturedCell density 3X 104cells/mL) was seeded at 180. mu.L/well in 96-well culture plates at 37 ℃ with 5% CO2After 24 hours of growth, the test sample was added at 20. mu.L/well for each concentration, and four wells were placed for each concentration. (the final concentration of the sample at the initial screening was set to 10. mu.M, and IC was measured50Setting 5-7 concentration gradients by a double dilution method; the positive medicine is adriamycin 1 mu M; blank control is medium added with equal amount of corresponding concentration). The tumor cells after drug addition were incubated at 37 ℃ with 5% CO2The culture was continued for 72 hours under the conditions, then the culture solution was decanted, the cells were fixed with 10% cold trichloroacetic acid (TCA), left at 4 ℃ for 1 hour, washed 5 times with distilled water, and air-dried. Sulfonylromine B (SRB, Sigma)4mg/ml solution prepared from 1% glacial acetic acid was then added at 100. mu.L/well, stained for 15 minutes at room temperature, the supernatant removed, washed 5 times with 1% acetic acid, and air dried. Finally, 150. mu.L/well of Tris solution was added, and the OD value of absorbance was measured at 540nm using a microplate reader. In terms of IR% (OD)Blank control-ODSample (I))/ODBlank controlX 100% formula the inhibition of cell proliferation (IR%) was calculated at each concentration. Determining IC50。
Selection Index (SI) is CC for the growth inhibition of normal cell lines by test samples50Value and inhibition of tumor cell proliferation IC50The ratio of the values can indirectly reflect the selectivity and the safety of the sample to a certain extent.
Calculating the formula: SI ═ CC50(Normal cell L-02 Strain)/IC50(tumor cell line)
2. Results of the experiment
TABLE 3 cytotoxic Activity IC of Compound 1 against various tumor cell lines and Normal cell lines50(. mu.M) and selection index SI
| Cell lines | Compound 1 (IC)50/SIb) |
| HCT-116 | 5.7/41.4 |
| Jurkat | 7.5/31.5 |
| PANC-1 | 7.9/29.9 |
| BXPC-3 | 4.5/52.4 |
| L-02a | 235.9/- |
Note:a CC50；band (3) SI: selection index CC50(Normal cell L-02 Strain)/IC50(tumor cell line).
As can be seen from the results of the activity tests in Table 3, IC of Compound 1 against HCT-116, Jurkat, BXPC-1, BXPC-3505.7 μ M, 7.5 μ M, 7.9 μ M and 4.5 μ M, respectively, have good antitumor activity, and have CC of human normal cell L-0250Up to 235.9 mu M, has little toxic and side effect on normal human cells and high safety factor.
TABLE 4 cytotoxic Activity IC of Compound 4 against various tumor cell lines and Normal cell lines50(. mu.M) and selection index SI
| Cell lines | Compound 4 (IC)50/SIb) |
| HCT-116 | 4.4/3.7 |
| Jurkat | 1.9/8.5 |
| PANC-1 | 5.4/3 |
| BXPC-3 | 4.1/3.9 |
| L-02a | 16.1/- |
Note:aCC50；band (3) SI: selection index CC50(Normal cell L-02 Strain)/IC50(tumor cell line).
As can be seen from the results of the activity tests in Table 4, IC of Compound 4 for HCT-116, Jurkat, BXPC-1, BXPC-3504.4 mu M, 1.9 mu M, 5.4 mu M and 4.1 mu M respectively, and has good anti-tumor activity; CC of Compound 4 against human Normal cell L-025016.1 mu M, has small toxic and side effect on normal human cells and high safety factor.
TABLE 5 cytotoxic Activity IC of Compound 5 against various tumor cell lines and Normal cell lines50(. mu.M) and selection index SI
| Cell lines | Compound 5 (IC)50/SIb) |
| HCT-116 | 4.6/3.2 |
| Jurkat | 6.7/2.2 |
| PANC-1 | 7.0/2.1 |
| BXPC-3 | 4.0/3.6 |
| L-02a | 14.5/- |
Note:aCC50；band (3) SI: selection index CC50(Normal cell L-02 Strain)/IC50(tumor cell line).
As can be seen from the results of the activity test in Table 5, IC of Compound 5 against HCT-116, Jurkat, BXPC-1, BXPC-3504.6 mu M, 6.7 mu M, 7.0 mu M and 4.0 mu M respectively, and has good anti-tumor activity; CC of Compound 5 against human Normal cell L-0250Is 14.5 mu M, has little toxic and side effect on normal human cells and high safety factor.
TABLE 6 Compound 2 on various tumor cell lines IC50(μM)
| Cell lines | Compound 2 (IC)50) |
| K562 | 4.9 |
| HCT-116 | 2.9 |
| Jurkat | 1.7 |
| PANC-1 | 2.1 |
| BXPC-3 | 4.3 |
As can be seen from the results of the activity tests in Table 6, IC of Compound 2 for K562, HCT-116, Jurkat, BXPC-1, BXPC-350Respectively 4.9 mu M, 2.9 mu M, 1.7 mu M, 2.1 and 4.3 mu M, and has better anti-tumor activity.
TABLE 7 Compound 3 on various tumor cell lines IC50(μM)
| Cell lines | Compound 3 (IC)50) |
| K562 | 5.7 |
| HCT-116 | 2.9 |
| Jurkat | 1.4 |
| PANC-1 | 2.3 |
| BXPC-3 | 2.9 |
As can be seen from the results of the activity tests in Table 7, Compound 3 has better in vitro anti-tumor activity against HCT-116, Jurkat, BXPC-1 and BXPC-3.
In conclusion, the compound can effectively inhibit the proliferation of tumor cells, and has the advantages of high selectivity, low toxicity and high safety factor.
[ test example 2 ] Aspergillus fumigatus resistance Activity test
1. Experimental sample and experimental method
Preparing a solution of a sample to be detected: 1mg/mL DMSO solution is prepared by itraconazole as a positive drug, 10mg/mL is prepared by 1-5 compounds of the formula I, 10 mu L of the DMSO solution is respectively added with 990 mu L of sterile water release solution by 100 times, and working solutions with initial concentrations of 10 mu g/mL and 100 mu g/mL are prepared for standby.
Preparing an RPMI-1640 culture medium for aspergillus fumigatus: 6.906g of 3-morpholine propanesulfonic acid (MOPS) is dissolved in 70mL of 70 ℃ distilled water, 4g of glucose is continuously added, after the solution is cooled, 2.08g of solid RPMI1640 culture medium is added, and the distilled water is supplemented to 90 mL; dissolving 0.5g of NaOH in 10ml of distilled water, slowly adding the solution into a culture medium, and adjusting the pH value to 7.0; the prepared culture medium is filtered and sterilized by a 0.2mm microporous filter membrane, and is stored at 4 ℃ for later use.
Preparing a bacterial liquid: scraping mature spores of Aspergillus fumigatus growing well on PDA plate culture medium in 4mL physiological saline, grinding with mortar, pouring into test tube, standing for 10min, collecting liquid 1/2-2/3 below liquid level, counting with blood counting plate, diluting with sterile RPMI-1640 culture medium to final concentration of 2.0 × 104CFU/ml。
The activity of aspergillus fumigatus resistance is tested by a 96-pore plate turbidimetry method:
add separately in 96-well plates:
(1) control group: adding blank sterile RPMI-1640 culture medium and sterile distilled water into each well of the negative control group, wherein each volume is 100 mu L; adding 100 mu L of bacterial liquid and sterile distilled water into each hole of the growth control group; the positive control group is added with 100 mul of bacteria liquid and positive medicine working solution respectively.
(2) Measurement group: 100 μ L of each of the inoculum and compound solutions were added to each well (thus the final concentration of positive and drug tested per well was 1/2 of the concentration of the solution before loading). Each well was run in 3 replicates. And (4) interpretation of results: horizontally shaking the culture plate with the sample for about 3min, then placing the culture plate in a wet box, culturing the culture plate in an incubator at the temperature of 28 ℃ for 3-5 days, and observing the culture plate;
visual inspection was performed with the growth control as a reference standard. If the concentration is active, the working solution is diluted by a two-fold dilution method sequentially by using sterile distilled water before adding the medicines, and then the test is carried out until the MIC value of the compound is measured, and the break point with obvious growth change of the aspergillus fumigatus is taken as the MIC end point (the culture solution is changed into turbid from clear).
2. Results of the experiment
TABLE 8 Positive drug itraconazole anti-Aspergillus fumigatus Activity test results
Note: + indicates that the test concentration has obvious inhibition effect on the growth of the strain (clear culture solution, the same below); indicates no significant inhibition at the tested concentration (turbidity of the culture broth, same below).
TABLE 9 results of the Activity test of Compounds 1-5 against Aspergillus fumigatus
Note: + shows that the test concentration has obvious inhibition effect on the growth of the strain; -no significant inhibition at the tested concentration; and/means no test was performed.
From the test results in table 8, the MIC of the positive drug itraconazole was 1.25 μ g/mL; as can be seen from the test results in Table 9, the MIC of the minimum inhibitory concentration of Compound 2 is 1.5625. mu.g/mL, which is comparable to that of the positive drug; the minimum inhibitory concentrations MIC of the compounds 3 and 5 are both 25 mug/mL; the minimum inhibitory concentration MIC of Compound 4 was 3.125. mu.g/mL.
In conclusion, the compound of formula I has good inhibitory activity on the growth of aspergillus fumigatus.
Claims (20)
1. The application of the following compounds or pharmaceutically acceptable salts thereof in preparing antitumor medicaments, wherein the antitumor medicaments are medicaments for resisting human colon cancer cells HCT-116, medicaments for resisting human peripheral blood leukemia T cells Jurkat, medicaments for resisting human pancreatic cancer cells PANC-1, medicaments for resisting human pancreatic cancer cells BXPC-3 or medicaments for resisting human chronic myelogenous leukemia cells K562;
2. the application of the following compounds or pharmaceutically acceptable salts thereof in aspergillus fumigatus growth inhibitors or anti-aspergillus fumigatus drugs,
3. the use according to claim 1 or 2, wherein the pharmaceutically acceptable salt is a salt of the compound with: hydrochloric acid; sulfuric acid; phosphoric acid; formic acid; acetic acid; propionic acid; lactic acid; citric acid; tartaric acid; succinic acid; fumaric acid; maleic acid; mandelic acid; malic acid; camphorsulfonic acid.
4. The following compounds, or pharmaceutically acceptable salts thereof,
5. a compound according to claim 4, or a pharmaceutically acceptable salt thereof, wherein the pharmaceutically acceptable salt is a salt of the compound with: hydrochloric acid; sulfuric acid; phosphoric acid; formic acid; acetic acid; propionic acid; lactic acid; citric acid; tartaric acid; succinic acid; fumaric acid; maleic acid; mandelic acid; malic acid; camphorsulfonic acid.
6. A process for preparing the following compounds or pharmaceutically acceptable salts thereof,
it is characterized by comprising:
fermentation culture: culturing actinomycetes A. cyanogeneus WH1-2216-6 in seed culture medium, inoculating into fermentation culture medium, culturing, and fermenting to obtain fermentation product;
seed culture medium: a carbon source, a nitrogen source and an aqueous solution containing sodium chloride;
fermentation medium: soluble starch, glycerol, peptone, calcium carbonate, macroporous adsorption resin and aged seawater;
separation and purification: extracting the fermentation liquor with an organic solvent, concentrating an organic phase, adding an acidic solution, extracting with the organic solvent, removing the organic phase, adding alkali into a water phase to adjust the pH value, extracting with the organic solvent, concentrating the organic phase to obtain an alkaloid part, performing gradient elution and separation on the obtained alkaloid part by using reduced pressure silica gel column chromatography, and performing reverse phase silica gel column chromatography, gel column chromatography and high performance liquid semi-preparative separation on the eluted components.
7. The method of claim 6, wherein the seed medium comprises: peptone, glycerol, soybean meal, soluble starch, calcium carbonate and seawater.
8. The method of claim 7, wherein the seed medium is peptone 15 parts, glycerol 15 parts, soybean flour 5 parts, soluble starch 15 parts, calcium carbonate 2 parts, and aged seawater 1000 parts, and has a pH of 7.8.
9. The method according to claim 6, wherein the fermentation medium comprises 20 parts by weight of soluble starch, 20 parts by weight of glycerol, 20 parts by weight of peptone, 2 parts by weight of calcium carbonate, 50 parts by weight of XAD-16 macroporous adsorbent resin and 1000 parts by weight of aged seawater, and has a pH of 7.5.
10. The process of claim 6, wherein each organic solvent for extraction is independently selected from ethyl acetate, dichloromethane, chloroform, petroleum ether; the acid solution is selected from hydrochloric acid, sulfuric acid, nitric acid and phosphoric acid; the alkali is selected from ammonia water, sodium hydroxide, potassium hydroxide, sodium carbonate and potassium carbonate; the eluent of the reduced pressure silica gel chromatographic column is selected from petroleum ether, dichloromethane, methanol, dichloromethane-methanol mixed solution and water; the eluent for the gel column chromatography is selected from methanol and dichloromethane-methanol mixed solution; the eluent for the high-efficiency liquid-phase semi-preparation is a methanol-trifluoroacetic acid mixed solution.
11. The method of any one of claims 6-10, wherein the compounds 1-6 are prepared by a process comprising: culturing actinomycetes A.cyanogliseus WH1-2216-6 in a seed culture medium, inoculating the actinomycetes A.cyanogliseus WH1-2216-6 into a fermentation culture medium, culturing and fermenting in a shaking table to obtain a fermented product, extracting the fermented product with ethyl acetate, concentrating an organic phase to obtain a crude extract, adding an HCl solution into the crude extract, extracting with dichloromethane, adjusting a water phase to pH 8.0 with ammonia water, extracting with dichloromethane, concentrating the organic phase to obtain an alkaloid part, separating the obtained alkaloid part by using a reduced pressure silica gel column chromatography, and performing gradient elution by using petroleum ether, dichloromethane and dichloromethane-methanol in a volume ratio of 100:1, 50:1, 25:1, 15:1, 10:1, 5:1, 4:1, 2:1, 1:1 and 0:1 as solvents in sequence: wherein the components eluted by dichloromethane and methanol with the volume ratio of 5:1 in dichloromethane-methanol eluent are separated by reverse phase silica gel column chromatography and eluted by methanol-1.5 per thousand trifluoroacetic acid aqueous solution with the volume ratio of 70:30 to obtain a compound 6; eluting components with dichloromethane-methanol volume ratio of 4:1 in dichloromethane-methanol eluent are separated by Sephadex LH20 gel column chromatography, eluted by methanol, the obtained components are separated by high performance liquid semi-preparative separation, and eluted by methanol-1.5 per thousand trifluoroacetic acid aqueous solution volume ratio of 75:25 to obtain compounds 1-5.
12. A pharmaceutical composition comprising at least one compound of claim 4 or 5, a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
13. The pharmaceutical composition of claim 12, wherein the dosage form of the pharmaceutical composition comprises a solid formulation and a liquid formulation.
14. The pharmaceutical composition according to claim 12, wherein the dosage form of the pharmaceutical composition comprises an oral preparation, an injection preparation and a transdermal preparation.
15. The pharmaceutical composition of claim 12, wherein the pharmaceutical composition is in the form of a tablet, capsule, powder, granule, lozenge, suppository, oral liquid, sterile parenteral suspension, or ampoule.
16. The pharmaceutical composition of claim 12, wherein the injectable solution comprises a lyophilized powder injection.
17. Use of a pharmaceutical composition according to any one of claims 12 to 16 for the preparation of an anti-tumor medicament; the anti-tumor drug is a drug for resisting human colon cancer cells HCT-116, a drug for resisting human peripheral blood leukemia T cells Jurkat, a drug for resisting human pancreatic cancer cells PANC-1, a drug for resisting human pancreatic cancer cells BXPC-3 or a drug for resisting human chronic myelogenous leukemia cells K562.
18. Use of a pharmaceutical composition according to any one of claims 12 to 16 in the manufacture of an aspergillus fumigatus growth inhibitor or an anti-aspergillus fumigatus medicament.
19. A low molecular weight biological probe for inhibiting cell proliferation or for inhibiting growth of aspergillus fumigatus comprising a compound according to claim 4 or 5, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to any one of claims 12 to 16.
20. A kit of low molecular weight biological probes, comprising the low molecular weight biological probe of claim 19, and optionally a biocompatible medium; the biocompatible medium is selected from one or more of methanol, water and dimethyl sulfoxide.
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