CN101045046A - Use of Brazil hemoatoxy type compound for preparing antineoplastic - Google Patents
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Abstract
An application of the Brazilian hematoxylin compounds in preparing the antineoplastic medicines for treating cancers is disclosed.
Description
Technical field
The present invention relates to the purposes of Brazil wood chlorins compound, relate in particular to the purposes of Brazil wood chlorins compound in the preparation antitumor drug.
Background technology
Lignum Sappan (Lignum Sappan) is a Chinese medicine material simply, is the dry duramen of pulse family (Leguminosae) Semen Caesalpiniae platymiscium Lignum Sappan (Caesalpinia sappan L.).Lignum Sappan is born in that high temperature is how wet, sun-drenched Pingba or hillside fields, is distributed in Guangxi, Guangdong, Yunnan, Guizhou, Sichuan, Taiwan.The traditional Chinese medical science is thought Lignum Sappan sweet in the mouth, salty, little suffering, and property is flat, and the promoting the circulation of blood blood stasis dispelling is arranged, and the function of reducing swelling and alleviating pain is used for the amenorrhea dysmenorrhea, postpartum stagnation, and breast ventral spine pain, wound swells and ache.
Modern pharmacology studies show that Lignum Sappan has the effect of maincenter inhibition, antiinflammatory, lipidemia and blood sugar regulation, and potential antitumor action is arranged.Domestic many scholars' experimentation shows, aqueous extract of lignum sappan has stronger cytotoxicity to HL-60 (human promyelocytic leukemia cell strain), its ethanol extract has the obvious suppression effect to human body tumour cell HCT-8, KB, A2780, directly acts on tumor cell, cell death inducing, the propagation of anticancer, and present certain concentration dependence (clinical pharmacology of Lignum Sappan and chemical constitution study progress. Wang Dong, Chen Chao, all two pieces of jade put togethers. Chinese medicine information, 2003,20:15-16).
An amount of Lignum Sappan aqueous solution can strengthen the contractility of blood vessel, has syngignoscism, and anesthetic action is still arranged in a large number, even dead, the central excitation effect that can resist strychnine and cocaine, but the excitation that can not resist morphine.10% Lignum Sappan decocting liquid also has antibacterial action.
One of main chemical compositions of Lignum Sappan is Brazil wood chlorins compound (shown in I):
The Brazil wood chlorins compound comprise brazilin (brazilin), 3 '-O-methyl brazilin (3 '-O-methylbrazilin), 4 '-O-methyl brazilin (4 '-O-methylbrazilin), 4-hydroxyl brazilin (4-hydroxylbrazilin), 8-hydroxyl brazilin (8-hydroxylbrazilin) etc.Brazilin is met air and promptly is oxidized to brasilein (Brazilein), and brasilein is a kind of pigment commonly used.1993, humans such as Davis have the optics conformation optionally method synthesized trimethyl brazilin in the Brazil wood chlorins compound first.2005, the complete synthesis route of brazilin also was in the news out (Synthesis of (+/-)-brazilin using IBX.Y Huang, J Zhang, and TR Pettus.Org Lett., 2005,7:5841-5844.).Lignum Sappan contains Lignum Sappan phenol (Sappanin, promptly 2,4,3 ', 4 '-tetrahydroxybiphenyl) in addition, can cook organic reagent, checks aluminium ion; Contain volatile oil again, main body of oil is phellandrene (d-α-Phellandrene) and an ocimene (Ocimene); Also contain tannin.
External research is primarily aimed at the pharmacological action of brazilin, mainly concentrates on aspects such as immunomodulating, saccharic metabolism, anticoagulation and sterilization, particularly its sterilization and hypoglycemic effect.Discover that brazilin has killing action to multiple drug-resistant bacteria, minimal inhibitory concentration is 4～32mg/mL (Theantibacterial principle of Caesalpina sappan.Hx Xu, SF Lee.Phytother Res., 2004,18:647-651.).Also there are some researches show, brazilin can reduce the gluconeogenesis ability of the hepatic parenchymal cells of diabetic mice, and the phosphorylation that can pass through the reduction serine increases the function of Insulin receptor INSR, thereby effect (the Mechanism of action of Brazilin ongluconeogenesis in isolated rat hepatocytes.HS Won of performance blood sugar lowering, J Lee, LY Khil, SH Chae, et al.Planta Med., 2004,70:740-744.Brazilin inhibits activities of protein kinaseC and insulin receptor serine kinase in rat liver.SG Kim, YM Kim, LY Khil, et al.Arch Pharm Res., 1998,21:140-146.).
Calendar year 2001, people such as RL Tolman find that brazilin has the effect that suppresses dna polymerase activity, and have applied for international patent of invention WO 0,193,864 for this reason.2003, the Korea S scholar found that in laboratory the Lignum Sappan ethyl acetate extract can produce shear action on the DNA chain, thereby generates breach on two strands.Through further segmentation to crude extract, determined that brazilin is main active (the A DNA strand-nicking principle of a higher plant that produces this effect, Caesalpinia sappan.W Mar, HT Lee, KH Je, et al.Arch Pharm Res., 2003,26:147-150.).
In sum, chemical compound as a class single component, the application record aspect cell proliferation of brazilin and derivant thereof is less, especially up to the present, and both at home and abroad all less than about the report of brazilin chemical compound in the direct pharmaceutical research result of anti-tumor aspect.
Summary of the invention
The purpose of this invention is to provide the Brazil wood chlorins compound shown in the formula I, and/or Brazil wood chlorins compound pharmaceutically acceptable salt, and/or be the purposes of plant extract in the preparation antitumor drug of effective ingredient with Brazilian brazilin compound;
Wherein,
R
1, R
2, R
3And R
4Be hydrogen atom independently of one another, C
1-4The alkyl of straight or branched, or, C
1-4The acyl group of straight or branched, preferred hydrogen atom;
R
5Be hydrogen atom or hydroxyl, preferred hydrogen atom.
Described tumor can be various tumors, for example: human leukemia, renal carcinoma, hepatocarcinoma, pulmonary carcinoma, rectal cancer, gastric cancer, esophageal carcinoma or breast carcinoma or the like.
In a preferred embodiment, described C
1-4The alkyl of straight or branched is meant methyl, ethyl, propyl group, isopropyl, butyl, isobutyl group, the tert-butyl group or sec-butyl, preferable methyl, ethyl; Described C
1-4The acyl group of straight or branched is meant formoxyl, acetyl group, propiono, bytyry or isobutyryl, preferred formoxyl.
In another preferred embodiment, described Brazil wood chlorins compound is the R among the above-mentioned formula I
1, R
2, R
3, R
4And R
5All be hydrogen atom, the i.e. brazilin of formula II:
The Brazil wood chlorins compound of above-mentioned formula I can obtain by the chemosynthesis mode, also can obtain by extracting from the dry duramen of leguminous plant Lignum Sappan (Caesalpinia sappan L.); Described is that the plant extract of effective ingredient also can extract from the dry duramen of leguminous plant Lignum Sappan and obtains with Brazilian brazilin compound.
A kind of extracting method of preferred Brazil wood chlorins compound comprises the steps:
95% alcohol heat reflux with 6 times of amounts after the exsiccant Lignum Sappan pulverizing medicinal materials is extracted 3 times, each 1 hour, merge extractive liquid,, concentrating under reduced pressure, the extractum that obtains carries out the distribution of ethyl acetate and water, gets ethyl acetate phase evaporate to dryness, carries out silica gel column chromatography, carry out gradient elution with the chloroform-methanol system, collect 116 stream parts altogether,, merge stream part according to the TLC testing result, wherein Fr.91～93 are through after silica gel column chromatography carries out purification process repeatedly, and the orange powder that obtains is the brazilin chemical compound.
In the said extracted thing, the weight purity of formula II chemical compound preferably is 40%～99.9%, more preferably is 50～98%.
In another preferred embodiment, chemical compound of the present invention can use with pharmaceutically acceptable acid or the deutero-salt form of alkali.Described Brazil wood chlorins compound pharmaceutically acceptable salt preferably is meant the salt that brazilin compounds and following material are derived and formed: hydrochloric acid, hydrobromic acid, sulphuric acid, citric acid, tartaric acid, phosphoric acid, lactic acid, acetone acid, acetic acid, succinic acid, oxalic acid, fumaric acid, maleic acid, oxaloacetic acid, methanesulfonic acid, ethyl sulfonic acid, benzenesulfonic acid, isethionic acid, alkali metal is (as sodium, potassium etc.), alkaline-earth metal is (as magnesium, calcium etc.), ester, the form of " prodrug " of carbamate or other routines (when with this form administration, can change into active part in vivo).
In another preferred embodiment, purposes of the present invention also comprises Brazil wood chlorins compound and/or its salt and/or is that the plant extract of effective ingredient is applied to prepare the pharmaceutical composition for the treatment of malignant tumor with this chemical compound, it contain (a) effective dose as formula I Brazil wood chlorins compound and/or its salt of active component and/or contain the plant extract of this chemical compound and (b) pharmaceutically acceptable carrier.
Usually, when the treatment tumor, with Brazilian brazilin compound and/or its salt and/or with this chemical compound is that the plant extract of effective ingredient is an active component, preparation process with routine, use separately or prepare the medicine of operable various different dosage forms clinically with other drug, as: powder, pill, capsule, tablet, microcapsule, soft capsule, membrane, suppository, injection, unguentum, tincture, electuary aerosol or other various external preparation etc.
In a preferred embodiment, chemical compound of the present invention can be by oral, intravenous, intramuscular or subcutaneous route administration.
Positive progressive effect of the present invention is:
1. the present invention's class Brazil wood chlorins compound of having found to be present in the leguminous plant Lignum Sappan can be used to treat multiple malignant tumor.Test cell line shows that this chemical compound pair cell mitosis has the effect of checking significantly, and can kill kinds of tumor cells; Animal experiment shows that also it can significantly suppress growth of tumour cell, and human body is had no side effect.
2. The compounds of this invention can be made the medicine for the treatment of malignant tumor as active component separately or with other medicines jointly with it.
Description of drawings
The negative matched group people of Figure 1A gastric cancer HGC cell cycle sketch map;
Figure 1B is a brazilin group people gastric cancer HGC cell cycle sketch map;
Fig. 2 is the influence of brazilin to female S180 tumor-bearing mice body weight.
The specific embodiment
Below in conjunction with specific embodiment, further set forth the present invention.These embodiment only are used to the present invention is described and are not used in and limit the scope of the invention.
From the dry duramen of leguminous plant Lignum Sappan (Caesalpinia sappan L.), extract the brazilin chemical compound
95% alcohol heat reflux with 6 times of amounts after the exsiccant Lignum Sappan pulverizing medicinal materials is extracted 3 times, each 1 hour, merge extractive liquid,, concentrating under reduced pressure, the extractum that obtains carries out the distribution of ethyl acetate and water, the ethyl acetate phase evaporate to dryness that obtains carries out silica gel column chromatography, carries out gradient elution with the chloroform-methanol system, collect 116 stream parts altogether, according to the TLC testing result, merge stream part, wherein Fr.91～93 are through after silica gel column chromatography carries out purification process repeatedly, obtain the orange powder chemical compound, detecting (purity is more than 90%) through TLC and HPLC, is a monomeric compound, its molecular formula, UV;
1H-NMR and
13The C-NMR data are as follows:
Molecular formula: C
16H
14O
5
UVλ
max(MeOH，nm)：200，286
1H-NMR(400MHZ，δ
ppm，CD
3OD)：7.18(1H，d，J＝8.4HZ)，6.47(1H，dd，J＝8.4，2.4HZ)，6.29(1H，d，J＝2.8HZ)，6.70(1H，s)，6.60(1H，s)，3.68(1H，d，J＝11.6HZ)，3.92(1H，dd，J＝11.2，1.2HZ)，3.96(1H，s)，2.76(1H，d，J＝15.6HZ)，3.02(1H，d，J＝15.6HZ)
13C-NMR(100MHZ，δ
ppm，CD
3OD)：156.7(4a)，154.5(3)，144.5(9)，144.1(10)，136.2(11a)，131.1(1)，130.1(7a)，114.3(1a)，111.7(8)，111.2(11)，108.8(2)，103.1(4)，76.9(6a)，69.6(6)，49.8(12)，39.2(7)
Can push away to such an extent that the gained chemical compound is a brazilin by above-mentioned data, i.e. formula II chemical compound.The brazilin that this extraction obtains is used for following each embodiment.
Brazilin is to the inhibitory action of kinds of tumor cells growth in embodiment 1 in vitro tests
In vitro culture murine sarcoma S180 cell, human embryo kidney (HEK) cancer 293 cells, human hepatoma HepG2 cell, people's pulmonary carcinoma A549 and CRL-5895 cell, people's gastric cancer HGC-27 cell.Cell grows to the logarithmic growth after date, uses trypsin digestion cell, and centrifugal 5 minutes of 1000rpm abandons supernatant, and an amount of culture medium suspends, and adjusts cell concentration to 8 * 10
4/ mL.With cell suspension inoculation in 96 porocyte culture plates, every hole 100 μ L, place cell culture incubator (37 ℃, 5%CO
2) in cultivate 24h after, the every hole of medication group adds brazilin (formula II) the 100 μ L of cell culture medium dilution, final concentration is 0.5ug/mL, the blank group adds the cell culture medium of equivalent, each group is all established 6 multiple holes.After cultivating 66h in the incubator, every hole adds the MTT 20 μ L of 5mg/mL, places 4h for 37 ℃.Every hole adds three liquid (5% SDS, 10mM HCl, 5% isopropyl alcohol), and 37 ℃ are spent the night.492nm/620nm surveys absorbance (OD).The OD value is carried out the t check, and calculate the suppression ratio of medicine: suppression ratio=(matched group OD value-administration group OD value)/matched group OD value * 100% each growth of tumour cell.
Table 1 brazilin is to the inhibitory action of kinds of tumor cells growth
| The cell title | Medication group OD value | Matched group OD value | Suppression ratio (%) |
| S180 293 | 0.0203±0.00 * 0.0038±0.08 * | 0.3098±0.01 0.2561±0.03 | 93.45 98.52 |
| HepG2 A549 CRL-5895 HGC-27 | 0.0480±0.01 * 0.0375±0.00 * 0.1369±0.01 * 0.1085±0.01 * | 0.2577±0.03 0.1989±0.03 0.2435±0.01 0.4342±0.08 | 81.37 81.15 43.78 75.01 |
*Expression p＜0.01 is compared with matched group, and difference has significance.
Experimental result: as shown in table 1, in various tumor cell culture liquid, add brazilin, final concentration is 0.5 μ g/mL, after hatching 66h altogether, the OD value of medication group all is lower than the blank group, difference has significance (p＜0.01), and the inhibitory rate of cell growth of mice S180 cell, human cancer cell 293, HepG2, A549, CRL-5895, HGC-27 is respectively 93.45%, 98.52%, 81.37%, 81.15%, 43.78%, 75.01%.Illustrate that brazilin all has the effect of very strong inhibition growth of tumour cell external to murine sarcoma, human embryo kidney (HEK) cancer, hepatocarcinoma, pulmonary carcinoma, gastric cancer at 0.5ug/ml dosage, antitumor spectra is wide.
In vitro culture HGC cell when growth conditions is good, digests and inoculates 1 * 10
5Individual cell is in the 6cm culture dish, and it is adherent to spend the night.Deng cell state good after, inhale and go culture medium, add brazilin (formula II) with the culture medium dilution, final concentration is 2 μ g/mL, negative control hole adds culture medium, cultivates 24h for 37 ℃.Observation of cell metamorphosis under the mirror.(0.25% pancreatin/0.02%EDTA), blow down gently moves into centrifuge tube, the centrifugal 5min of 2000rpm, PBS washing 2 times, the centrifugal 5min of 1000rpm with trypsin digestion cell.Slowly add 75% ethanol (20 ℃ of pre-coolings), 800 μ L in cell precipitation, vibration (Vortex) makes it to form unicellular as far as possible while dripping.4 ℃ fixedly spend the night after, the centrifugal 5min of 1000rpm, the PBS washed twice, centrifugal.Be resuspended in 300 μ L PBS, add the RNase (final concentration is 50 μ g/mL) that boiled in advance, hatch 30min for 37 ℃.300 order nylon net filters add propidium iodide (PI) (final concentration is 25 μ g/mL), 4 ℃ of lucifuge 1h, and flow cytometer detects cell cycle.
Experimental result: after brazilin acted on HGC cell 24h, it is round that cell all becomes, and part is floating, and collecting cell carries out flow cytometer and detects.The result shows that after (as Figure 1A and Figure 1B) brazilin effect, G1, S phase cell obviously reduce, G2 phase cell obviously increases, and brazilin is described under 2 μ g/mL dosage, makes people's gastric cancer HGC cell stagnate the phase in G2-M, it is blocked, stop tumor cell to carry out normal mitosis.
Laboratory animal: female, male SPF level KM mice provides (credit number: SCXK (Shanghai) 2003-0003 by Shanghai Slac Experimental Animal Co., Ltd.; Certification of fitness numbering: 0011979), body weight is 18～22g, and SPF level Animal House is raised, and feedstuff and water are freely absorbed in 12h illumination/12h dark.
Experimental technique: get 7 days S180 ascites mice of inoculation, aseptic condition extracts ascites down, adjusts cell concentration to 5 * 10 with normal saline
6/ mL.It is subcutaneous that S180 cell suspension is seeded in mice right fore armpit with 0.2mL/ amount only.Behind the inoculation 24h, the male and female mice is divided into 2 groups (10 every group) respectively at random: the brazilin group, with dissolved in distilled water brazilin (formula II), dosage is 1mg/kg; Matched group gives distilled water, and the administration volume is 0.1mL/10g, and every day, gastric infusion was 1 time, continuous 10 days.Next day is put to death mice in drug withdrawal, strips the tumor piece and weighs, and calculates every cell mean, carries out the t check.Calculate tumour inhibiting rate, tumour inhibiting rate=(matched group tumor weight-administration group tumor is heavy)/matched group tumor heavy * 100%.
Table 2 brazilin is to the inhibitory action of S180 tumor-bearing mice tumor growth
| Group | Sex | Quantity (only) | Body weight (g) | Heavy (g) X ± SD of tumor | The P value | Suppression ratio (%) | |
| Before the experiment | After the experiment | ||||||
| Matched group brazilin group matched group brazilin group | | 10 10 10 10 | 20.60 20.73 21.59 21.46 | 30.13 30.67 31.48 31.38 | 1.93±0.45 1.17±0.40 * 1.83±0.38 0.90±0.52 * | - 0.007 - 0.000 | - 39.38％ - 50.82％ |
*Expression p＜0.01 is compared with matched group, and difference has significance.
Experimental result: the data show of table 2, behind the brazilin successive administration 10 days, the administration group is female, male mouse tumor weigh less than matched group, difference has significance (p＜0.01), the tumour inhibiting rate of medicine reaches 50.82% and 39.38% respectively, illustrates that brazilin can obviously suppress S180 tumor-bearing mice growth of tumor when 1mg/kg dosage.Simultaneously, the body weight of brazilin group does not obviously descend (as Fig. 2), compares with matched group, and difference does not have significance, illustrates that medicine is nontoxic substantially.
The preparation of embodiment 4 tablets
Utilize routine techniques, mix following component, tabletting wraps film-coat then, makes the pharmaceutical composition of film coating tablet form.Its prescription is as follows:
| Composition | Recipe quantity (g/1000 sheet) |
| Brazilin (shown in II) sweet mellow | 5 54.1 35.4 |
The preparation of embodiment 5 injections
Take by weighing 5.0g purity and be 98% brazilin (shown in II), add an amount of normal saline, it is dissolved fully; The phosphate buffer of preparation 500g pH5.5 takes by weighing the 0.3g sodium sulfite and joins in the above-mentioned phosphate buffer; Buffer is joined in the Brazil wood cellulose solution, add the 1.0g benzyl alcohol again, add the injection water to cumulative volume 1000mL, mix homogeneously adds 0.01% pin and is incubated 30 minutes, G for 100 ℃ with activated carbon
3Sintered glass funnel filters, 0.22 μ m filtering with microporous membrane, and filtered liquid medicine is distributed into 500 of the injections that 2mL/ props up, and divides the injection tamponade, the jewelling that install to cover into injection.
Claims (7)
1, the Brazil wood chlorins compound shown in the formula I, and/or Brazil wood chlorins compound pharmaceutically acceptable salt, and/or be the purposes of plant extract in the preparation antitumor drug of effective ingredient with Brazilian brazilin compound;
Wherein,
R
1, R
2, R
3And R
4Be hydrogen atom independently of one another, C
1-4The alkyl of straight or branched, or, C
1-4The acyl group of straight or branched;
R
5Be hydrogen atom or hydroxyl.
2, purposes as claimed in claim 1 is characterized in that: described tumor is meant human leukemia, renal carcinoma, hepatocarcinoma, pulmonary carcinoma, rectal cancer, gastric cancer, esophageal carcinoma or breast carcinoma.
3, purposes as claimed in claim 1 or 2 is characterized in that: described C
1-4The alkyl of straight or branched is meant methyl, ethyl; Described C
1-4The acyl group of straight or branched is meant formoxyl.
4, purposes as claimed in claim 1 or 2 is characterized in that: described Brazil wood chlorins compound is the brazilin of formula II:
5, purposes as claimed in claim 1 or 2 is characterized in that: described Brazil wood chlorins compound pharmaceutically acceptable salt is meant the salt that Brazil wood chlorins compound and following material are derived and formed: hydrochloric acid, hydrobromic acid, sulphuric acid, citric acid, tartaric acid, phosphoric acid, lactic acid, acetone acid, acetic acid, succinic acid, oxalic acid, fumaric acid, maleic acid, oxaloacetic acid, methanesulfonic acid, ethyl sulfonic acid, benzenesulfonic acid, isethionic acid, alkali metal, alkaline-earth metal, ester or carbamate.
6, purposes as claimed in claim 1 or 2 is characterized in that: described medicine is following dosage form: powder, pill, capsule, tablet, microcapsule, soft capsule, membrane, suppository, injection, unguentum, tincture, electuary or aerosol.
7, purposes as claimed in claim 1 or 2 is characterized in that: the described plant extract that contains the Brazil wood chlorins compound is to extract from the dry duramen of leguminous plant Lignum Sappan.
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| CN115215830A (en) * | 2022-08-17 | 2022-10-21 | 山西省肿瘤医院 | C-8 hydroxyl substituted brazilein analogue and preparation method and application thereof |
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