CN101215277A - Two anti-cancer medicament raw material compounds - Google Patents

Two anti-cancer medicament raw material compounds Download PDF

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CN101215277A
CN101215277A CNA2008100256559A CN200810025655A CN101215277A CN 101215277 A CN101215277 A CN 101215277A CN A2008100256559 A CNA2008100256559 A CN A2008100256559A CN 200810025655 A CN200810025655 A CN 200810025655A CN 101215277 A CN101215277 A CN 101215277A
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dihydroxyl
xylidine
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trimethoxy flavones
flavones
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张南
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Abstract

The invention belongs to the chemical medicine field, in particular to two anti-cancer medicine raw material compounds. The invention synthesizes several chemical raw materials to obtain novel 3- methoxy flavoine derivative-compound 5, 7-dihydroxy-8-(1, 1-dimethylaniline-3, 3', 4'- 3-methoxyflavone and compound 5, 7-dihydroxy-8-(1, 1-dimethylaniline-3, 4'- 2-methoxyflavone in four steps. The two compounds can reach the level of poly-methoxyl flavones (PMFS) compound which is separated from natural plants and poly-methylation flavones C-glycosylated derivative which are separated from medical plants, which have equal role and effect of inhibiting human tumor generation, play positive inhibition in anti-inflammatory diseases and anti-atherosclerosis diseases, and are two important raw materials of wide-spectrum antineoplastic medicines.

Description

Two kinds of anti-cancer medicament raw material compounds
Technical field:
The invention belongs to the chemicals field, particularly two kinds of anti-cancer medicament raw material compounds 5,7-dihydroxyl-8-(1, the 1-xylidine)-3,3 ', 4 '-trimethoxy flavones, and 5,7-dihydroxyl-8-(1, the 1-xylidine)-3,4 '-dimethoxy flavone.
Background technology:
The 3-methoxy flavone belongs to the polymethoxyflavone compound of separating (PMFs) from orange, because it has the biologic activity of wide spectrums such as comprising anti-inflammatory, anticancer and atherosclerosis, receive special concern always.The interest that people explore PMFs health care characteristic in the citrus trees fruit is constantly increasing.Therefore, separate from sweet tangerine peel, identify that PMFs will make the byproduct of orange juice processing obtain new application, and citrus is consumed in other healthcare products and medicine.
PMFs realizes its antitumous effect by different potential mechanisms.From the ethyl acetate extract of natsudaidai (GFJ), separate 3,3 ', 4 ', 5,6,7,8-Heptamethoxyflavone (a kind of 3-methoxy flavone) significantly strengthens people's myelocytic leukemia cellular uptake [3H] vincristine(VCR) that Zorubicin is resisted in the concentration dependent mode.Data presentation, 3,3 ', 4 ', 5,6,7, the 8-Heptamethoxyflavone suppresses the output of [3H] vincristine(VCR) of P-glycoprotein mediation, causes chemotherapeutics in the cell inner accumulated.This compound is expected to become the multidrug resistance reversal agent of a candidate in the chemotherapy of tumors.
Except other flavonoid compound, methylate flavones and C-glycosylated derivative of isolating poly from medicinal plant, they are to FeSO in the rats'liver microbody 4+The influence of the lipid oxidation that halfcystine causes has all obtained research, and wherein gardenin D is the inhibitor of non-enzymatic lipid peroxidation.Set up structure-activity relation, and the constitutional features of observing active poly oxy-compound is different from polymethoxyflavone, the anti-peroxidation flavonoid has the lipophilicity of height.
Obtain seven kinds of 3-methoxy flavones from the separation of white mouse Qu plant shoot, discriminating, studied their group and removed activity, anti-oxidant activity and pig pancreas Alpha-starch enzyme inhibition activity.In the 3-methoxy flavone, 5,7,4 '-trihydroxy--3, the 6-dimethoxy flavone, 5,7,4 '-trihydroxy--3,3 '-dimethyl flavones and 5,4 '-dihydroxyl-3,7,3 '-the trimethylammonium flavones shown that significant group removes active.5,7,4 '-trihydroxy--3, the 6-dimethoxy flavone, 5,7,4 '-trihydroxy--3,3 '-dimethoxy flavone and 5,4 '-dihydroxyl-3,6,7-trimethoxy flavones has the anti-oxidant activity in the linoleic acid system.5,7,4 '-dihydroxyl-3, the 6-dimethoxy flavone, 5,7,4 '-trihydroxy--3,3 '-dimethoxy flavone and 5,4 '-dihydroxyl-3,6,7-trimethoxy flavones, 5,7,4 '-trihydroxy--3-methoxy flavone and 5,4 '-dihydroxyl-3, the 7-dimethoxy flavone then shows very high pig pancreas Alpha-starch enzyme inhibition activity.
Sergeev studies show that, derive from the 5-hydroxyl-3 of sweet tangerine, 6,7,8,3 ', 4 '-hexa methoxy flavones (5-OH-HxMF) and 3 '-hydroxyl-5,6,7, (3 '-OH-TtMF) suppresses human breast cancer cell (MCF-7) by calcium ion dependent cell apoptosis mechanism grows 4 '-tetramethoxy flavones.These results point out strongly, the cell Ca of PMFs 2+Regulating activity is the basis of its Apoptosis Mechanism, and the hydroxylation of PMFs can be induced Ca for them 2+Increase, and then the caspase-3 that the activation calcium ion relies on is most important.
Summary of the invention:
The objective of the invention is to study two kinds of new 3-methoxy flavone derivative-compounds (A) 5,7-dihydroxyl-8-(1, the 1-xylidine)-3,3 ', 4 '-trimethoxy flavones (compound A) and compound (B) 5,7-dihydroxyl-8-(1, the 1-xylidine)-3,4 '-dimethoxy flavone (compound B), these two kinds of compounds are effective fatty acid synthetase (FAS) inhibitor, can extensively suppress polytype human tumor cell line growth, the one-step inducing apoptosis of tumor cells of going forward side by side.In human tumor xenograft model's research, 5,7-dihydroxyl-8-(1, the 1-xylidine)-3,3 ', 4 '-trimethoxy flavones is proved to be a kind of effective antitumour agent, and energy strongly inhibited people's lung cancer and colon cancer cell are grown in vivo.
To achieve these goals, the present invention adopts following scheme to come synthetic compound 5,7-dihydroxyl-8-(1, the 1-xylidine)-3, and 3 ', 4 '-trimethoxy flavones, its chemical structural formula is:
Figure S2008100256559D00031
Synthesis material and synthesis step:
The first step: 10g (55mmol) 3,4-dimethoxybenzoic acid and 2.2ml methylsulfonyl chloride (28.4mmol) output 8.47g of following time of room temperature 3,4-dimethoxybenzoic acid acid anhydride (24.5mmol; Output capacity 89%);
Second step: 1.6g 2 ', 4 ', 6 '-trihydroxy--2-methoxyacetophenone (8.1mmol) and 8.4 g 3,40 ℃ of reactions of 4-dimethoxybenzoic acid acid anhydride (21.0mmol) output 2.2g 5,7-dihydroxyl-3,3 ', 4 '-trimethoxy flavones (5.9mmol; Output capacity 74%), at hexane: crystallization in the acetone (50: 50), 0.85g pure 5,7-dihydroxyl-3,3 ', 4 '-trimethoxy flavones;
The 3rd step: 0.34g 5,7-dihydroxyl-3,3 ', 4 '-trimethoxy flavones (0.98mmol), 0.25ml isoprene bromide (1.97mmol) and the 50ml acetone soln room temperature that contains 0.4g Anhydrous potassium carbonate (2.0mmol) refluxed 5 hours, filtrate is evaporated after filtration, and residue crystallization in methyl alcohol gets 0.3g 5-hydroxyl-7-isopentene oxygen base-3,3 ', 4 '-trimethoxy flavones (0.73mmol; Productive rate 74%);
The 4th step: 0.3g 5-hydroxyl-7-isopentene oxygen base-3,3 ', the solution of acetic anhydride 20ml of 4 '-trimethoxy flavones (0.73mmol) and 0.12g dehydrated sodium acetate refluxed 48 hours, after the chloroform dilution extraction, residue at room temperature 70ml contains in the 5% methyl alcohol KOH solution and to stir 4 hours, solution is through the ethyl acetate acidizing extraction then, at hexane: crystallization in the acetone (50: 50), get 0.183g pure substance 5,7-dihydroxyl-8-(1, the 1-xylidine)-3,3 ', 4 '-trimethoxy flavones (0.44mmol; Productive rate 60%).
Illustrate its molecular structure by nuclear magnetic resonance technique, and calculate its molecular weight by mass spectrum:
H NMR (300MHz, CDCl 3): δ 1.68 (s, 6H, H4 "+H5 "), 3.82 (s, 3H, 3OMe), 3.94 (s, 3H, 3 ' OMe), 3.97 (s, 3H, 4 ' OMe), 5.39 (d, 1H, J=10.7Hz, H3 "), 5.46 (d, 1H, J=17.7Hz, H3 "), 6.29 (s, 1H, H6), 6.46 (dd, 1H, J=17.7 and 10.7Hz, H2 "), 7.00 (d, 1H; J=8.7Hz, H5 '), 7.25 (s, 1H; 7OH), 7.53 (d, 1H, J=2.1Hz; H2 '), 7.63 (dd, 1H, J=8.7 and 2.1Hz; H6 '), 13.03 (s, 1H, 5OH); 13C NMR (75MHz, CDCl 3): δ 28.06 (C4 "+C "), 40.64 (C1 "), 55.97 (3 ' OMe); 55.98 (4 ' OMe), 60.29 (3-OMe), 101.17 (C6); 106.95 (C10); 109.70 (C8), 110.84 (C5 '), 11.54 (C2 '); 113.68 (C3 "), 122.53 (C6 '), 122.74 (C1 '), 138.65 (C3), 148.69 (C3 '), 148.96 (C2 "), 151.08 (C4 '), 155.27 (C9); 156.54 (C2); 160.54 (C5), 161.48 (C7), 179.07 (C4); Chemical ionization mass spectrometry and high resolution mass spectrum are confirmed (C 23H 24O 7) molecular weight be 412.
The present invention adopts following scheme to come synthetic compound 5,7-dihydroxyl-8-(1, the 1-xylidine)-3, and 4 '-dimethoxy flavone, its chemical structural formula is:
Figure S2008100256559D00051
Synthesis material and synthesis step:
The first step: 10g (65.7mmol) anisic acid and 2.6ml methylsulfonyl chloride (33.6mmol) room temperature reaction get 6.13g anisic acid acid anhydride (24.5mmol; Productive rate 89%);
Second step: 0.6g 2 ', 4 ', and 6 '-trihydroxy--2-methoxyacetophenone (3mmol) and 2.6g anisic acid acid anhydride (9mmol) room temperature reaction get 0.763g ergotocine (2.43mmol; Productive rate 81%);
The 3rd step: contain 0.30g ergotocine (0.95mmol), the 50ml acetone soln room temperature of 0.2ml prenyl bromide (1.73mmol) and 0.4g Anhydrous potassium carbonate (2.0mmol) refluxed 5 hours.Evaporation after filtration, residue is crystallization in methyl alcohol, gets 0.33g 5-hydroxyl-7-isopentene oxygen base-3,4 '-dimethoxy flavone (0.86mmol; Productive rate 91%);
The 4th step: 0.3g 5-hydroxyl-7-isopentene oxygen base-3, the 20ml acetic anhydride of 4 '-dimethoxy flavone (0.78mmol) and 0.12g sodium acetate, anhydrous refluxed 48 hours.After the chloroform dilution extraction, residue at room temperature 70ml contains in the 5% methyl alcohol KOH solution and stirred 4 hours.Solution gets the pure product 5 of 0.21g, 7-dihydroxyl 8-(1, the 1-xylidine)-3,4 '-dimethoxy flavone (0.55mmol through the ethyl acetate acidizing extraction; Productive rate 71%).
Resolve its structure by nuclear magnetic resonance technique, and calculate molecular weight by mass-spectrometric technique:
1H NMR (200MHz, DMSO-d 6): δ 1.55 (s, 6H, 1 " Me), 3.75 (s, 3H, 3OMe), 3.84 (s; 3H, 4 ' OMe), 4.77 (dd, 1H, J=10.5 and 1.1Hz, H3 "), 4.80 (dd, 1H, J=17.5 and 1.1Hz, H3 "), 6.27 (dd, 1H; J=17.5and 10.5Hz, H2 "), 6.30 (s 1H, H6), 7.10 (d, 2H, J=9.0Hz, H3 '+H5 '), 7.91 (d, 2H, J=9.0Hz, H2 '+H6 '), 10.52 (brs, 1H, 7OH), 13.00 (s, 1H, 5OH); 13C NMR (50MHz, DMSO-d 6): δ 29.54 (1 " Me), 40.34 (C1 "), 55.25 (4 ' OMe), 59.66 (3-OMe), 99.60 (C6), 105.02 (C10), 108.36 C3 "); 110.75 (C8), 113.80 (C '+C5 '), 121.95 (C1 '); 130.33 (C2 '+C6 "), 137.42 (C3), 149.66 (C2 "); 154.75 (C2), 156.07 (C9), 158.98 (C5); 161.03 (C4 '), 162.89 (C7), 178.13 (C4); Chemical ionization mass spectrometry and high resolution mass spectrum are confirmed (C 22H 22O 6) molecular weight be 382.
Two kinds of new 3-methoxy flavone derivatives of synthetic of the present invention, compound 5,7-dihydroxyl-8-(1, the 1-xylidine)-3,3 ', 4 '-trimethoxy flavones and compound 5,7-dihydroxyl-8-(1, the 1-xylidine)-3,4 '-dimethoxy flavone are effective fatty acid synthetase (FAS) inhibitor, can extensively suppress polytype human tumor cell line growth, the one-step inducing apoptosis of tumor cells of going forward side by side.In human tumor xenograft model's research, 5,7-dihydroxyl-8-(1, the 1-xylidine)-3,3 ', 4 '-trimethoxy flavones is proved to be a kind of effective antitumour agent, and energy strongly inhibited people's lung cancer and colon cancer cell are grown in vivo.5,7-dihydroxyl-8-(1, the 1-xylidine)-3,3 ', 4 '-trimethoxy flavones and 5,7-dihydroxyl-8-(1, the 1-xylidine)-3,4 '-dimethoxy flavone has the tremendous potential that is developed to new broad-spectrum anti-cancer drug.
Description of drawings:
Fig. 1 is a compound 5, and 7-dihydroxyl-8-(1, the 1-xylidine)-3,3 ', 4 '-trimethoxy flavones suppress Human Prostate Cancer Cells LnCAP steatogenesis-concentration curve;
Fig. 2 is a compound 5, and 7-dihydroxyl-8-(1, the 1-xylidine)-3,4 '-dimethoxy flavone suppress Human Prostate Cancer Cells LnCAP steatogenesis-concentration curve;
Fig. 3 is a compound 5, and 7-dihydroxyl-8-(1, the 1-xylidine)-3,3 ', 4 '-trimethoxy flavones suppress Human Prostate Cancer Cells LnCAP fatty acid synthetase activity-concentration curve;
Fig. 4 is a compound 5, and 7-dihydroxyl-8-(1, the 1-xylidine)-3,4 '-dimethoxy flavone suppress Human Prostate Cancer Cells LnCAP fatty acid synthetase activity-concentration curve;
Fig. 5 is a compound 5,7-dihydroxyl-8-(1, the 1-xylidine)-3,3 ', 4 '-trimethoxy flavones and compound 5,7-dihydroxyl-8-(1, the 1-xylidine)-3, the data sheet of 4 '-dimethoxy flavone vitro inhibition growth of human tumor cells;
Fig. 6 is a compound 5,7-dihydroxyl-8-(1, the 1-xylidine)-3, the gross tumor volume-treatment fate graphic representation of 3 ', 4 '-trimethoxy flavones treatment mouse hypodermic inoculation Human Prostate Cancer Cells LnCAP tumour;
Fig. 7 is a compound 5,7-dihydroxyl-8-(1, the 1-xylidine)-3, the gross tumor volume treatment fate graphic representation of 3 ', 4 '-trimethoxy flavones treatment mouse hypodermic inoculation human breast cancer cell ZR-75-1 tumour;
Fig. 8 is a compound 5,7-dihydroxyl-8-(1, the 1-xylidine)-3, the gross tumor volume treatment fate graphic representation of 3 ', 4 '-trimethoxy flavones treatment mouse hypodermic inoculation human lung carcinoma cell NCI-H23 tumour;
Fig. 9 is a compound 5,7-dihydroxyl-8-(1, the 1-xylidine)-3, the gross tumor volume treatment fate graphic representation of 3 ', 4 '-trimethoxy flavones treatment mouse hypodermic inoculation human colon cancer cell HCT-116 tumour;
Figure 10 is a compound 5,7-dihydroxyl-8-(1, the 1-xylidine)-3, the gross tumor volume treatment fate graphic representation of 4 '-dimethoxy flavone treatment mouse hypodermic inoculation Human Prostate Cancer Cells LnCAP tumour;
Figure 11 is a compound 5,7-dihydroxyl-8-(1, the 1-xylidine)-3, the gross tumor volume treatment fate graphic representation of 4 '-dimethoxy flavone treatment mouse hypodermic inoculation human breast cancer cell ZR-75-1 tumour;
Figure 12 is a compound 5,7-dihydroxyl-8-(1, the 1-xylidine)-3, the gross tumor volume treatment fate graphic representation of 4 '-dimethoxy flavone treatment mouse hypodermic inoculation human lung carcinoma cell NCI-H23 tumour;
Figure 13 is a compound 5,7-dihydroxyl-8-(1, the 1-xylidine)-3, the gross tumor volume treatment fate graphic representation of 4 '-dimethoxy flavone treatment mouse hypodermic inoculation human colon cancer cell HCT-116 tumour.
Embodiment:
Be the medicinal effect of proof starting compound of the present invention, can verify in order to following method:
Experimental technique
1.[2- 14C] acetate mixes method
With the compound 5 of different concns, 7-dihydroxyl-8-(1, the 1-xylidine)-3,3 ', 4 '-trimethoxy flavones or compound 5,7-dihydroxyl-8-(1, the 1-xylidine)-3,4 '-dimethoxy flavone was handled 1 hour or 20 hours, added 2-in the LnCAP cell culture fluid 14The acetate of C-mark was hatched 4 hours, collected nutrient solution and cell, and centrifugal, 0.8ml PBS is resuspended.Use Bligh Dyer method extracting lipid; Use [the 2-that the scintillation counting standard measure mixes cytolipin 14C] acetate.The gained result proofreaies and correct with the sample protein content.
2. fatty acid synthetase determination of activity (in vitro tests)
Press the method for bibliographical information and measure LnCAP cell extract fatty acid synthetase activity.Collect the LnCAP cell, centrifugal, hypotonic buffer liquid (1 mmole EDTA, 20 mmole Tris-hydrochloric acid, pH7.5) resuspended; Use BCA method working sample protein content subsequently.The compound 5 that is containing different concns in advance, 7-dihydroxyl-8-(1, the 1-xylidine)-3,3 ', 4 '-trimethoxy flavones (0.01-10 μ M) or compound 5,7-dihydroxyl-8-(1, the 1-xylidine)-3,37 ℃ of protein (50 μ g) of hatching same amount is 30 minutes in the 2.5ml potassium phosphate salt damping fluid of 4 '-dimethoxy flavone (0.3-30uM) (100mM, pH 7.0).Add 20 μ l reaction mixed liquid (2.5mM NADPH, 1.25mM acetyl-CoA, 1.25mM CoA malonyl CoA-CoA and 0.02mM[2-then 14C] CoA malonyl CoA-CoA (60 millicuries/mmole; PerkinElmer life science company), sample was hatched in 37 ℃ 15 minutes.The 1M HCl/ methyl alcohol of adding 3ml precooling (6: 4, V/V) termination reaction, petroleum ether extraction the lipid acid, [2-that the scintillation counting technique analysis is mixed 14C] CoA malonyl CoA-CoA.
3. cytotoxicity analysis
Use human tumor cell line analysis of compounds 5,7-dihydroxyl-8-(1, the 1-xylidine)-3,3 ', 4 '-trimethoxy flavones and compound 5,7-dihydroxyl-8-(1, the 1-xylidine)-3, the cytotoxicity of 4 '-dimethoxy flavone (being dissolved in DMSO).Human tumor cell line in the DMEM of 10%FBS nutrient solution, places 5%CO available from ATCC and NCI 237 ℃ of incubators in cultivate.Make oxicity analysis after the cell growth converges, with the nutrient solution washing, count then behind the trypsin digestion and cell.The every hole of 96 orifice plates passes 3000-6000 cell and hatched 16-24 hour, adds the compound 5 of different concns again, 7-dihydroxyl-8-(1, the 1-xylidine)-3,3 ', 4 '-trimethoxy flavones or compound 5,7-dihydroxyl-8-(1, the 1-xylidine)-3,4 '-dimethoxy flavone.Cultivate after 72 hours, use cell and control cells after MTT analyzes drug treating.
4. human tumor metastasis model
T cell defect nude mouse (nu/nu) in 6 ages in week, available from Charles River laboratory, according to university's animal rearing and the council of use regulations, is raised in gnotobasis, handles.48 mouse rib belly subcutaneous vaccinations 5 * 10 respectively 6Individually be suspended in 0.2ml HBSS/ matrigel (50: 50, V/V) the mammary cancer ZR-75-1 in, prostate cancer cell LnCAP, human lung carcinoma cell NCI-H23 and human colon cancer cell HCT-116, when tumor average diameter grows to 7-8mm, gross tumor volume is about 100-200mm 3When size, 24 mouse be divided into the treatment group (2 groups, 8 every group, totally 16), press 50mk/kg and 100mg/kg compound 5,7-dihydroxyl-8-(1, the 1-xylidine)-3,3 ', 4 '-trimethoxy flavones or 50mk/kg and 100mg/kg compound 5,7-dihydroxyl-8-(1, the 1-xylidine)-3,4 '-dimethoxy flavone (being dissolved in 15%Captisol) administration, control group (a group, totally 8) is only accepted vehicle (15%Captisol).
For guaranteeing compound 5,7-dihydroxyl-8-(1, the 1-xylidine)-3,3 ', 4 '-trimethoxy flavones or compound 5,7-dihydroxyl-8-(1, the 1-xylidine)-3, the distribution of 4 '-dimethoxy flavone treatment group and control group tumour size when handling beginning is basic identical, and mouse is divided into three classes: the small volume tumour (＜4mm), medium volumetric tumor (4-8mm) and large volume tumour (＞8mm).The mouse of similar number in each class is divided respectively at control group and compound 5, and 7-dihydroxyl-8-(1, the 1-xylidine)-3 is in 3 ', 4 '-trimethoxy flavones treatment group.
The compound 5 of tumour transplatation nude mice, 7-dihydroxyl-8-(1, the 1-xylidine)-3,3 ', 4 '-trimethoxy flavones or compound 5,7-dihydroxyl-8-(1, the 1-xylidine)-3,4 '-dimethoxy flavone dosage regimen: oral administration, with compound 5,7-dihydroxyl-8-(1, the 1-xylidine)-3,3 ', 4 '-trimethoxy flavones or compound 5,7-dihydroxyl-8-(1, the 1-xylidine)-3,4 '-dimethoxy flavone is dissolved in 15%Captisol.Give 200 μ l every day and contain 1.25mg or 2.5mg compound 5,7-dihydroxyl-8-(1, the 1-xylidine)-3,3 ', 4 '-trimethoxy flavones or compound 5,7-dihydroxyl-8-(1, the 1-xylidine)-3, the soup of 4 '-dimethoxy flavone (15%Captisol), 5 days weekly, continuous 3 weeks, or 200 μ l placebos (15%captisol) 3 weeks (control group).Two treated animals are separately raised, ad lib.
The evaluation of antitumous effect: measured the tumour size in per 3 or 4 days, the formula below adopting calculates gross tumor volume:
V＝(a×b)/2
Wherein a representative wide (short diameter), b representative long (long diameter).The ratio of the volume the when relative tumour volume of each knurl body (RTV) is showed the volume of fixing time and treated beginning.Each treatment batch total is calculated average RTV and standard error (SE).Formula below using calculates the tumor growth inhibiting value and determines anti-tumor activity.
TGI(％)＝T/C×100
Wherein the average RTV of end point (4 week) treatment group tumour is tested in the T representative, and C represents the average RTV of control group.Anti-tumor activity minimum level (T/C≤42%) standard that adopts National Cancer Institute to formulate.Experiment finishes back excision knurl body, and methyl alcohol is fixed.
Experimental result
1. the comparative analysis compound 5,7-dihydroxyl-8-(1, the 1-xylidine)-3, and 3 ', 4 '-trimethoxy flavones and compound 5,7-dihydroxyl-8-(1, the 1-xylidine)-3,4 '-dimethoxy flavone is active to the lipogenetic inhibition of tumour cell
In order to study compound 5,7-dihydroxyl-8-(1, the 1-xylidine)-3,3 ', 4 '-trimethoxy flavones and compound 5,7-dihydroxyl-8-(1, the 1-xylidine)-3,4 '-dimethoxy flavone suppresses lipogenetic ability, with the compound 5 of different concns, 7-dihydroxyl-8-(1, the 1-xylidine)-3,3 ', 4 '-trimethoxy flavones or compound 5,7-dihydroxyl-8-(1, the 1-xylidine)-3,4 '-dimethoxy flavone was handled the LnCAP prostate cancer cell 5 hours, the incorporation of 2-14C mark acetate in the detection by quantitative cytolipin.As shown in Figure 1, compound 5,7-dihydroxyl-8-(1, the 1-xylidine)-3,3 ', 4 '-trimethoxy flavones suppress the lipogenesis rate and surpass 50% when 0.3 μ m concentration.As shown in Figure 2, compound 5,7-dihydroxyl-8-(1, the 1-xylidine)-3,4 '-dimethoxy flavone suppress the lipogenesis rate and surpass 50% when 1 μ M concentration.Greater concn then further reduces lipogenesis, and presents concentration dependence mode.Handle after 24 hours and then further reduce.
2. compound 5,7-dihydroxyl-8-(1, the 1-xylidine)-3,3 ', 4 '-trimethoxy flavones and compound 5,7-dihydroxyl-8-(1, the 1-xylidine)-3,4 '-dimethoxy flavone is by suppressing lipogenesis in FAS active reduction prostate cancer cell and the breast cancer cell
For confirming compound 5,7-dihydroxyl-8-(1, the 1-xylidine)-3,3 ', 4 '-trimethoxy flavones or compound 5,7-dihydroxyl-8-(1, the 1-xylidine)-3,4 '-dimethoxy flavone is a FAS inhibitor, with the compound 5 of different concns, 7-dihydroxyl-8-(1, the 1-xylidine)-3,3 ', 4 '-trimethoxy flavones or compound 5,7-dihydroxyl-8-(1, the 1-xylidine)-3,4 '-dimethoxy flavone is handled LnCAP cell protein extract, the incorporation of 2-14C mark CoA malonyl CoA-CoA in the detection by quantitative lipid acid.As shown in Figure 3, compound 5,7-dihydroxyl-8-(1, the 1-xylidine)-3,3 ', 4 '-trimethoxy flavones reduces external fatty acid synthetase activity below 50% when 0.1 μ M concentration.As shown in Figure 4, compound 5,7-dihydroxyl-8-(1, the 1-xylidine)-3,4 '-dimethoxy flavone reduce external fatty acid synthetase activity below 50% when 0.3 micro-molar concentration.Western Blot analyzes demonstration, compound 5,7-dihydroxyl-8-(1, the 1-xylidine)-3,3 ', 4 '-trimethoxy flavones or compound 5,7-dihydroxyl-8-(1, the 1-xylidine)-3,4 '-dimethoxy flavone does not influence FAS protein level in the LnCAP cell.Hence one can see that, and suppressing lipid synthetic is the direct result that suppresses the FAS enzymic activity, rather than the result of FAS expression decreased.
3. compound 5,7-dihydroxyl-8-(1, the 1-xylidine)-3,3 ', 4 '-trimethoxy flavones and compound 5,7-dihydroxyl-8-(1, the 1-xylidine)-3,4 '-dimethoxy flavone extensively suppresses human body tumour cell strain growth, but does not suppress normal cell strain growth
26 strain tumor cell lines are containing compound 5,7-dihydroxyl-8-(1, the 1-xylidine)-3, and 3 ', 4 '-trimethoxy flavones and compound 5,7-dihydroxyl-8-(1, the 1-xylidine)-3 cultivates in the ordinary culture medium of 4 '-dimethoxy flavone.Use MTT after 3 days and measure cell survival.The result as shown in Figure 5, most of human tumor cells are to compound 5,7-dihydroxyl-8-(1, the 1-xylidine)-3,3 ', 4 '-trimethoxy flavones and compound 5,7-dihydroxyl-8-(1, the 1-xylidine)-3,4 '-dimethoxy flavone sensitivity.And find that most of human tumor cells are to compound 5,7-dihydroxyl-8-(1, the 1-xylidine)-3,3 ', 4 '-trimethoxy flavones and compound 5,7-dihydroxyl-8-(1, the 1-xylidine)-3,4 '-dimethoxy flavone are responsive, and compound 5,7-dihydroxyl-8-(1, the 1-xylidine)-3,3 ', 4 '-trimethoxy flavones is than compound 5,7-dihydroxyl-8-(1, the 1-xylidine)-3, the effect of 4 '-dimethoxy flavone is stronger.But normal human mammary epithelial cell (MCF10A) and mouse embryo fibroblasts are insensitive to these two compounds.These cells still can normally be grown up when two kinds of compound concentrations were 50 μ M.
The tumour transplatation nude mice model research compound 5 of should choosing, 7-dihydroxyl-8-(1, the 1-xylidine)-3,3 ', 4 '-trimethoxy flavones and compound 5,7-dihydroxyl-8-(1, the 1-xylidine)-3, the validity of 4 '-dimethoxy flavone
At compound 5,7-dihydroxyl-8-(1, the 1-xylidine)-3,3 ', 4 '-trimethoxy flavones and compound 5,7-dihydroxyl-8-(1, the 1-xylidine)-3, on the basis of 4 '-dimethoxy flavone to the external antiproliferative effect of tumor cell line, use Human Prostate Cancer Cells (LnCAP), human breast cancer cell (ZR-75-1), the subcutaneous transplantation nude mice model assessing compound 5 of human lung carcinoma cell (NCI-H23) and human colon cancer cell (HCT-116), 7-dihydroxyl-8-(1, the 1-xylidine)-3,3 ', 4 '-trimethoxy flavones and compound 5,7-dihydroxyl-8-(1, the 1-xylidine)-3, the antitumous effect of 4 '-dimethoxy flavone (dosage is 100mg/kg).The results are shown in Figure 6-9, compound 5,7-dihydroxyl-8-(1, the 1-xylidine)-3,3 ', 4 '-trimethoxy flavones is 14.2%, 0%, 31% and 20% o'clock strongly inhibited LnCAP respectively in the T/C value, ZR-75-1, NCI-H23 and HCT-116 growth of tumour cell; Compound 5,7-dihydroxyl-8-(1, the 1-xylidine)-3,4 '-dimethoxy flavone is 17.5%, 60%, 50% and 30% o'clock strongly inhibited LnCAP respectively in the T/C value, ZR-75-1, NCI-H23 and HCT-116 growth of tumour cell (seeing shown in Figure 10-13).Do not find simultaneously compound 5,7-dihydroxyl-8-(1, the 1-xylidine)-3,3 ', 4 '-trimethoxy flavones and compound 5,7-dihydroxyl-8-(1, the 1-xylidine)-3, the animal of 4 '-dimethoxy flavone administration produces any significant side effects, comprises losing weight etc.These data show strongly, compound 5,7-dihydroxyl-8-(1, the 1-xylidine)-3,3 ', 4 '-trimethoxy flavones and compound 5,7-dihydroxyl-8-(1, the 1-xylidine)-3,4 '-dimethoxy flavone is the good candidate that can be developed to new cancer therapy drug.

Claims (4)

1. two kinds of anti-cancer medicament raw material compounds is characterized in that: compound 5, and 7-dihydroxyl-8-(1, the 1-xylidine)-3,3 ', 4 '-trimethoxy flavones, its chemical structural formula is:
Figure S2008100256559C00011
2. two kinds of anti-cancer medicament raw material compounds according to claim 1 is characterized in that: compound 5, and 7-dihydroxyl-8-(1, the 1-xylidine)-3,3 ', 4 '-trimethoxy flavones, synthesis step is as follows:
The first step: 10g (55mmol) 3,4-dimethoxybenzoic acid and 2.2ml methylsulfonyl chloride (28.4mmol) output 8.47g of following time of room temperature 3,4-dimethoxybenzoic acid acid anhydride (24.5mmol; Output capacity 89%);
Second step: 1.6g 2 ', 4 ', 6 '-trihydroxy--2-methoxyacetophenone (8.1mmol) and 8.4g 3,40 ℃ of reactions of 4-dimethoxybenzoic acid acid anhydride (21.0mmol) output 2.2g5,7-dihydroxyl-3,3 ', 4 '-trimethoxy flavones (5.9mmol; Output capacity 74%), at hexane: crystallization in the acetone (50: 50), 0.85g pure 5,7-dihydroxyl-3,3 ', 4 '-trimethoxy flavones;
The 3rd step: 0.34g 5,7-dihydroxyl-3,3 ', 4 '-trimethoxy flavones (0.98mmol), 0.25ml isoprene bromide (1.97mmol) and the 50ml acetone soln room temperature that contains 0.4g Anhydrous potassium carbonate (2.0mmol) refluxed 5 hours, filtrate is evaporated after filtration, and residue crystallization in methyl alcohol gets 0.3g 5-hydroxyl-7-isopentene oxygen base-3,3 ', 4 '-trimethoxy flavones (0.73mmol; Productive rate 74%);
The 4th step: 0.3g 5-hydroxyl-7-isopentene oxygen base-3,3 ', the solution of acetic anhydride 20ml of 4 '-trimethoxy flavones (0.73mmol) and 0.12g dehydrated sodium acetate refluxed 48 hours, after the chloroform dilution extraction, residue at room temperature 70ml contains in the 5% methyl alcohol KOH solution and to stir 4 hours, solution is through the ethyl acetate acidizing extraction then, at hexane: crystallization in the acetone (50: 50), get 0.183g pure substance 5,7-dihydroxyl-8-(1, the 1-xylidine)-3,3 ', 4 '-trimethoxy flavones (0.44mmol; Productive rate 60%).
3. two kinds of anti-cancer medicament raw material compounds is characterized in that: compound 5, and 7-dihydroxyl-8-(1, the 1-xylidine)-3,4 '-dimethoxy flavone, its chemical structural formula is:
Figure S2008100256559C00021
4. two kinds of anti-cancer medicament raw material compounds according to claim 3 is characterized in that: compound 5, and 7-dihydroxyl-8-(1, the 1-xylidine)-3,4 '-dimethoxy flavone, synthesis step is as follows:
The first step: 10g (65.7mmol) anisic acid and 2.6ml methylsulfonyl chloride (33.6mmol) room temperature reaction get 6.13g anisic acid acid anhydride (24.5mmol; Productive rate 89%);
Second step: 0.6g 2 ', 4 ', and 6 '-trihydroxy--2-methoxyacetophenone (3mmol) and 2.6g anisic acid acid anhydride (9mmol) room temperature reaction get 0.763g ergotocine (2.43mmol; Productive rate 81%);
The 3rd step: contain 0.30g ergotocine (0.95mmol), 0.2ml the 50ml acetone soln room temperature of prenyl bromide (1.73mmol) and 0.4g Anhydrous potassium carbonate (2.0mmol) refluxed 5 hours, evaporation after filtration, residue is crystallization in methyl alcohol, get 0.33g 5-hydroxyl-7-isopentene oxygen base-3,4 '-dimethoxy flavone (0.86mmol; Productive rate 91%);
The 4th step: 0.3g 5-hydroxyl-7-isopentene oxygen base-3, the 20ml acetic anhydride of 4 '-dimethoxy flavone (0.78mmol) and 0.12g sodium acetate, anhydrous refluxed 48 hours, after the chloroform dilution extraction, residue at room temperature 70ml contains in the 5% methyl alcohol KOH solution and to stir 4 hours, solution gets the pure product 5 of 0.21g, 7-dihydroxyl 8-(1 through the ethyl acetate acidizing extraction, the 1-xylidine)-3,4 '-dimethoxy flavone (0.55mmol; Productive rate 71%).
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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110054605A (en) * 2019-05-31 2019-07-26 北京盛诺基医药科技有限公司 A kind of preparation method of icariine intermediate
CN110092770A (en) * 2019-05-31 2019-08-06 北京盛诺基医药科技有限公司 A kind of preparation method of chromocor compound intermediate

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110054605A (en) * 2019-05-31 2019-07-26 北京盛诺基医药科技有限公司 A kind of preparation method of icariine intermediate
CN110092770A (en) * 2019-05-31 2019-08-06 北京盛诺基医药科技有限公司 A kind of preparation method of chromocor compound intermediate

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