CN103193601A - 2-phenylnaphthalene derivative and application thereof in preparation of anti-tumor medicaments - Google Patents

2-phenylnaphthalene derivative and application thereof in preparation of anti-tumor medicaments Download PDF

Info

Publication number
CN103193601A
CN103193601A CN2013101254937A CN201310125493A CN103193601A CN 103193601 A CN103193601 A CN 103193601A CN 2013101254937 A CN2013101254937 A CN 2013101254937A CN 201310125493 A CN201310125493 A CN 201310125493A CN 103193601 A CN103193601 A CN 103193601A
Authority
CN
China
Prior art keywords
hydrogen
hydroxyl
cancer
methoxyl group
cell
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
CN2013101254937A
Other languages
Chinese (zh)
Inventor
沈月毛
沈燕
陈旺
鲁春华
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Shandong University
Original Assignee
Shandong University
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Shandong University filed Critical Shandong University
Priority to CN2013101254937A priority Critical patent/CN103193601A/en
Publication of CN103193601A publication Critical patent/CN103193601A/en
Pending legal-status Critical Current

Links

Images

Landscapes

  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The invention discloses a 2-phenylnaphthalene derivative. The structural formula is as shown in formula (I), wherein R1 is hydrogen, R2 is hydroxy or hydrogen, R3 is hydroxy or hydrogen, R4 is hydrogen, R5 is hydrogen, R6 is hydrogen, R7 is hydroxy or hydrogen, R8 is hydroxy or hydrogen and R9 is hydrogen. The compound is obtained by utilizing suzuki coupling and boron tribromide demethylation. Tests prove that the 2-phenylnaphthalene derivative disclosed by the invention can significantly inhibit proliferation and migration of tumor cells, has development potential in preparation of medicaments for resisting breast cancer, breast ductal cancer, lung cancer, cervical cancer, prostatic cancer, colon cancer and gastric cancer, and has good application prospects.

Description

2-phenylnaphthalene derivative and the application in the preparation antitumor drug thereof
Technical field
The present invention relates to class phenylnaphthalene derivative and an application thereof, relate in particular to a class 2-phenylnaphthalene derivative and the application in the preparation antitumor drug thereof.
Background technology
Along with generation rate of malignant tumour improves year by year, seek the primary research task that the effective antitumour medicine early becomes world's pharmaceutical industries.The antitumor drug majority of listing is micromolecular compound, and majority derives from natural product and derivative thereof.Natural product is owing to yield poorly, and acquiring way is limited, and the antitumor drug of synthetic a new generation is the research focus of antitumor drug always.
Richard E.M. etc. find that the compound of 2-phenylnaphthalene class can emulative and estradiol beta receptor combination, it has stronger avidity and the selectivity of Geng Gao than natural product canary bird glycosides, the effect that some this compounds of while also has the anti-inflammatory factor, this makes this compounds have effect antitumor and cell death inducing and anti-inflammatory.The phenylnaphthalene analog derivative that a series of hydroxyls of discoveries such as Martin Frotscher replace has the activity that competition suppresses I type and II type 17 β desaturases, thereby break the oestrogen balance in cell and the organism, be useful on oestrogenic hormon according to the potential quality of patience treatment of diseases and control.Therefore the 2-phenylnaphthalene vinyl derivative of this compounds has antifertility action.The compound of discovery 2-phenylnaphthalene classes such as Sang Woon Chung has tyrosine kinase inhibitory activity, can suppress melanic synthetic, thereby have the depigmentation activity.Because of its complex structure, still there is synthetic loaded down with trivial details, the indefinite problem of the high biological action mechanism of cost in the present Research of comprehensive present 2-phenylnaphthalene derivative.So be necessary more these compounds of preparation, further investigation different substituents group, isomorphic map is not developed the specificity small molecules antineoplastic compound at different target spots to the influence of its activity.
Summary of the invention
At the present Research of present 2-phenylnaphthalene derivative, the purpose of this invention is to provide a class 2-phenylnaphthalene derivative and the application in the preparation antitumor drug thereof.
2-phenylnaphthalene derivative of the present invention, its chemical structure of general formula is suc as formula shown in (I):
Wherein: R 1=hydrogen, hydroxyl, amino or methoxyl group; R 2=hydrogen, hydroxyl, amino, carboxyl or methoxyl group; R 3=hydrogen, hydroxyl, amino, carboxyl or methoxyl group; R 4=hydrogen, hydroxyl or methoxyl group; R 5=hydrogen, hydroxyl or methoxyl group; R 6=hydrogen, hydroxyl or methoxyl group; R 7=hydrogen, hydroxyl or methoxyl group; R 8=hydrogen, hydroxyl or methoxyl group; R 9=hydrogen, hydroxyl or methoxyl group.
In the structural formula of above-mentioned 2-phenylnaphthalene derivative preferred embodiment be: R 1Be hydrogen, R 2Be hydroxyl or hydrogen, R 3Be hydroxyl or hydrogen, R 4Be hydroxyl or hydrogen, R 5Be hydroxyl or hydrogen, R 6Be hydrogen, R 7Be hydroxyl or hydrogen, R 8Be hydroxyl or hydrogen, R 9Be hydrogen.
Further preferred embodiment is in the structural formula of above-mentioned 2-phenylnaphthalene derivative: R 1Be hydrogen, R 2Be hydroxyl or hydrogen, R 3Be hydroxyl or hydrogen, R 4Be hydrogen, R 5Be hydrogen, R 6Be hydrogen, R 7Be hydroxyl or hydrogen, R 8Be hydroxyl or hydrogen, R 9Be hydrogen.
Most preferred compound is 2-(3' in the above-mentioned 2-phenylnaphthalene derivative, the 4'-dihydroxyl) phenyl-6-naphthols (HL33).
Above-mentioned 2-phenylnaphthalene analog derivative is realized by following synthetic route, the following reaction formula of concrete steps:
Figure BDA00003038738500021
Wherein: compound 1 in the following formula, 2 and 4 R 1'～R 4' be hydroxyl, methoxyl group or hydrogen, compound 3 and 4 R 1' '～R 5' ' be methoxyl group, amino, nitro, methyl, trifluoromethyl, ester group or hydrogen, the R of other compounds 1～R 9Be hydroxyl, hydrogen, amino or methoxyl group.
A in the above-mentioned synthesis step, b, c reaction are respectively:
A: utilize the corresponding bromonaphthalene that replaces and two valeryl two boron reaction to introduce the boron ester, solvent is dioxane, and alkali is Potassium ethanoate, and catalyzer is the two diphenylphosphine ferrocene of 1,1'-, temperature of reaction: 30 ℃～100 ℃, and the reaction times: 2～24 hours.
B: do the suzuki coupling with the corresponding naphthalene boron ester derivative that replaces and corresponding bromobenzene derivative, solvent is dioxane, and alkali is Potassium monofluoride, catalyzer is 1, the two diphenylphosphine ferrocene of 1'-, temperature of reaction: 30 ℃～100 ℃, the reaction times: 2～24 hours.
C: with corresponding acid, basic hydrolysis and oxidation, reduction and boron tribromide demethylation, carry out functional group's conversion.Boron tribromide demethylation, solvent are methylene dichloride, temperature of reaction :-10 ℃～-80 ℃, and the reaction times: 10～24 hours.
In the following formula 2 synthetic: with compound 1(1 mole) and pair valeryl two boron (1～3 mole) be dissolved in dioxane; add acetic acid potassium (2～4 moles); temperature: 30 ℃～100 ℃; magnetic agitation; add catalyzer 1 under the nitrogen protection, two 2～24 hours (2%～5% mole) reaction times of diphenylphosphine ferrocene of 1'-.With methylene dichloride or ethyl acetate extraction, extracting solution through the washing, drying, concentrating under reduced pressure, the residue purification by silica gel column chromatography, sherwood oil: the acetone wash-out obtains compound 2.
In the following formula 4 synthetic: with compound 2(1 mole) and compound 3(1～2 mole) be dissolved in dioxane; add Potassium monofluoride (2～4 moles); temperature: 30 ℃～100 ℃; magnetic agitation; add catalyzer 1 under the nitrogen protection, two 2～24 hours (2%～5% mole) reaction times of diphenylphosphine ferrocene of 1'-.With methylene dichloride or ethyl acetate extraction, extracting solution through the washing, drying, concentrating under reduced pressure, the residue purification by silica gel column chromatography, sherwood oil: eluent ethyl acetate obtains compound 4.
In the following formula 5 synthetic: compound 4 (1 mole) is dissolved in the methylene dichloride, and temperature is down to-10 ℃～-78 ℃, adds boron tribromide (1.5 moles), rise again, stirred ethyl acetate extraction 24 hours, the extract purification by silica gel column chromatography, sherwood oil: the acetone wash-out obtains compound 5.
Above-mentioned preparation feedback route is referring to embodiment 1.
Wherein 1,3 and two valeryl two boron all available from Sigma-Aldrich.
Wherein 1 or 3 available from Sigma-Aldrich or buy raw material through bromo and other transformations.
The application of 2-phenylnaphthalene analog derivative of the present invention in the preparation antitumor drug.
Wherein: above-mentioned antitumor drug is mainly and suppresses the medicine that tumour cell shifts.Described tumour refers to mammary cancer, breast ductal cancer, lung cancer, cervical cancer, prostate cancer, colorectal carcinoma or cancer of the stomach; The antitumor drug of preparation is the medicine of malignant tumours such as anti-breast cancer, breast ductal cancer, lung cancer, cervical cancer, prostate cancer, colorectal carcinoma, cancer of the stomach, the preferably medicine of anti-breast cancer.
Utilize ordinary method, 2-phenylnaphthalene analog derivative of the present invention is cooperated with medically acceptable vehicle or additive, namely can be made into various antitumor drug formulations, formulation optimizing injection, capsule or the tablet of described medicine.
2-phenylnaphthalene derivant structure of the present invention is simple, and is synthetic convenient, with low cost, is suitable for large-scale production.
Utilization is measured restraining effect screening, simulated animal experiment and the Multitest of kinds of tumor cells and found: 2-phenylnaphthalene derivative of the present invention shows higher cytotoxic activity, can significantly suppress tumor cell proliferation and migration, have the potential quality that is developed as antitumor drug.
2-phenylnaphthalene derivative of the present invention and antitumor action thereof are open first in this area, and it is for the exploitation high-efficiency low-toxicity and to have a new type antineoplastic medicine of independent intellectual property right significant.
Description of drawings
Fig. 1: the structure of 2-phenylnaphthalene derivative and to MDA-MB-231, (data represent 2-phenylnaphthalene derivative to MDA-MB-231, the IC of A549 and HeLa cell in the bracket for A549 and the effect of HeLa cell inhibiting 50, "-" represents IC 50Greater than 20 μ M).
Fig. 2: 2-phenylnaphthalene derivative 1 (HL33) is to the restraining effect of mammary cancer MDA-MB-231 cell migration.
Fig. 3: 2-phenylnaphthalene derivative 1 (HL33), the interior restraining effect to mammary cancer MDA-MB-231 tumour of 5 (HL55) and positive control Etoposide (VP16) body.
Fig. 4: 2-phenylnaphthalene derivative 1 (HL33), 5 (HL55) and positive control Etoposide (VP16) are to the influence of nude mice body weight.
Embodiment
The present invention will be further described below in conjunction with embodiment, and the numbering of wherein said compound is as the criterion to relate to statement in the summary of the invention, and described per-cent number does not specify is mass percent, and institute's raw material that uses does not have being of special instruction commercially available.
Embodiment 1:
Preparation compound 2-(6-methoxynaphthalen-2-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(structural formula 2, wherein R 2'=OCH 3, R 1'=R 4'=H)
2-methoxyl group-6-naphthols (1 mole) and two valeryl two boron (1.2 moles) are put into dioxane (10ml), add Potassium ethanoate (3 moles), add the Pd-DPPF(2% mole under the nitrogen protection), reflux 24 hours, ethyl acetate extraction,
The extract purification by silica gel column chromatography, sherwood oil: acetone=10:1 wash-out.
1H?NMR(600MHz,CDCl 3,δ):8.29(s,1H),7.81(d,J=12.0Hz,1H),7.78(d,J=12.0Hz,1H),7.73(d,J=12.0Hz,1H),7.14(d,J=12.0Hz,1H),7.12(s,1H),3.93(s,3H),1.39(s,12H); 13C?NMR(125MHz,CDCl 3,r.t.):δ158.5,136.41,136.0,131.1,130.3,128.4,125.9,118.7,105.6,83.3,55.3,24.9;MS(ESI):m/z285.2[M+H] +.
Preparation compound 2-(3,4-dimethoxyphenyl)-6-methoxynaphthalene-(structural formula 4, wherein R 2'=R 2' '=R 3' '=OCH 3, R 1'=R 4'=R 1' '=R 4' '=R 5' '=H)
With 3,4-dimethoxy bromobenzene (1.5 moles) and 2-(6-methoxynaphthalen-2-yl)-4,4; 5; 5-tetramethyl-1,3,2-dioxaborolane(1 mole) puts into dioxane (10ml); add Potassium monofluoride (3 moles); add the Pd-DPPF(2% mole under the nitrogen protection), reflux 24 hours, ethyl acetate extraction; the extract purification by silica gel column chromatography, sherwood oil: acetone=10:1 wash-out.
1H?NMR(600MHz,CDCl 3,δ):7.94(s,1H),7.81(d,J=6.0Hz,1H),7.80(d,J=12.0Hz,1H),7.71(d,J=12.0Hz,1H),7.27(s,1H),7.24(s,1H),7.20(d,J=12.0Hz,1H),7.18(d,J=12.0Hz,1H),7.00(d,J=6.0Hz,1H),4.01(s,3H),3.96(s,6H); 13C?NMR(125MHz,CDCl 3,δ):157.6,149.2,148.5,136.2,134.3,133.5,129.6,129.2,127.2,126.0,125.0,119.5,119.2,111.6,110.5,105.6,56.0,56.0,55.3;MS(ESI):m/z295.4[M+H] +.
Preparation compound 4-(6-hydroxynaphthalen-2-yl) benzene-1,2-diol-(structural formula 5, wherein R 2'=R 2' '=R 3' '=OH, R 1'=R 4'=R 1' '=R 4' '=R 5' '=H)
With 2-(3,4-dimethoxyphenyl)-6-methoxynaphthalene (1 mole) is dissolved in the methylene dichloride, temperature is down to-45 ° of C, add boron tribromide (4.5 moles), rise again, stirred ethyl acetate extraction 24 hours, the extract purification by silica gel column chromatography, sherwood oil: acetone=5:1 wash-out obtains this compound.
1H?NMR(600MHz,Acetone-d 6,δ):7.95(s,1H),7.83(d,J=6.0Hz,1H),7.73(d,J=6.0Hz,1H),7.66(dd,J=12.0Hz,J=6.0Hz,1H),7.26(d,J=6.0Hz,1H),7.21(d,J=6.0Hz,1H),7.16(dd,J=12.0Hz,J=6.0Hz,1H),7.12(dd,J=12.0Hz,J=6.0Hz,1H),6.95(d,J=6.0Hz,1H); 13CNMR(125MHz,Acetone-d 6,δ):155.1,145.4,144.6,135.6,133.7,133.2,129.6,128.8,126.6,125.5,124.4,118.6,118.4,115.7,113.9,108.7;MS(ESI):m/z253.3[M+H] +.
Embodiment 2:
Preparation compound 2-methoxy-5-(6-methoxynaphthalen-2-yl) benzaldehyde(structural formula 5, wherein R 2'=CHO, R 2' '=R 3' '=OCH 3, R 1'=R 4'=R 1' '=R 4' '=R 5' '=H)
With 2-methoxyl group-5-bromobenzaldehyde (1.5 moles) and 2-(6-methoxynaphthalen-2-yl)-4; 4,5,5-tetramethyl-1; 3; the 2-dioxaborolane(1 mole) puts into dioxane (10ml), add Potassium monofluoride (3 moles), add the Pd-DPPF(2% mole under the nitrogen protection); reflux 24 hours; ethyl acetate extraction, extract purification by silica gel column chromatography, sherwood oil: acetone=10:1 wash-out.
1H?NMR(600MHz,CDCl 3,δ):10.55(s,1H),8.19(d,J=6.0Hz,1H),7.96(s,1H),7.91(dd,J=12.0Hz,J=6.0Hz,1H),7.81(d,J=6.0Hz,1H),7.79(d,J=6.0Hz,1H),7.69(dd,J=12.0Hz,J=6.0Hz,1H),7.18(dd,J=12.0Hz,J=6.0Hz,1H),7.16(d,J=6.0Hz,1H),7.11(d,J=6.0Hz,1H),4,04(s,3H),3.94(s,3H); 13C?NMR(100MHz,CDCl 3,δ):189.9,161.2,157.8,134.6,134.3,133.8,133.7,129.6,129.2,127.4,126.8,125.5,125.1,125.0,119.3,112.2,105.8,55.9,55.4;MS(ESI):m/z293.4[M+H] +.
Preparation compound 2-hydroxy-5-(6-hydroxynaphthalen-2-yl) benzaldehyde(structural formula 5, wherein R 2'=CHO, R 2' '=R 3' '=OH, R 1'=R 4'=R 1' '=R 4' '=R 5' '=H)
2-methoxy-5-(6-methoxynaphthalen-2-yl) benzaldehyde (1 mole) is dissolved in the methylene dichloride, temperature is down to-45 ° of C, add boron tribromide (3 moles), rise again, stirred 24 hours, ethyl acetate extraction, the extract purification by silica gel column chromatography, sherwood oil: acetone=5:1 wash-out obtains this compound.
1H?NMR(600MHz,Acetone-d 6,δ):10.98(s,1H),10.18(s,1H),8.73(s,1H),8.20(d,J=6.0Hz,1H),8.10(s,1H),8.05(dd,J=12.0Hz,J=6.0Hz,1H),7.88(d,J=12.0Hz,1H),7.81(d,J=6.0Hz,1H),7.77(d,J=6.0Hz,1H),7.25(d,J=6.0Hz,1H),7.21(dd,J=12.0Hz,J=6.0Hz,1H),7.13(d,J=6.0Hz,1H); 13C?NMR(100MHz,Acetone-d 6,δ):197.4,160.5,155.6,135.3,134.2,133.7,133.1,131.7,129.8,128.8,127.0,125.0,124.8,121.3,118.9,117.7,108.8;MS(ESI):m/z265.4[M+H] +.
Embodiment 3:
Preparation compound 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) the naphthalene-2-ol(structural formula 2, wherein R 2'=OH, R 1'=R 4'=H)
2-hydroxyl-6-naphthols (1 mole) and two valeryl two boron (1.2 moles) are put into dioxane (10ml); add Potassium ethanoate (3 moles); add the Pd-DPPF(2% mole under the nitrogen protection); reflux 24 hours; ethyl acetate extraction; the extract purification by silica gel column chromatography, sherwood oil: acetone=10:1 wash-out.
1H?NMR(600MHz,Acetone-d 6,δ):8.31(s,1H),7.95(d,J=12.0Hz,1H),7.86(d,J=12.0Hz,1H),7.80(d,J=12.0Hz,1H),7.21(d,J=12.0Hz,1H),7.16(s,1H),1.40(s,12H); 13C?NMR(125MHz,Acetone-d 6,δ):159.2,137.3,136.2,131.7,130.68,128.9,126.2,119.1,106.0,83.7,24.7;MS(ESI):m/z271.2[M+H] +.
Preparation compound 6-(4-hydroxy-3-(hydroxymethyl) phenyl) naphthalen-2-ol(structural formula 5, wherein R 2'=CH 2OH, R 2' '=R 3' '=OH, R 1'=R 4'=R 1' '=R 4' '=R 5' '=H)
With 4-bromo-2-salicylic alcohol (1.5 moles) and 6-(4; 4,5,5-tetramethyl-1; 3; 2-dioxaborolan-2-yl) naphthalene-2-ol(1 mole) puts into dioxane (10ml), add Potassium monofluoride (3 moles), add the Pd-DPPF(2% mole under the nitrogen protection); reflux 24 hours; ethyl acetate extraction, extract purification by silica gel column chromatography, sherwood oil: acetone=10:1 wash-out.
1H?NMR(600MHz,Acetone-d 6,δ):9.72(s,1H),9.50(s,1H),7.95(s,1H),7.81(d,J=6.0Hz,1H),δ7.73(d,J=12.0Hz,1H),δ7.70(s,1H),δ7.66(d,J=12.0Hz,1H),7.46(d,J=6.0Hz,1H),7.11(s,1H),7.09(d,J=12.0Hz,1H),6.88(d,J=6.0Hz,1H),5.07(s,1H),4.56(s,1H); 13CNMR(125MHz,Acetone-d 6,δ):159.2,137.3,136.2,131.7,130.7128.9,126.2,119.1,106.0,83.7,24.7;MS(ESI):m/z267.3[M+H] +.
Embodiment 4:2-phenylnaphthalene derivative is to the antitumor action of mammary cancer, lung cancer and cervical cancer
(referring to document V.Vichai and K.Kirtikara, Nat Protoc2006,1,1112-1116.)
Test philosophy:
Sulfo group rhodamine B (SRB, Sulforhodamine B) is a peach amino first xanthene compounds, contain 2 sulfo groups, it can the cell after trichoroacetic acid(TCA) is fixing under sour environment in basic aminoacids on the macromole be combined by electrostatic attraction, the amount that how much reflects protein within the specific limits linearly of combined dyestuff, and therefore how much being directly proportional with the number of cell of protein, can infer cell quantity according to staining power.
Test material:
(1) human breast cancer cell MDA-MB-231, human lung cancer cell A549 and human cervical carcinoma cell HeLa.
(2) SRB(sulfo group rhodamine B), the TCA(trichoroacetic acid(TCA)), Tris, DMSO(dimethyl sulfoxide (DMSO)) and 96 orifice plates.
(3) DMEM substratum: Gibco BRL company product;
Foetal calf serum (FBS): Tianjin tbd bio tech ltd;
(4) sample preparation: sample faces with before being dissolved in DMSO and is made into 100mM, and-20 ° of C preserve, and redilution becomes respective concentration during application.
Testing method:
Get the mammary cancer MDA-MB-231 cell that is in logarithmic phase, small cell lung cancer A549 cell and cervical cancer HeLa cell are inoculated in 96 orifice plates with the density of 3000-8000cells/well, and dosing behind the 12h cell attachment continues to cultivate 72h.It is fixing that every hole, cell cultures end back adds 100 μ L10% Tricholroacetic Acids (TCA), and room temperature leaves standstill 5min and goes to 4 ℃ of placement 1h.Cell fixation finishes, and abandons stationary liquid, washes 5 times with deionized water, dries dry air.Every hole adds 100 μ L4mg/mL SRB liquid, places 10min in room temperature, does not wash 5 times dry air with 1% acetate solution with protein bound SRB.Dissolve with 150 μ L10mM non-buffering Tris alkali lye (pH10.5) with protein bound SRB.Measure the OD value with microplate reader 570nm wavelength place at last.Calculate IC according to the OD value 50With IC 50The value size is judged the anti-tumor activity of compound.
IC 50The expression sample is 50% o'clock concentration to the inhibiting rate of tumour cell.
Inhibiting rate to tumour cell is calculated as follows:
Test result is seen Fig. 1:
As seen from Figure 1,24 compounds are arranged to the IC of MDA-MB-231 cell among the compound 1-23a 50Less than 20 μ M, wherein compound 1,3,5,7,9,10,11,13,19,21,23 couples of MDA-MB-231, the IC of A549 and HeLa cell 50Less than 5 μ M, these 11 compounds show than powerful antitumor activity.
Embodiment 5:2-(3', 4'-dihydroxyl) phenyl-6-naphthols (HL33) is to mammary cancer, breast ductal cancer, lung cancer, cervical cancer, prostate cancer, cancer of the stomach, the antitumor action of colorectal carcinoma
Test philosophy: with embodiment 1
Test material:
(1) human breast cancer cell MDA-MB-231, human breast cancer cell MCF-7, human lung cancer cell A549, human cervical carcinoma cell HeLa, human prostata cancer PC3, gastric carcinoma cells BGC-823, people's mammary gland duct carcinoma cell MDA-MB-435 and human colon cancer cell SW620; The normal umbilical vein epithelial cell of people HUVEC cell; Purchase in ATCC.
(2) DMEM substratum: Gibco BRL company product;
Foetal calf serum (FBS): Tianjin tbd bio tech ltd and Gibco BRL company product.
Testing method: with embodiment 1, test result sees Table 1.
Table 1. compound H L33 is to the restraining effect of 9 cell strains
Figure BDA00003038738500071
As can be seen from Table 1, compound H L33 is to the average IC of 8 tumor cell lines 50Be 8.64 μ M, to the IC of HeLa, MDA-MB-231, SW620 and MDA-MB-435 cell 50All less than 5 μ M, but the normal umbilical vein epithelial cell of the people of HL33 HUVEC IC 50Up to 40.67 μ M, cytotoxicity is little.The result shows that compound H L33 comprises mammary gland to multiple types of organization, and the tumour cell in reproduction and respiratory system source has significant inhibitory effect, but little to the umbilical vein epithelial cell toxicity in people's healthy tissues source, has to become the property of medicine preferably.
Embodiment 6:2-(3', the 4'-dihydroxyl) phenyl-6-naphthols (HL33) inhibition tumor cell migration effect
(referring to document R.Preet, et.al.International journal of cancer.2012,130,1660-1670.)
Test philosophy:
Cell wound healing experiment is widely used in estimating cell proliferation and transfer ability, and the tumor cell proliferation ability is strong, and travelling speed is fast, can move the damage field that covering is caused by the rifle head, and the cell injury reparation generally needs several hours to several days.The influence of can detection of drugs tumour cell being shifted by this experiment.
Test material:
(1) human breast carcinoma MDA-MB-231 cell.
(2) 6 orifice plates: Corning company produces; Fluorescent microscope: Olympus company product.
Testing method:
Get be in logarithmic phase the MDA-MB-231 cell inoculation in 6 orifice plates, cell concn is 2 * 10 5Cells/mL, when treating that cell grows to the total area and accounts for container bottom 90%, at the standardized road of monolayer scar, the cell of scuffing is washed off with PBS with 30 ° of 200 aseptic μ L rifle head tilts.Adding the substratum that contains different concns HL33 continues to cultivate.12h, 24h and 36h, the microscope observation of taking pictures.The results are shown in Figure 2.
As seen from Figure 2 behind the 36h not the cell migration handled of dosing cover damage field, the cell migration speed of handling through compound H L33 is suppressed, and is dose-dependently.2.5 μ M and 5 μ M HL33 can significantly suppress the MDA-MB-231 cell migration, 10 μ M and 15 μ M HL33 suppress the migration of MDA-MB-231 cell fully.
MDA-MB-231 belongs to high transitivity malignant galactophore cancerous cell line, and it is significant to treatment mammary cancer that HL33 suppresses the MDA-MB-231 tumor cell migration.
Embodiment 7:2-(3', the 4'-dihydroxyl) phenyl-6-naphthols (HL33) and 2-(3'-methylol, the 4'-hydroxyl) phenyl-6-naphthols (HL55) anti-tumor in vivo effect
(experimental technique is seen: chief editors such as Sun Jingfang, " animal experiment method ", and Beijing: the People's Health Publisher, 2001 editions, 152-192)
Test material:
(1) human breast carcinoma MDA-MB-231 cell.
(2) rely on pool to do (VP16) and DMSO:Sigma-Aldrich company product.
(3) nude mice: Jinan En Weisen economy and trade company limited produces.
(4) sample preparation: medicine is dissolved to 500mg/mL with DMSO, earlier with 10 times of alcohol dilutions, is diluted to 5mg/mL with the physiological saline that contains 20% poly(oxyethylene glycol) 400 again during administration.
Testing method:
The MDA-MB-231 cell in vegetative period of taking the logarithm, nude mice oxter injection knurl liquid treats that tumour grows to 100mm 3-300mm 3Back random packet is respectively control group, HL33 group, HL55 group and positive drug VP16 group, administration every other day, tail vein injection administration 100 μ L/, administration 7 times.The mouse dislocation is put to death after 15 days, gets tumour, weighs.
The results are shown in Figure 3 and Fig. 4.
Calculate by following formula and respectively to organize medicine to the inhibiting rate of tumour:
Found that the control group exemplary embodiment lock is 1.809g, HL33 organizes 0.8184g, and HL55 organizes 1.030g, and positive control VP16 organizes 0.5608g, compares the P value with control group all less than 0.001.Administration group inhibiting rate is respectively 54.76%, 43.06%, 69.01%(Fig. 2).The administration of VP16 group is nude mouse reopening beginning reduction after 3 days, and 15 days body weight of administration are reduced to 20.1g from 24.0g, and the body weight reduced rate reaches 16.25%.But nude mice body weight no change (Fig. 3) almost during HL33 and the HL55 administration, known positive drug VP16 can cause secondary tumour, and strong side effect is arranged, and can infer that from the nude mice body weight change HL33 and HL55 are littler than VP16 toxic side effect, have the good one-tenth property of medicine.
Embodiment 8: the injection for the treatment of mammary cancer
Table 2. treatment mammary cancer injection prescription
Preparation method: with the dilution of polyoxyethylene glycol-400 usefulness water for injection, add the HL33 stirring and dissolving.Add sodium-chlor and phenylcarbinol, make whole dissolvings, filter, embedding, 100 ℃ of sterilization 30min, active component content is 10mg/mL.
Embodiment 9: the tablet for the treatment of mammary cancer
Table 3. treatment mammary cancer tablet formulation
Figure BDA00003038738500092
The preparation method: HL33 is mixed with lactose and W-Gum, after water is evenly wetting, sieve, make particle, dry then, after sieve, add Magnesium Stearate, even back compressing tablet, every heavy 240mg, active component content is 5mg.

Claims (9)

1. a class 2-phenylnaphthalene derivative, it is characterized in that: the structural formula of described compound is suc as formula shown in (I):
Figure FDA00003038738400011
Wherein: R 1=hydrogen, hydroxyl, amino or methoxyl group; R 2=hydrogen, hydroxyl, amino, carboxyl or methoxyl group; R 3=hydrogen, hydroxyl, amino, carboxyl or methoxyl group; R 4=hydrogen, hydroxyl or methoxyl group; R 5=hydrogen, hydroxyl or methoxyl group; R 6=hydrogen, hydroxyl or methoxyl group; R 7=hydrogen, hydroxyl or methoxyl group; R 8=hydrogen, hydroxyl or methoxyl group; R 9=hydrogen, hydroxyl or methoxyl group.
2. 2-phenylnaphthalene derivative as claimed in claim 1 is characterized in that: R in the structural formula of described compound 1Be hydrogen, R 2Be hydroxyl or hydrogen, R 3Be hydroxyl or hydrogen, R 4Be hydroxyl or hydrogen, R 5Be hydroxyl or hydrogen, R 6Be hydrogen, R 7Be hydroxyl or hydrogen, R 8Be hydroxyl or hydrogen, R 9Be hydrogen.
3. 2-phenylnaphthalene derivative as claimed in claim 2 is characterized in that: R in the structural formula of described compound 1Be hydrogen, R 2Be hydroxyl or hydrogen, R 3Be hydroxyl or hydrogen, R 4Be hydrogen, R 5Be hydrogen, R 6Be hydrogen, R 7Be hydroxyl or hydrogen, R 8Be hydroxyl or hydrogen, R 9Be hydrogen.
4. 2-phenylnaphthalene derivative as claimed in claim 3, it is characterized in that: described compound is 2-(3', the 4'-dihydroxyl) phenyl-6-naphthols.
5. claim 1,2, the application of 3 or 4 described 2-phenylnaphthalene derivatives in the preparation antitumor drug.
6. application as claimed in claim 5 is characterized in that: described antitumor drug is for suppressing the medicine that tumour cell shifts.
7. application as claimed in claim 5 is characterized in that: described tumour is mammary cancer, breast ductal cancer, lung cancer, cervical cancer, prostate cancer, colorectal carcinoma or cancer of the stomach.
8. application as claimed in claim 7 is characterized in that: described tumour is mammary cancer.
9. application as claimed in claim 5 is characterized in that: the formulation of described medicine is selected injection or tablet.
CN2013101254937A 2013-04-11 2013-04-11 2-phenylnaphthalene derivative and application thereof in preparation of anti-tumor medicaments Pending CN103193601A (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN2013101254937A CN103193601A (en) 2013-04-11 2013-04-11 2-phenylnaphthalene derivative and application thereof in preparation of anti-tumor medicaments

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN2013101254937A CN103193601A (en) 2013-04-11 2013-04-11 2-phenylnaphthalene derivative and application thereof in preparation of anti-tumor medicaments

Publications (1)

Publication Number Publication Date
CN103193601A true CN103193601A (en) 2013-07-10

Family

ID=48716438

Family Applications (1)

Application Number Title Priority Date Filing Date
CN2013101254937A Pending CN103193601A (en) 2013-04-11 2013-04-11 2-phenylnaphthalene derivative and application thereof in preparation of anti-tumor medicaments

Country Status (1)

Country Link
CN (1) CN103193601A (en)

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111792999A (en) * 2020-06-30 2020-10-20 五邑大学 Dinaphthylamine compounds, and preparation method and application thereof
CN112759741A (en) * 2020-12-18 2021-05-07 上海瀚岱化学有限公司 High-stability water-based epoxy resin and preparation method thereof
CN115260052A (en) * 2022-08-02 2022-11-01 山东大学 2-phenylnaphthalene derivative and preparation method and application thereof
CN115475158A (en) * 2022-09-27 2022-12-16 广西科技大学 Application of naphthacenitrile derivative in preparation of antitumor pharmaceutical composition
CN115957204A (en) * 2023-02-23 2023-04-14 山东大学 Application of diphenyl sulfide compounds in preparation of antitumor drugs

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1738788A (en) * 2001-12-13 2006-02-22 惠氏公司 Substituted phenyl naphthalenes as estrogenic agents
CN101094664A (en) * 2004-12-31 2007-12-26 安万特药物公司 Use of certain phenyl-naphthyl compounds that do not have significant affinity to er alpha or er beta for protection of neurons and oligodendrocytes in the treatment of multiple sclerosis
US20100204234A1 (en) * 2007-03-27 2010-08-12 Rolf Hartmann 17Beta-Hydroxysteroid Dehydrogenase Type 1 Inhibitors for the Treatment of Hormone-Related Diseases
KR20120099540A (en) * 2011-01-18 2012-09-11 동아대학교 산학협력단 Pharmaceutical composition for treating prostate cancer comprising resveratrol analogue hs-1793 or pharmaceutically acceptable salts thereof

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1738788A (en) * 2001-12-13 2006-02-22 惠氏公司 Substituted phenyl naphthalenes as estrogenic agents
CN101094664A (en) * 2004-12-31 2007-12-26 安万特药物公司 Use of certain phenyl-naphthyl compounds that do not have significant affinity to er alpha or er beta for protection of neurons and oligodendrocytes in the treatment of multiple sclerosis
US20100204234A1 (en) * 2007-03-27 2010-08-12 Rolf Hartmann 17Beta-Hydroxysteroid Dehydrogenase Type 1 Inhibitors for the Treatment of Hormone-Related Diseases
KR20120099540A (en) * 2011-01-18 2012-09-11 동아대학교 산학협력단 Pharmaceutical composition for treating prostate cancer comprising resveratrol analogue hs-1793 or pharmaceutically acceptable salts thereof

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
CE´DRIC MAURIN ET AL.: "Facile access to methoxylated 2-phenylnaphthalenes and epoxydibenzocyclooctenes", 《TETRAHEDRON》 *
HEE JUNG UM ET AL.: "Differential effects of resveratrol and novel resveratrol derivative,HS-1793，on endoplasmic reticulum stress-mediated apoptosis and Akt inactivation", 《INTERNATIONAL JOURNAL OF ONCOLOGY》 *
SEUNG HUN JEONG ET AL.: ""An Analogue of Resveratrol HS-1793 Exhibits Anticancer Activity Against MCF-7 Cells Via Inhibition of Mitochondrial Biogenesis Gene Expression", 《 MOL. CELLS》 *
SUHEE SONG ET AL.: "Syntheses of hydroxy substituted 2-phenyl-naphthalenes as inhibitors of tyrosinase", 《 BIOORG. MED. CHEM. LETT.》 *

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111792999A (en) * 2020-06-30 2020-10-20 五邑大学 Dinaphthylamine compounds, and preparation method and application thereof
CN111792999B (en) * 2020-06-30 2022-08-09 五邑大学 Dinaphthylamine compounds, and preparation method and application thereof
CN112759741A (en) * 2020-12-18 2021-05-07 上海瀚岱化学有限公司 High-stability water-based epoxy resin and preparation method thereof
CN115260052A (en) * 2022-08-02 2022-11-01 山东大学 2-phenylnaphthalene derivative and preparation method and application thereof
CN115260052B (en) * 2022-08-02 2023-07-25 山东大学 2-phenyl naphthalene derivative and preparation method and application thereof
CN115475158A (en) * 2022-09-27 2022-12-16 广西科技大学 Application of naphthacenitrile derivative in preparation of antitumor pharmaceutical composition
CN115957204A (en) * 2023-02-23 2023-04-14 山东大学 Application of diphenyl sulfide compounds in preparation of antitumor drugs
CN115957204B (en) * 2023-02-23 2024-03-19 山东大学 Application of diphenyl sulfide compound in preparation of antitumor drugs

Similar Documents

Publication Publication Date Title
Wang et al. The conversion of oridonin to spirolactone-type or enmein-type diterpenoid: Synthesis and biological evaluation of ent-6, 7-seco-oridonin derivatives as novel potential anticancer agents
CN103193601A (en) 2-phenylnaphthalene derivative and application thereof in preparation of anti-tumor medicaments
Vue et al. Silibinin derivatives as anti-prostate cancer agents: Synthesis and cell-based evaluations
CN113730391B (en) Application of myrtle ketone compound in preparation of medicine for resisting novel coronavirus SARS-CoV-2
JP5547167B2 (en) Composition for the treatment of cancer cells and method of synthesis thereof
Li et al. A new coumestan with immunosuppressive activities from Flemingia philippinensis
CN101260121A (en) Complex compound of heteroaromatic thiosemicarbazone and transition metal, and application thereof in preparing antineoplastic medicine
He et al. Synthesis and biological evaluation of novel derivatives of gambogic acid as anti-hepatocellular carcinoma agents
Farooq et al. Click chemistry inspired synthesis and bioevaluation of novel triazolyl derivatives of osthol as potent cytotoxic agents
CN107556361A (en) Driffractive ring lupinane derivative and its anticancer usage
EP2460812B1 (en) Sterol derivatives and their synthesis and use
CN104523664A (en) Curcumin antineoplastic drug and application thereof
Marchesi et al. Molecular hybridization as a strategy for developing artemisinin-derived anticancer candidates
CN107793410B (en) Derivative of benzoselenadiazole and application thereof
CN110437285A (en) Qinghaosu ruthenium metal complex and preparation method thereof and medical usage
Kang et al. Discovery of a novel water-soluble, rapid-release triptolide prodrug with improved drug-like properties and high efficacy in human acute myeloid leukemia
Liu et al. Novel octapeptide-DTX prodrugs targeting MMP-7 as effective agents for the treatment of colorectal cancer with lower systemic toxicity
CN104744518B (en) Ruthenium complex and its preparation method and application
CN113527391B (en) Catalpol derivative and preparation method and application thereof
CN106167461B (en) Water-soluble isatin derivative and preparation method and application thereof
CN100434419C (en) Compound of monocyclic polysubstitution saturated cyclohexanones, prepartion method and usage
US7842721B2 (en) Composition for treating cancer cells and synthetic method for the same
CN109734561B (en) Farnesyl phenol compound, pharmaceutical composition and application thereof
CN100347163C (en) Cyclohexenone analog bicyclo (condensed ring) compound and its preparation method and uses
CN106946974B (en) Ursolic amide derivative containing pyrazole heterocycle and synthesis and application thereof

Legal Events

Date Code Title Description
C06 Publication
PB01 Publication
C10 Entry into substantive examination
SE01 Entry into force of request for substantive examination
C05 Deemed withdrawal (patent law before 1993)
WD01 Invention patent application deemed withdrawn after publication

Application publication date: 20130710