CN101492371A - Disubstituted benzene alkene propionyl resorcinol compounds and medical use - Google Patents
Disubstituted benzene alkene propionyl resorcinol compounds and medical use Download PDFInfo
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- CN101492371A CN101492371A CNA2008100625483A CN200810062548A CN101492371A CN 101492371 A CN101492371 A CN 101492371A CN A2008100625483 A CNA2008100625483 A CN A2008100625483A CN 200810062548 A CN200810062548 A CN 200810062548A CN 101492371 A CN101492371 A CN 101492371A
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Abstract
The invention relates to a bi-substituted phenyl allyl acyl resorcin compound indicated by Formula (I) and the pharmaceutical application, in particular to a compound in Formula (I) and the medicine salt, as well as a preparation method of the compounds and the pharmaceutical application and a drug composition containing the compound. The compound in Formula (I) and the medicine salt thereof, as well as 1, 3-bi-oxygen-[3-(4-metoxybenzene) allyl acyl]-5-methyl resorcin and the medicine salt thereof, have the function of inhibiting HBsAg and display certain cytotoxicity to four-strain human tumor cells. The compound can be used to prepare the medicine for curing hepatitis B infectious diseases and tumor diseases in anticipation.
Description
Technical field
The present invention relates to organic chemistry, pharmaceutical chemistry and area of pharmacology, particularly, the present invention relates to a class disubstituted benzene allyl acyl group-oreinol diphenols compound and a pharmacologically acceptable salt thereof, and their preparation method and medicinal use.This compounds is found the function of inhibition hepatitis B virus surface antigen (HBsAg); Simultaneously four strain human body tumour cells are demonstrated definite cytotoxicity, can expect to be used to prepare the relevant hepatitis B virus infection disease of treatment and the pharmaceutical use of tumor disease.
Background technology
B virus type hepatitis (Hepatitis B) is the multiple and common heavy communicable disease of China, and its pathogenic agent is hepatitis B virus (HBV).The about 1.2 hundred million HBV carrier in the whole nation die from 150,000 philtrums of primary hepatocarcinoma every year, and its great majority are relevant with hepatitis B infection.At present, treatment plan to the HBV sufferer can only reach inhibition hbv replication and secondary infection clinically, main medicine is still nucleoside medicine such as lamivudine (3-TC), Entecavir, Adefovir (ADV) etc., though their disease controlling, fetch long prices first effectively; Second life-time service all resistance can occur, and knock-on in various degree; The 3rd, the comparatively tangible well-known undesirable action that the life-time service nucleoside medicine occurs.So find that from the medicine of national folk life-time service new non-nucleoside hepatitis B virus inhibitor has very big meaning, select the main judge index of lead compound to be that such novel non-nucleoside material must have the inhibition activity to hepatitis B virus thymus nucleic acid (HBVDNA) and/or hepatitis B surface antigen (HBsAg).
Chlorogenic acid in the natural product (chlorogenic acid) is by coffic acid (caffeic acid) and quinic acid (quinovic acid, quinic acid) the monobasic depside of Zu Chenging, for the main effective constituent of antibacterial and detoxicating, anti-inflammatory and choleretic in numerous medicinal materials (as Japanese Honeysuckle, oriental wormwood, the bark of eucommia) and the Chinese patent medicine (as Fuganning, honeysuckle injection liquid, acne oral liquid), be the important indicator of some Chinese medicine preparation quality control simultaneously.Chlorogenic acid is a kind of important biological material, have antibiotic, antiviral, increase effects such as white cell, hepatic cholagogic, antitumor, hypotensive, reducing blood-fat, removing free radical and stimulating central nervous system system, important use [Zhao Yu etc.: " caffetannic acid compounds progress " are especially arranged in the prevention and cure of viruses field, CHINA JOURNAL OF CHINESE MATERIA MEDICA, 2006,31 (11), 869-874].
The three-dimensional arrangement of quinic acid is too complicated, need consider the mechanism problem of raw-material cost and three-dimensional location, protection and deprotection etc., is not easy to suitability for industrialized production.So scientist is devoted to streamline any further with simple five-ring or six-ring ring-type system or further that this is complicated six-ring always.Recently, scientist has found new antiviral caffeoyl organic acid ester compound L-chicoric acid (chicoric acid) [Robinson, W.E.Jr.Infect Med.1998,15,129-137] successively from the feverfew witloof.This lead compound has potent inhibition activity to HIV viral integrase enzyme (IN), and nontoxic scope is bigger simultaneously, helps developing into inverase.Many therebetween structure activity studies are carried out in succession, prepare multiple L-chicoric acid derivative, and wherein active compound suppresses the active IC of HIV-1 intergrase
50Value is about 0.8～1.1 μ M[King, P.J., Robinson, W.E.Jr. etc., J.Med.Chem.1999,42,497-509; Lin, Z., Bruke, T.R.Jr., J.Med.Chem.1999,42,1401-1414].Above-mentioned research report result also points out: the pyrocatechol part in the caffeoyl structure plays considerable effect in the inhibition activity of whole molecule, yet too much phenolic hydroxyl group also can bring bigger toxicity.Consider above factor, and caffetannic acid class and L-chicoric acid compound separate comparatively factor such as difficulty, scientists designs synthetic a series of change quinic acid parent nucleus again, remove the ring-type system and still keep its bioactive compound.By continuous simplification, obtained a series of higher bioactive chicoric acid analogue that has, comprising keeping a chicoric acid carboxyl to linker in the chicoric acid; With two carboxyl alkyl or cycloalkyl alternate; That two carboxyls are directly removed and with connection chain between two hydroxyls increase etc. different series, all have certain activity.
Report according to document can sum up: the structure of the center link molecule between two hydroxyl substituents and size all can influence the biological activity of whole molecule, and at interval carbon number is many more between two hydroxyls, and activity will be low more.So it is transformed between two hydroxyls at interval three carbon for our design and the center link molecule is the analogue of ring compound, therefore the inventor has selected oreinol diphenol parent nucleus as an alternative, has synthesized the disubstituted benzene acryloyl among the present invention-oreinol diphenol series compound.
The relevant report that up to the present physiologically active of disubstituted benzene acryloyl-oreinol diphenol is not also arranged.Only there is one piece of document describing preparation 3,5-orcin phosphoric acid ester and other organic acid acetic relate to 1 among the present invention during as radio-protector, 3-two-oxygen-[3-(4-anisole) acrylyl]-oreinol diphenol [Wang Rongxian etc., China's radiological medicine and protection magazine, 1992,115-117].
Consider the high homology of inverase and HBV medicine, the present invention has tested its inhibition activity to hepatitis B surface antigen HBsAg to disubstituted benzene acryloyl-oreinol two phenolic compound that synthesize, and more various can produce inhibiting caffetannic acid analogue to hepatitis B virus duplication in the hope of seeking.
In order to explore other physiologically actives of disubstituted benzene acryloyl-oreinol diphenols compound that the present invention prepares, we have also adopted MTT, and (3-(4,5-dimethylthiazole-2)-2,5-phenylbenzene tetrazole bromine salt) method has been carried out the growth inhibitory activity test to this compounds at four kinds of human tumor cultured cell in vitro strain [human cervical carcinoma cell (Hela), the chronic myelogone leukemia cell of people (K562), people's promyelocytic leukemia cell (HL-60), human colon adenocarcinoma (LS 174T)], thereby finishes the present invention.
Summary of the invention
The object of the present invention is to provide a class to be used to prepare the compound of new hepatitis B virus resisting and/or cell toxicant series antineoplastic medicament, particularly, the invention provides the disubstituted benzene acryloyl-oreinol diphenols compound and the pharmacologically acceptable salt thereof of structure shown in the class formula (I):
Wherein: aromatic substituent R
1And R
2Can be identical or different, be selected from the phenyl that methoxyl group replaces respectively, the phenyl that an ortho position or a position or contraposition dimethoxy replace, the phenyl that halogen replaces, or ortho position or a position or the dibasic phenyl of contraposition halogen; Its condition is: R
1And R
2Can not be the 4-p-methoxy-phenyl simultaneously.
Another purpose of the present invention has provided described disubstituted benzene acryloyl-oreinol two phenolic compound and pharmacologically acceptable salt is used for the purposes that preparation suppresses hepatitis B virus surface antigen (HBsAg) medicine.
A further object of the present invention has provided the purposes that formula (I) compound and pharmacologically acceptable salt thereof are used to prepare the cell toxicant series antineoplastic medicament.
A further object of the present invention has provided a kind of pharmaceutical composition that is used for the hepatitis B virus resisting disease and/or cell toxicant series antineoplastic medicament that contains formula (I) compound.According to the present invention, can add various pharmaceutical excipients, additive and carrier in this pharmaceutical composition.
The preferred formula of the present invention (I) compound is listed below:
I-a.1,3-two-oxygen-[3-(2,4 dichloro benzene) acrylyl]-oreinol diphenol;
I-b.1,3-two-oxygen-[3-(4-chlorobenzene) acrylyl]-oreinol diphenol;
I-c.1,3-two-oxygen-[3-(3, the 4-dimethoxy benzene) acrylyl]-oreinol diphenol.
The present invention also provides 1, and (Compound I-d) be used for preparation reduces the purposes that hepatitis B virus surface antigen (HBsAg) is expressed medicine and/or cell toxicant series antineoplastic medicament to 3-two-oxygen-[3-(4-anisole) acrylyl]-oreinol diphenol.
Embodiment:
Formula of the present invention (I) compound or pharmaceutically acceptable salt thereof, and compound (I-d) or its pharmacologically acceptable salt have certain restraining effect to hepatitis B surface antigen(HBsAg) (HBsAg), and it also has certain restraining effect to four kinds of human tumor cultured cell in vitro strain [human cervical carcinoma cell (Hela), the chronic myelogone leukemia cell of people (K562), people's promyelocytic leukemia cell (HL-60), human colon adenocarcinoma (LS 174T)].According to the present invention, such compound or pharmaceutically acceptable salt thereof can combine with auxiliary material or carrier pharmaceutically commonly used, prepares the pharmaceutical composition and/or the cell toxicant series antineoplastic medicament that can be used for the treatment of the viral hepatitis B disease-related.Further specify the present invention below by embodiment.Embodiment has provided the synthetic and dependency structure appraising datum of representative compounds.Mandatory declaration, following embodiment is used to illustrate the present invention rather than limitation of the present invention, essence according to the present invention all belongs to the scope of protection of present invention to the simple modifications that the present invention carries out.
Embodiment 1: Compound I-a is 1, the preparation of 3-two-oxygen-[3-(2,4 dichloro benzene) acrylyl]-oreinol diphenol
In reaction flask, add 3-(2, the 4-dichlorobenzene) allyl acid (87 milligrams, 0.40 mmole), (83 milligrams of dicyclohexylcarbodiimide, 0.40 mmole), 8 milliliters of anhydrous methylene chlorides at room temperature stirred 20 minutes, white casse appears and after, add (20 milligrams of oreinol diphenol, 0.16 mmole), 4-Dimethylamino pyridine (DMAP, 4.9 milligrams, 0.04 mmole), whole solution at room temperature reacts and spends the night, and suction filtration is removed insolubles, boils off solvent, precipitation obtains white solid, column chromatography purification (petrol ether/ethyl acetate=10: 1) separates obtaining 56 milligrams of white solids, and productive rate is 67%.
Compound I-a: white solid, fusing point: 160～162 ℃ (chloroform); R
f(petrol ether/ethyl acetate=3: 1): 0.51; Proton nmr spectra (400MHz, deuterated methanol): δ 2.41 (3H, unimodal, CH
3), 6.59 (2H, bimodal, J=16.4Hz, H-2 ', 2 "), 6.91 (3H, unimodal, H-2,4; 6), 7.33 (2H, bimodal, J=2.0Hz, H-8 '; 8 "), 7.48 (2H, bimodal, J=2.0Hz, H-9 ', 9 "), 7.63 (2H, unimodal, H-6 ', 6 "), 8.19 (2H, bimodal, J=16.0Hz, H-3 ', 3 "); Electrospray ionization mass spectrum ESI-MS m/z:423.16 ([M+H
2O]
+).
Prepare table one illustrated embodiment 2-5 compound according to embodiment 1 identical method:
Table one
List the physicochemical data of each compound in the table one below:
Compound I-b: white solid, R
f(petrol ether/ethyl acetate=3: 1): 0.4; Proton nmr spectra (400MHz, deuterated methanol): δ 2.40 (3H, unimodal, CH
3), 6.38 (2H, bimodal, J=16.4Hz, H-2 ', 2 "), 6.88 (3H, unimodal, H-2,4,6), 7.23 (4H, bimodal, J=8.0Hz, H-6 ', 6 "; H-8 ', 8 "), 7.26 (4H, bimodal, J=8.0Hz, H-5 ', 5 "; H-9 ', 9 "), 7.68 (2H, bimodal, J=16.0Hz, H-3 ', 3 ").
Compound I-c: white solid, R
f(petrol ether/ethyl acetate=3: 1): 0.36; Proton nmr spectra (400MHz, deuterated methanol): δ 2.43 (3H, unimodal, CH
3), 3.91 (6H, unimodal, OCH
3), 3.92 (6H, unimodal, OCH
3), 6.32 (2H, bimodal, J=16.4Hz, H-2 ', 2 "), 6.92 (3H, unimodal, H-2,4; 6), 6.86 (2H, bimodal, J=8.0Hz, H-8 '; 8 "), 7.05 (2H, unimodal, H-5 ', 5 "); 7.13 (2H, bimodal, J=8.0Hz, H-9 ', 9 "), 7.67 (2H, bimodal, J=16.0Hz, H-3 ', 3 ").
Compound I-d: white solid, R
f(petrol ether/ethyl acetate=3: 1): 0.54; Proton nmr spectra (400MHz, deuterated methanol): δ 2.18 (3H, unimodal, CH
3), 3.85 (6H, unimodal, OCH
3), 6.47 (2H, bimodal, J=16.0Hz, H-2 ', 2 "), 6.88 (3H, unimodal, H-2,4; 6), 6.90 (4H, bimodal, J=8.8Hz, H-6 ', 8 ', 6 " 8 "), 7.54 (4H, bimodal, J=8.8Hz; H-5 ', 9 ', 5 ", 9 "), 7.81 (2H, bimodal, J=16.0Hz, H-3 ', 3 "); Electrospray ionization mass spectrum ESI-MS m/z:462.09 ([M+H
2O]
+).
Formula of the present invention (I) compound or pharmaceutically acceptable salt thereof, and compound (I-d) (promptly 1,3-two-oxygen-[3-(4-anisole) acrylyl]-oreinol diphenol) or its pharmacologically acceptable salt have the function of inhibition hepatitis B virus surface antigen (HBsAg); Can be used to prepare the medicine of the relevant hepatitis B virus infection disease of treatment.This medicine can combine with auxiliary material or carrier pharmaceutically commonly used, has the pharmaceutical composition that anti-hepatitis B virus activities can be used to prevent and treat the disease that hepatitis B virus causes thereby prepare with the routine techniques in the pharmacy field.Above-mentioned various kinds of drug composition can adopt drug forms such as injection, tablet, capsule, aerosol, suppository, film, pill, externally-applied liniment, ointment, can also utilize existing known technology to be prepared into its controlled release, slow release formulation and nanometer formulation, can also use the targeted drug preparation technique and be prepared into relative medicine formulation and administering mode.
Formula of the present invention (I) compound or pharmaceutically acceptable salt thereof, and 1,3-two-oxygen-[3-(4-anisole) acrylyl]-oreinol diphenol (Compound I-d) or its pharmacologically acceptable salt can with treatment hepatitis B medicine that has now gone on the market such as lamivudine (lamivuding), Adefovir and two volt esters (adevovir/adevovir dipivoxil) thereof, Entecavir (entecavir), emtricitabine (emtricitabine), Ke Laifuding (clevudine), general former times network Wei (famciclovir), Lobucavir (lobucavir), Interferon, rabbit (IFN) etc. is united use, prepares the medicine with treatment hepatitis B.Above-mentioned various kinds of drug composition all can adopt drug forms such as injection, tablet, capsule, aerosol, suppository, film, pill, externally-applied liniment, ointment, can also utilize existing known technology to be prepared into its controlled release, slow release formulation and nanometer formulation, can also use the targeted drug preparation technique and be prepared into relative medicine formulation and administering mode.
In addition, formula (I) compound or pharmaceutically acceptable salt thereof that the present invention is prepared, and 1, (Compound I-d) or its pharmacologically acceptable salt have certain growth inhibitory activity for four kinds of human tumor cultured cell in vitro strain [human cervical carcinoma cell (Hela), the chronic myelogone leukemia cell of people (K562), people's promyelocytic leukemia cell (HL-60), human colon adenocarcinoma (LS 174T)] to 3-two-oxygen-[3-(4-anisole) acrylyl]-oreinol diphenol, can expect as control related neoplasms disease medicament purposes.
Formula (I) compound or pharmaceutically acceptable salt thereof that the present invention is prepared, and compound (I-d) or its pharmacologically acceptable salt can combine with auxiliary material or carrier pharmaceutically commonly used, prepares the pharmaceutical composition with anticancer usage.Aforementioned pharmaceutical compositions can adopt injection, tablet, capsule, paster, the subcutaneous formulations such as burying agent of planting, or other adopt controlled release, slow release formulation and the nanometer formulation of known theory and technology preparation.
Formula of the present invention (I) compound or pharmaceutically acceptable salt thereof, and compound (I-d) or its pharmacologically acceptable salt can with antitumor drug that has now gone on the market such as platinum medicine cis-platinum (DDP), camptothecine irinotecan (Irinatecan, CPT-11), the vinca alkaloids medicine loses carbon vincaleucoblastine (Vinorebine, the NVB nvelbine), deoxidation born of the same parents former times class medicine gemcitabine (Gemcitabine, Gemzar, strong selecting), etoposide (Etoposide), taxol (Paclitaxel) etc. is united use, prepare and have tumor growth and suppress active Cytotoxic pharmaceutical composition, can be used for preparing the medicine of treatment kinds of tumors disease.
In order to understand essence of the present invention better, sketch formula (I) compound or pharmaceutically acceptable salt thereof with the form of pharmacology embodiment respectively below, and 1, (Compound I-d) or its pharmacologically acceptable salt illustrate its purposes in antiviral and antitumor drug development field to the The pharmacological results of the growth-inhibiting of hepatitis B virus surface antigen (HBsAg) inhibition test and four strain human vitronectin culture of tumor cell strains to 3-two-oxygen-[3-(4-anisole) acrylyl]-oreinol diphenol.Pharmacology embodiment has provided formula (I) compound or pharmaceutically acceptable salt thereof, and the part activity data of compound (I-d) or its pharmacologically acceptable salt.Same mandatory declaration, pharmacology embodiment of the present invention is still and is used to illustrate the present invention rather than limitation of the present invention, and essence according to the present invention all belongs to the scope of protection of present invention to the simple modifications that the present invention carries out.
Pharmacology embodiment 1: Compound I-a is to the restraining effect of the hepatitis B virus surface antigen (HBsAg) of HepG2.2.15 emiocytosis
1.1 cell cultures:
In containing 10% inactivated fetal bovine serum, 100U/ ml penicillin and 100 mcg/ml Streptomycin sulphates in the DMEM substratum of 100 mcg/ml G418, are put 37 ℃, 5% carbonic acid gas CO with the HepG2.2.15 cell cultures
2, cultivate in the incubator of 100% relative humidity.
Measure the restraining effect of Compound I-a 1.2 adopt mtt assay to the growth of HepG2.2.15 cell:
The HepG2.2.15 cell of taking the logarithm vegetative period becomes 1 * 10 with substratum with cell dilution
5Individual/milliliter, be inoculated in 96 porocyte culture plates, every hole 100 microlitres, at 37 ℃, 5%CO
2, cultivate the Compound I-a that adds after 24 hours with the substratum dilution in the incubator of 100% relative humidity, concentration is respectively 100 mcg/ml, 20 mcg/ml and 4 mcg/ml, every hole 200 microlitres, each concentration is established three multiple holes, places 37 ℃, 5%CO
2Cultivate in the incubator of 100% relative humidity, cultivate after 72 hours, every hole adds 5 mg/ml MTT reagent (3-(4,5-dimethylthiazole-2)-2,5-phenylbenzene tetrazole bromine salt) 10 microlitres, continue to cultivate 4 hours, discard substratum, every hole adds dimethyl sulfoxide (DMSO) (DMSO) 200 microlitres, with vibrator vibration 20 minutes, under the 570nm wavelength, measure the OD value with microplate reader.With the culture hole that only adds substratum is control wells.The experiment triplicate.
Inhibiting rate (%)=(control wells OD value-experimental group OD value)/control wells OD value * 100%.
1.3 measure the restraining effect of Compound I-a to hepatitis B surface antigen(HBsAg) (HBsAg):
The HepG2.2.15 cell of taking the logarithm vegetative period becomes 1 * 10 with substratum with cell dilution
5Individual/milliliter, be inoculated in 96 porocyte culture plates, every hole 100 microlitres are at the 5%CO of 100% relative humidity
2Cultivate the Compound I-a that adds after 24 hours with the substratum dilution for 37 ℃ in the incubator, concentration is respectively 100 mcg/ml, 20 mcg/ml and 4 mcg/ml, and every hole 200 microlitres, each concentration is established three multiple holes, places 37 ℃, 5%CO
2, cultivate in the incubator of 100% relative humidity, changed the substratum that contains the same concentrations sample in per 4 days, with the substratum equal-volume mixing that swaps out of the same concentration of same sample, as testing sample.With hepatitis B surface antigen(HBsAg) (HBsAg) concentration in the integrated enzyme reaction ELISA kit measurement substratum, represent with P/N; With the positive contrast of lamivudine (3-TC).
1.4 experimental result:
Experimental result as shown in Table 2, Compound I-a has the effect of significant inhibition hepatitis B surface antigen(HBsAg) (HBsAg).Its growth to the HepG2.2.15 cell does not have obvious restraining effect, all is higher than lamivudine but the hepatitis B surface antigen(HBsAg) HBsAg of HepG2.2.15 emiocytosis is suppressed activity under high, medium and low dosage.
Table two Compound I-a is to HepG2.2.15 excretory hepatitis B surface antigen(HBsAg) inhibiting rate (%)
aExpression unrestraint activity.
1.5 presentation of results:
Hepatitis B surface antigen(HBsAg) (HBsAg) inhibiting rate is to judge hepatitis b virus infected important symbol, and effectively suppressing the HBsAg secretion and the HBsAg reaction is turned out cloudy is one of target of treatment hepatitis B.Compound I-a has significant inhibitory effect at the 8th day hepatitis B surface antigen(HBsAg) (HBsAg) to HepG2.2.15 emiocytosis, illustrates that this type of disubstituted benzene acryloyl-oreinol diphenols compound can be expected to develop into the medicine that reduces hepatitis B surface antigen(HBsAg), control Type B viral hepatitis symptom.
Pharmacology embodiment 2: Compound I-d is to the restraining effect of the hepatitis B virus surface antigen (HBsAg) of HepG2.2.15 emiocytosis
2.1 cell cultures: with pharmacology embodiment 1.
Measure the restraining effect of Compound I-d to the growth of HepG2.2.15 cell 2.2 adopt mtt assay: the HepG2.2.15 cell in the vegetative period of taking the logarithm, method is with pharmacology embodiment 1.
2.3 measure the restraining effect of Compound I-d, with the positive contrast of lamivudine (3-TC) to hepatitis B surface antigen(HBsAg) (HBsAg).Concrete grammar is with pharmacology embodiment 1.
2.4 experimental result
Experimental result as shown in Table 3, Compound I-d has the effect of significant inhibition hepatitis B surface antigen(HBsAg) (HBsAg).Its growth to the HepG2.2.15 cell does not have obvious restraining effect, all is higher than lamivudine but the hepatitis B surface antigen(HBsAg) HBsAg of HepG2.2.15 emiocytosis is suppressed activity under high, medium and low dosage.
Table three Compound I-d is to HepG2.2.15 excretory hepatitis B surface antigen(HBsAg) inhibiting rate (%)
2.5 presentation of results:
Hepatitis B surface antigen(HBsAg) (HBsAg) inhibiting rate is to judge hepatitis b virus infected important symbol, and effectively suppressing the HBsAg secretion and the HBsAg reaction is turned out cloudy is one of target of treatment hepatitis B.Compound I-d has certain restraining effect at the 8th day hepatitis B surface antigen(HBsAg) (HBsAg) to HepG2.2.15 emiocytosis, illustrates that such disubstituted benzene acryloyl-oreinol diphenols compound can be expected to develop into the medicine that reduces hepatitis B surface antigen(HBsAg), control Type B viral hepatitis symptom.
Pharmacology embodiment 3: Compound I-a and I-d are to the cytotoxic activity of human cervical carcinoma cell
3.1 human cervical carcinoma (Hela) cell contains 10% calf serum, 100U/ ml penicillin and 100U/ milliliter Streptomycin sulphate with RPMI 1640 culture medium culturing in the substratum.Cell is with every hole 1 * 10
4Individual density is inoculated in 96 orifice plates, at 37 ℃, and 5%CO
2Cultivated 24 hours in the incubator of damp atmosphere.
3.2 the measuring method of cell survival rate: with improvement MTT (3-(4,5-dimethylthiazole-2)-2,5-phenylbenzene tetrazole bromine salt) method.Cell is after 24 hours hatch, the dimethyl sulfoxide solution of Compound I-a that will newly join and I-d joins in each hole with concentration gradient respectively, makes that the ultimate density of compound is respectively 100 mcg/ml, 50 mcg/ml, 25 mcg/ml, 5 mcg/ml in the hole.After 72 hours, add the normal saline solution of 10 microlitre MTT (5 mg/ml), continue at 37 ℃ 5%CO again
2Cultivated 3 hours in the incubator of damp atmosphere, add 150 microlitre methyl-sulphoxides in every hole, the MTT crystal first that the vibration dissolving generates
(formazan), formed first
With microplate reader colorimetric under the 570nm wavelength, cell survival rate is by the ratio calculation of sample OD value for contrast OD value.Wherein compound is to the half-inhibition concentration (IC of Hela cell
50) obtain by dose effect curve.Experimental result shows the IC of each test compounds
50As shown in Table 4.As positive control, the positive control cis-platinum is to the IC of Hela cell with an antitumor line medication cis-platinum (DDP) in this test
50Be 19.6 μ M.
Table four test compounds I-a and I-d are to the half-inhibition concentration (IC of Hela cell
50) (mcg/ml)
Compound I-a I-d
Suppress active IC
5064.4 55.8
3.3 presentation of results: Compound I-a and I-d have clear and definite restraining effect to the growth of Hela cell, illustrate that such disubstituted benzene acryloyl-oreinol diphenols compound is expected to develop into the medicine of cell toxicant class treatment human cervical carcinoma.
Pharmacology embodiment 4: Compound I-a and I-d are to the chronic myelogone leukemia cell's of people cytotoxic activity
4.1 the chronic myelogone leukemia of people (K562) cell contains 10% calf serum, 100U/ ml penicillin and 100U/ milliliter Streptomycin sulphate with RPMI 1640 culture medium culturing in the substratum.Cell is with every hole 1 * 10
4Individual density is inoculated in 96 orifice plates, at 37 ℃, and 5%CO
2Cultivated 24 hours in the incubator of damp atmosphere.
4.2 the measuring method of cell survival rate: with the improvement mtt assay.Cell is after 24 hours hatch, the dimethyl sulfoxide solution of Compound I-a that will newly join and I-d joins in each hole with concentration gradient respectively, makes that the ultimate density of compound is respectively 100 mcg/ml, 50 mcg/ml, 25 mcg/ml, 5 mcg/ml in the hole.After 72 hours, add the normal saline solution of 10 microlitre MTT (5 mg/ml), continue at 37 ℃ 5%CO again
2Cultivated 3 hours in the incubator of damp atmosphere, add 150 microlitre methyl-sulphoxides in every hole, the MTT crystal first that the vibration dissolving generates
(formazan), formed first
With microplate reader colorimetric under the 570nm wavelength, cell survival rate is by the ratio calculation of sample OD value for contrast OD value.Wherein Compound I-a and I-d are to the half-inhibition concentration (IC of K562 cell
50) obtain by dose effect curve.Experimental result shows the IC of each test compounds
50As shown in Table 5, as positive control, the positive control cis-platinum is to the IC of K562 cell with an antitumor line medication cis-platinum (DDP) in this test
50Be 12.9 μ M.
Each test compounds of table five is to the half-inhibition concentration (IC of K562 cell
50) (mcg/ml)
4.3 presentation of results: Compound I-a and I-d have clear and definite restraining effect to the growth of K562 cell, illustrate that such disubstituted benzene acryloyl-oreinol diphenols compound is expected to develop into the leukemic medicine of the cell toxicant class treatment chronic myelogone of people.
Pharmacology embodiment 5: Compound I-a and I-d are to the cytotoxic activity of people's promyelocytic leukemia cell
5.1 people's promyelocytic leukemia (HL-60) cell contains 10% foetal calf serum, the Streptomycin sulphate of 100U/ ml penicillin and 100U/ milliliter with RPMI 1640 culture medium culturing in the substratum.Cell is with every hole 5 * 10
3Concentration join in 96 orifice plates, contain 5%CO at 37 ℃
2Cultivated 24 hours in the incubator of damp atmosphere.
5.2 the mensuration of cell survival rate: with improvement mtt assay, concrete grammar such as pharmacology embodiment 1.Wherein Compound I-a and I-d are to the half-inhibition concentration (IC of HL-60 cell
50) obtain by dose effect curve.Experimental result shows the IC of each test compounds
50As shown in Table 6.DDP is to the 503nhibiting concentration IC of HL-60 cell
50Be 7.6 μ M.
Table six Compound I-a and I-d are to the half-inhibition concentration (IC of HL-60 cell
50) (mcg/ml)
5.3 presentation of results: Compound I-a and I-d have clear and definite restraining effect to the growth of HL-60 cell, illustrate that such disubstituted benzene acryloyl-oreinol diphenols compound is expected to develop into the medicine of cell toxicant class treatment people promyelocytic leukemia.
Pharmacology embodiment 6: Compound I-a and I-d are to human colon adenocarcinoma cell's cytotoxic activity
6.1 human colon adenocarcinoma (LS 174T) cell contains 10% foetal calf serum, the Streptomycin sulphate of 100U/ ml penicillin and 100U/ milliliter with RPMI 1640 culture medium culturing in the substratum.Cell is with every hole 5 * 10
3Concentration join in 96 orifice plates, contain 5%CO at 37 ℃
2Cultivated 24 hours in the incubator of damp atmosphere.
6.2 the mensuration of cell survival rate: with improvement mtt assay, concrete grammar such as pharmacology embodiment 1.Wherein compound is to LS 174T cell 503nhibiting concentration (IC
50) obtain by dose effect curve.Experimental result shows the IC of each test compounds
50As shown in Table 7.The positive control cis-platinum is to the IC of LS 174T cell
50Be 4.43 μ M.
Table seven Compound I-a and I-d are to the half-inhibition concentration (IC of LS 174T cell
50) (mcg/ml)
6.3 presentation of results: Compound I-a and I-d have clear and definite restraining effect to the growth of LS 174T cell, illustrate that such disubstituted benzene acryloyl-oreinol diphenols compound is expected to develop into cell toxicant class treatment human colon adenocarcinoma's medicine.
When above-mentioned specification sheets elaboration was of the present invention, the purpose that embodiment and pharmacology embodiment are provided simultaneously was to illustrate actual mechanical process of the present invention and meaning of the present invention.In the time of in entering claim of the present invention and its equivalent scope, practical application of the present invention comprises all general variations, cooperates, or improves.
Claims (9)
1. a disubstituted benzene allyl acyl group-oreinol diphenols compound and pharmacologically acceptable salt thereof with structure shown in the formula (I):
Formula (I)
Wherein: aromatic substituent R
1And R
2Can be identical or different, be selected from the phenyl that methoxyl group replaces respectively, the phenyl that an ortho position or a position or contraposition dimethoxy replace, the phenyl that halogen replaces, or ortho position or a position or the dibasic phenyl of contraposition halogen; Its condition is: R
1And R
2Can not be the 4-p-methoxy-phenyl simultaneously.
2. according to formula (I) compound of claim 1, it is characterized in that described compound is to be selected from following compounds:
I-a.1,3-two-oxygen-[3-(2,4 dichloro benzene) acrylyl]-oreinol diphenol;
I-b.1,3-two-oxygen-[3-(4-chlorobenzene) acrylyl]-oreinol diphenol;
I-c.1,3-two-oxygen-[3-(3, the 4-dimethoxy benzene) acrylyl]-oreinol diphenol.
3. be used to prepare the pharmaceutical use that suppresses hepatitis B virus surface antigen according to arbitrary described disubstituted benzene allyl acyl group-oreinol diphenols compound of claim 1～2 and pharmacologically acceptable salt thereof.
4. the purposes that is used to prepare the cell toxicant series antineoplastic medicament according to the arbitrary described disubstituted benzene allyl acyl group-oreinol diphenols compound of claim 1～2 and pharmacologically acceptable salt thereof.
5. compound 1, and 3-two-oxygen-[3-(4-anisole) acrylyl]-oreinol diphenol and pharmacologically acceptable salt thereof are used to prepare the pharmaceutical use that suppresses hepatitis B virus surface antigen.
6. compound 1, and 3-two-oxygen-[3-(4-anisole) acrylyl]-oreinol diphenol and pharmacologically acceptable salt thereof are used to prepare the purposes of cell toxicant series antineoplastic medicament.
7. pharmaceutical composition that is used to reduce hepatitis B surface antigen(HBsAg), its contain the treatment significant quantity as activeconstituents according to claim 1,2,5 arbitrary described compounds and/or their mixture and their pharmacologically acceptable salt and pharmaceutically acceptable auxiliaries.
8. one kind is used for antineoplastic cytotoxic drug compositions, its contain the treatment significant quantity as activeconstituents according to claim 1,2,6 arbitrary described compounds and/or their mixture and their pharmacologically acceptable salt and pharmaceutically acceptable auxiliaries.
9. according to arbitrary described medicine of claim 7～8 and pharmaceutical composition, its formulation is injection, tablet, capsule, aerosol, suppository, film, pill, externally-applied liniment, or controlled release or slow release formulation or nanometer formulation.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108042484A (en) * | 2018-01-06 | 2018-05-18 | 张恒源 | A kind of cold compress gel for treating infant eczema and preparation method thereof |
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2008
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108042484A (en) * | 2018-01-06 | 2018-05-18 | 张恒源 | A kind of cold compress gel for treating infant eczema and preparation method thereof |
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