CN101274925A - Naphthofurans ortho-quinone compound, preparation and use thereof - Google Patents
Naphthofurans ortho-quinone compound, preparation and use thereof Download PDFInfo
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- CN101274925A CN101274925A CNA2007100386685A CN200710038668A CN101274925A CN 101274925 A CN101274925 A CN 101274925A CN A2007100386685 A CNA2007100386685 A CN A2007100386685A CN 200710038668 A CN200710038668 A CN 200710038668A CN 101274925 A CN101274925 A CN 101274925A
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Abstract
The invention provides a naphthofuran o-quinone compound, the structure of which is as formula A or A1 on the right. The compound, proved by tests, can effectively restrain the activity of Cdc25 of protein tyrosine phosphatase, and can be used for treating diseases mediated by Cdc25, in particular tumor. The invention also provides a preparation method of the inhibitor and the application in preparing drugs used for preventing and treating tumor.
Description
Technical field
The present invention relates to a class and have aphthofurans o-quinone compound of anti-tumor activity and preparation method thereof, also relate to this compound and prevent and/or treat application in the tumour medicine in preparation.
Background technology
Cancer greatly threatens human beings'health, the World Health Organization delivers in " report of world's cancer " on April 3rd, 2003 and points out that the following several years will be the global cancer time occurred frequently, not take urgent measure as various countries, cancer morbidity will increase by 50%, will increase 1,500 ten thousand cases newly every year to the year two thousand twenty.Dieing ten thousand deaths to die in the whole world 5800 in 2005 has 760 to die ten thousand deaths in cancer in the population, accounts for 13%.Wherein lung cancer, cancer of the stomach, liver cancer, colorectal carcinoma and mastocarcinoma mortality ratio are the highest.The World Health Organization announces " report of world's cancer " first in nineteen ninety-five, call upon States cancer is monitored, prevented and treats.Yet because environmental pollution, unsound mode of life, shortage motion and the aging of population are serious, cancer still becomes the second largest cause of the death of developed country after cardiovascular disorder.In recent years, developing rapidly of genomics, molecule and cytobiology allowed people that tumor pathogenesis has been had more deep understanding, and some new oncotherapy strategies also are provided.But up to the present, chemotherapy of tumors is still an important means for the treatment of malignant tumor.
The essential characteristic of tumour is the property out of control growth of cell, comprises the minimizing of death (apoptosis) of cell and the increase of propagation, and cell a plurality of cell activities such as dedifferente.Therefore tumour can be thought the disease of cell cycle again.(cyclin-dependent kinases suppresses its active phosphoric acid, thereby regulates the cell cycle Cdc25 on tyrosine CDKs) and the Threonine by removing cyclin kinase.Three kinds of Cdc25 phosphoesterase: Cdc25A, Cdc25B and Cdc25C are arranged in the mammalian body.Wherein Cdc25A and Cdc25B cross in kinds of tumors and express, as: mammary cancer, ovarian cancer, lymphatic cancer, head and neck cancer, colorectal carcinoma, nonsmall-cell lung cancer etc.As: Cdc25A mRNA is high expression level in 52% mammary cancer, and its albumen is crossed in the former cancer of 47% mammary gland and expressed [J.Clin.Invest., 2000,106,753～761]; Cdc25A and B mRNA have 35% and 39% to cross expression in lymphatic cancer respectively, and all reach 67%[Int.J.Cancer (Pred.Oncol.) 2000 in the wetting property lymphatic cancer, 89:148-152].Studies show that in a large number, Cdc25s be at least two oncogene (Raf1, potential target spot c-Myc), can with other oncogene actings in conjunction, be the target spot of reliable antitumor drug.
The lead compound that is had anti-tumor activity by discovery in the natural phant is an important means of carrying out antitumor drug research, for example the antitumor drug taxol of using clinically, topotecan etc.The red sage root (Salvia miltiorrhiza) is a kind of traditional Chinese medicine, have wide biological activity, be mainly used in treatment: menoxenia, dysmenorrhoea, wei lump in the abdomen is gathered through closing, chest ventral spine pain, hot numbness pain, sore swell and ache, dysphoria and insomnia, hepatosplenomegaly, stenocardia.Up to the present, from the red sage root, isolated more than 50 diterpene-kind compound, be referred to as TANSHINONES with o-quinone structure.Bioactivity research to tanshinone compound shows in recent years, TANSHINONES not only has coronary artery dilator blood vessel, blood viscosity lowering, anti-infective, the ischemical reperfusion injury that improves the conscience lung and regulates pharmacological action such as immunne response, find also that simultaneously tanshinone compound has cytotoxicity, induction of differentiation and cell death inducing effect to various tumor cell strains, can be used as antitumor drug.A lot of TANSHINONES compounds are aphthofurans o-quinone compounds.Document [Planta Med.63 (1997) 339～342] has been measured the cytotoxicity of these TANSHINONES compounds, wherein Tanshinone II A (English name: Tanshinone IIA, structural formula is as follows) has shown stronger cytotoxicity (IC to five tumor cell lines such as A549
50Be respectively: A549:0.9 ± 0.1 μ g/ml; SK-OV-3:1.3 ± 0.2 μ g/ml; SK-MEL-2:1.2 ± 0.2 μ g/ml; XF498:0.4 ± 0.2 μ g/ml; HCT15:0.8 ± 0.2 μ g/ml).
The inventor finds that first on molecular level, this compound is to the IC of Cdc25A, Cdc25B
50Be respectively 6.11 ± 0.45 and 8.42 ± 1.02 μ M.The present invention carries out a series of structure of modification to it, and Naphthofurans ortho-quinone compound is provided.This compounds has the obvious suppression effect to Cdc25A, Cdc25B on molecular level, and has good antineoplastic activity on cell levels.
Summary of the invention
The purpose of this invention is to provide Naphthofurans ortho-quinone compound.
Another object of the present invention provides the preparation method of this compounds.
A further object of the present invention provides this compounds and prevents and/or treats purposes in the medicine of tumour in preparation.
The invention relates to Naphthofurans ortho-quinone compound, especially 2, aphthofurans o-quinone compound that the 3-position replaces and preparation method thereof, this compounds have on the molecule to the restraining effect of Cdc25A and Cdc25B and the antitumor action on the cell levels.
The invention provides Naphthofurans ortho-quinone compound, these compounds have the structure shown in general formula A or the A1:
Wherein in the said structure general formula, R
1Represent H, C
1～C
10Alkyl, contain two keys or triple-linked C
1～C
10Alkyl, contain the C of hydroxyl
1～C
10Alkyl, aromatic base or benzyl, specifically can be H, (CH
3)
2CCHCH
2-, (CH
3)
2CCH (CH
2)
2-, (CH
3)
2CCH (CH
2)
3-, CH
3-, CH
3CH
2-, CH
3(CH
2)
2-, CH
3(CH
2)
3-, CH
3(CH
2)
4-, CH
3(CH
2)
5-, HOCH
2-, HOCH
2CH
2-, HOCH
2(CH
2)
2-, HOCH
2(CH
2)
3-, CH
2CHCH
2-, CH
2CH (CH
2)
2-, CH
2CH (CH
2)
3-, C
6H
5-, C
6H
5CH
2-etc., and R
1Be preferably H.
R
2Can be H, C
1～C
10Straight or branched alkyl, contain the C of hydroxyl or alkoxyl group
1～C
10Alkyl, C
1～C
10Straight or branched alkoxyl group, contain the C of fat acyloxy or fragrant acyloxy
1～C
10Alkyl, contain halogen C
1～C
10Alkyl, replacement or unsubstituted aromatic base, C
1～C
10Acyloxy, C
1～C
10Alkene oxygen base, C
1～C
10Alkylthio, fatty acyl group, aromaticacyl radical, carboxylic acid ester groups, halogen, amido, amine alkyl.Specifically can be H, CH
3-, CH
3CH
2-, HOCH
2-, CH
3CH (OH)-, CH
3OCH
2-, CH
3CH
2OCH
2-, H
2NCH
2-, Me
2NCH
2-, Et
2NCH
2-, Et
2NCH
2CH
2-,
CH
3CO-, PhCO-, 4-OMe-PhCO-, COOEt ,-CH
2OCOCH
3,-CH (OCOCH
3) CH
3, Ph-etc.
R
3Can be H, C
1～C
10Straight or branched alkyl, contain the C of hydroxyl or alkoxyl group
1～C
10Alkyl, C
1～C
10Straight or branched alkoxyl group, contain the C of fat acyloxy or fragrant acyloxy
1～C
10Alkyl, contain halogen C
1～C
10Alkyl, replacement or unsubstituted aromatic base, C
1～C
10Acyloxy, C
1～C
10Alkene oxygen base, C
1～C
10Alkylthio, fatty acyl group, aromaticacyl radical, carboxylic acid ester groups, halogen, amido, amine alkyl, wherein said substituting group are cycloalkyl, cyclenes, aromatic ring, five yuan or hexa-member heterocycle.Specifically can be H, Br, CH
3-, CH
3CH
2-, HOCH
2-, HOCH
2CH
2-, CH
3OCH
2-, CH
3CH
2OCH
2-, H
2NCH
2-, Me
2NCH
2-, Me
2N-, Et
2NCH
2-, Et
2NCH
2CH
2-,
-CHO, Ph-, 4-OMe-Ph-, COOEt etc.
Simultaneously, R
2During for methyl, R
3Be not hydrogen.
Above-mentioned all compounds can be synthetic by following synthetic route, hereinafter will illustrate synthetic route respectively, but do not limit the present invention in any way.
Route 1: preparation R
3Aphthofurans o-quinone compound for bromine
Do not have the aphthofurans o-quinone compound (general structure A2 and A3) of replacement from the 2-position, in HOAc, carry out bromination and obtain B and B1.A2 and A3 are commercially available getting, and also can synthesize easily with reference to corresponding document, wherein R
1And R
2Representative with above-mentioned identical.
Route 2: preparation R
3Aphthofurans o-quinone compound for formyl radical
The aphthofurans o-quinone compound (general structure A2 and A3) that does not have replacement from the 2-position, at first reduce, obtain bisnaphthol (general structure C and C1), directly carry out two methyl-etherifieds then and obtain intermediate (general structure D and D1), obtain compound (general structure E and E1) by the Vilsmeier reaction then, use BBr then
3Demethylation directly carries out oxidation subsequently and obtains target compound (general structure G and G1) in air.
Route 3: preparation R
3Aphthofurans o-quinone compound for the amine methyl
The aphthofurans o-quinone compound (general structure A2 and A3) that does not have replacement from the 2-position obtains target compound (general structure H and H1) by the Mannich reaction.R wherein
4Be C
1～C
10The amino that alkyl replaces, also can be the N-heterocyclic radical, piperazine that described heterocycle such as tetramethyleneimine, piperidines, N replace and morphine quinoline etc.
Route 4: preparation R
2Aphthofurans o-quinone compound for acyl group or carboxylic acid ester groups
By at ZnCl
2Under the catalysis; the acyl acetic acid ester reaction that direct and corresponding acyl group ketone of corresponding naphthoquinones (general structure I and I1) or alkyl or aromatic base replace obtains intermediate (general structure J, J1, L and L1), obtains target product (general structure K, K1, M and M1) with nitric acid oxidation in acetum.Substituent R wherein
6And R
7Independently be C respectively
1～C
10Alkyl, C
1～C
10The aryl that contains two keys or triple-linked alkyl, do not replace or replace.
Route 5: preparation R
2The aphthofurans o-quinone compound of the alkyl that replaces for hydroxyl
Be raw material with intermediate (general structure J, J1, L and L1) respectively, obtain intermediate (general structure N, N1, Q and Q1) respectively, obtain target compound (P, P1, R and R1) with nitric acid oxidation then by reduction.
The compound (general structure P, P1, R and R1) that obtains is carried out esterification and etherificate has obtained other target compound (general structure S, S1, T and T1).Esterification products can react in pyridine with corresponding acid anhydrides or acyl chlorides and obtain.The etherificate product can obtain with corresponding alkyl halide reaction in the presence of alkali.R wherein
8, R
9Independently be C respectively
1～C
10Alkyl, C
1～C
10Containing two keys or triple-linked alkyl, also can be to replace or unsubstituted aryl.
Route 6: preparation R
3Aphthofurans o-quinone compound for carboxylic acid ester groups, alkyl.
(general structure U and U1) is raw material with corresponding acyl group naphthols, with bromoacetic acid or bromacetate reaction, has ShiShimonoseki ring at sodium-acetate then, obtains intermediate (general structure W and W1), reoxidizes and obtains target compound (general structure Y and Y1).Intermediate (general structure X and X1) also can be reduced to intermediate X a and X1a earlier and reoxidize and obtain target product (general structure Xb and X1b).To compounds X b with X1b carries out acidylate or alkylation can obtain product (general structure Xc, Xd, X1c and X1d), wherein R
8, R
9Can be C
1～C
10Alkyl, the aryl that does not replace or replace.Wherein raw material U and U1 can be simply according to document preparations (J.Am.Chem.Soc.1942,64,798).R
10And R
11Can be C
1～C
10Alkyl, C
1～C
10Containing two keys or triple-linked alkyl, also can be to replace or unsubstituted aryl.
The compound that part 2-position alkyl replaces can obtain with corresponding acid reaction by the compound of 2-bromo.
Beneficial effect
The present invention has introduced the preparation method of the aphthofurans o-quinone compound of multiple replacement, by simple experimental procedure, with the easy reagent preparation that is easy to get the aphthofurans o-quinone compound of different replacements.
Aphthofurans o-quinone compound of the present invention is to design synthetic with protein-tyrosine-phosphatase Cdc25 for target spot, and novel structure has shown that in active testing good Cdc25 suppresses activity and anti-tumor activity.Protein-tyrosine-phosphatase Cdc25 has vital role in the developing of multiple disease, the present invention is for providing new method with the various diseases of Cdc25 mediation especially tumor treatment.Be how to play a role many worth researchs are still arranged in generation, development and the signal of disease pass to about Cdc25 simultaneously, the highly active Cdc25 inhibitor among the present invention will provide strong instrument for the further research of the Cdc25 mechanism of action.
Embodiment
Raw materials usedly in synthetic compound except that specifying, be commercially available getting.Used column chromatography silica gel is 200～300 orders, is produced by Haiyang Chemical Plant, Qingdao.Solvent for use is all unprocessed except that particularly pointing out, and solvent treatment is with reference to the Purification ofLaboratory Chemicals (Fourth Edition) of century bibliogony society.
Embodiment 1
Reaction scheme schematically as follows, wherein compound 1 is a natural product, commercially available getting.The synthesized reference document of compound 3 (J.Chem.Soc.1961,5090.).
A. compound 2 is synthetic: (1.00g is 3.4mmol) with acetic acid 80mL, to wherein dripping Br to add compound 1 in flask
2(0.543g, the 3.4mmol) solution in 20mL acetic acid, room temperature reaction 4h.Thin up, CH
2Cl
2Extraction, combining extraction liquid washes with water, Na successively
2SO
3The aqueous solution is washed, saturated sodium-chloride is washed, anhydrous magnesium sulfate drying.Column chromatography (sherwood oil: ethyl acetate=30: 1) get red solid 2 (1.012g, productive rate 80%).
1H?NMR(300MHz，CDCl
3)δ1.30(s，6H)，1.65(m，2H)，1.78(m，2H)，2.20(s，3H)，3.16(t，J＝6.3Hz，2H)，7.52(d，J＝8.3Hz，1H)，7.63(d，J＝8.3Hz，1H).
EIMS(m/z)：374，372，359，357，313，232.
B. compound 4 is synthetic: (1.00g is 4.7mmol) with acetic acid 80mL, to wherein dripping Br to add compound 3 in flask
2(0.751g, the 4.7mmol) solution in 20mL acetic acid, room temperature reaction 4h.Thin up, CH
2Cl
2Extraction, combining extraction liquid washes with water, Na successively
2SO
3The aqueous solution is washed, saturated sodium-chloride is washed, anhydrous magnesium sulfate drying.Column chromatography (sherwood oil: ethyl acetate=30: 1) get red solid 4 (1.124g, productive rate 82%).
1H?NMR(300MHz，CDCl
3)δ2.22(s，3H)，7.46(dd，J＝7.6，7.7Hz，1H)，7.61-7.71(m，2H)，8.06(d，J＝7.9Hz，1H)；
EIMS(m/z)：293，291，219，149.
Embodiment 2
Reaction scheme is schematically as follows:
A. compound 6 is synthetic: (1g 4.7mmol) is dissolved in 100mL THF, adds 100mg 10%Pd/C, logical H with compound 3
2, room temperature reaction 2h.Add 110mL 10%NaOH and 19.4mL Me
2SO
4, room temperature reaction 4h.Filter, thin up, ethyl acetate extraction merges organic phase, washing, saturated sodium-chloride is washed, anhydrous magnesium sulfate drying.Simple column chromatography (sherwood oil: ethyl acetate=50: 1) get colourless oil liquid 6 (1.106g, productive rate 98%).
1H?NMR(300MHz，CDCl
3)δ2.28(s，3H)，4.00(s，3H)，4.10(s，3H)，6.87(s，1H)，7.59(m，2H)，8.15(d，J＝8.0Hz，1H)，8.35(J＝7.8Hz，1H)，10.10(s，1H)；
B. compound 7 is synthetic: add 1mL exsiccant DMF in the exsiccant flask, stir down to wherein dripping 0.2mL POCl
3, stirred 15 minutes, add compound 6 (309mg, 1.3mmol) solution in 3mL DMF.80～85 ℃ of reactions are spent the night.Be cooled to room temperature, pour in the frozen water, transfer pH to 7, ethyl acetate extraction merges organic phase, washing, and saturated sodium-chloride is washed, anhydrous magnesium sulfate drying, simple column chromatography (sherwood oil: ethyl acetate=25: 1), get colourless oil liquid 7 (337mg, productive rate 98%).
1H?NMR(300MHz，CDCl
3)δ2.50(s，3H)，4.00(s，3H)，4.10(s，3H)，7.59(m，2H)，8.15(d，J＝8.0Hz，1H)，8.35(d，J＝7.8Hz，1H)，10.10(s，1H)；
C. compound 9 is synthetic: (188mg 0.695mmol), leads to N to add compound 7 in the exsiccant flask
2, add 25mL exsiccant CH
2Cl
2, be cooled to 0 ℃, add the BBr of 7mL 1M
3CH
2Cl
2Solution, 0 ℃ of reaction 4h.Pour in the saturated sodium-chloride, ethyl acetate extraction merges organic phase, and saturated sodium-chloride is washed, anhydrous magnesium sulfate drying.Directly oxidation 4h in air under agitation after TLC reacts completely, concentrates, simple column chromatography (sherwood oil: ethyl acetate=8: 1) red solid 9 (134mg, productive rate 82%).
1H?NMR(300MHz，CDCl
3)δ2.65(s，3H)，7.62(dd，J＝7.7，7.5Hz，1H)；7.76(dd，J＝7.8，7.7Hz，1H)，7.95(d，J＝7.9Hz，1H)，8.16(d，J＝7.8Hz，1H)，9.92(s，1H)；
EIMS(m/z)：240，212，183，163.
D. remove that (204mg 0.694mmol) replaces outside 3, uses the method identical with compound 9 to synthesize compound 14 (179mg, productive rate 80%) with compound 1.
1H?NMR(300MHz，CDCl
3)δ1.43(s，6H)，1.68(m，2H)，1.72(m，2H)，2.65(s，3H)，3.22(t，J＝6.3Hz，2H)，7.70(d，J＝8.1Hz，1H)，8.80(d，J＝8.1Hz，1H)，9.85(s，1H).
EIMS(m/z)：322，307，289，279，261，105.
Embodiment 3
Reaction scheme is schematically as follows:
A. compound 15 is synthetic: in flask, add compound 1 (100mg, 0.34mmol), 0.032mL37% formaldehyde and 0.27mL dimethyl amine and 3.2mL acetic acid, 125～128 ℃ of reaction 3h.Pour in the water, ethyl acetate extraction merges organic phase, washing, and saturated sodium-chloride is washed, anhydrous magnesium sulfate drying.Column chromatography (sherwood oil: ethyl acetate=2: 1) get red-purple solid chemical compound 15 (96mg, productive rate 80%).
1H?NMR(300MHz，CDCl
3)δ1.31(s，6H)，1.65(m，2H)，1.78(m，2H)，2.25(s，3H)，2.32(brs，6H)，3.18(brs，2H)，3.50(s，2H)，1.60(brs，2H)
EIMS(m/z)：351，307，277，149.
B. compound 16 is synthetic:
Except that replacing the dimethyl amine, with the method synthetic compound 16 (100mg, productive rate 75%) identical with compound 15 with piperidines (0.30mL).
1H?NMR(300MHz，CDCl
3)δ1.28(s，6H)，1.40(m，2H)，1.54-1.70(m，4H)，1.72-1.80(m，4H)，2.03(s，3H)，2.40-2.50(brs，4H)，3.16(t，J＝6.6Hz，2H)，3.55(s，2H)，7.60(s，2H).
EIMS(m/z)：391，307，277.
C. compound 17 is synthetic:
Except that replacing the dimethyl amine, with the method synthetic compound 17 (91mg, productive rate 71%) identical with compound 15 with tetramethyleneimine (0.30mL).
1H?NMR(300MHz，CDCl
3)δ1.30(s，6H)，1.65(m，2H)，1.80(m，2H)，2.25(s，3H)，2.62(m，4H)，3.17(t，J＝6.1Hz，2H)，3.68(s，2H)，7.60(s，2H).
EIMS(m/z)：377，307.
D. compound 18 is synthetic:
Except that replacing the dimethyl amine, with the method synthetic compound 18 (98mg, productive rate 73%) identical with compound 15 with morphine quinoline (0.30mL).
1H?NMR(300MHz，CDCl
3)δ1.78(s，6H)，1.54(m，2H)，1.68(m，2H)，2.35(s，3H)，2.52(t，J＝4.6Hz，4H)，3.16(t，J＝6.3Hz，2H)，3.58(s，2H)，3.72(t，J＝4.4Hz，4H)，7.60(s，2H).
EIMS(m/z)：393，307.
E. compound 19 is synthetic:
Except that replacing the dimethyl amine, with the method synthetic compound 19 (90mg, productive rate 65%) identical with compound 15 with N methyl piperazine (0.30mL)
1H?NMR(300MHz，CDCl
3)δ1.28(s，6H)，1.6-1.8(m，4H)，2.23(s，3H)，2.30(s，3H)，2.42-2.64(m，8H)，3.18(t，J＝6.6Hz，2H)，3.60(s，2H)，7.6(s，2H).
EIMS(m/z)：406，335，307，149.
Embodiment 4
Reaction scheme is schematically as follows:
A. compound 21 is synthetic: in flask, add Zinc Chloride Anhydrous (3g, 22.1mmol), logical nitrogen adds the 5mL anhydrous methanol, stirred 15 minutes, adding compound 20 (1g, 6.3mmol) and methyl aceto acetate (1.2mL, 9.5mmol), back flow reaction 1h.Be cooled to room temperature, filter, wash, get light green solid 21 (1.039g, productive rate 61%) with methyl alcohol.
1H?NMR(300MHz，CDCl
3)δ1.45(t，J＝7.2Hz，3H)，2.82(s，3H)，4.45(q，J＝7.2Hz，2H)，5.7(brs，1H)，7.46(s，1H)，7.51(dd，J＝7.1，8.3Hz，1H)，7.60(dd，J＝7.1，8.1Hz，1H)，8.20(d，J＝7.9Hz，1H)，8.25(d，J＝8.5Hz，1H).
B. compound 22 is synthetic: with compound 21 (100mg 0.37mmol) is dissolved in the 5mL acetic acid, at 65 ℃ to wherein dripping HNO
35, the reaction 30min, pour in the water, filter red solid 22 (79mg, productive rate 75%).
1H?NMR(300MHz，CDCl
3)δ1.42(t，J＝7.2Hz，3H)，2.65(s，3H)，4.38(q，J＝7.1Hz，2H)，7.46(dd，J＝7.5，7.5Hz，1H)，7.65(dd，J＝7.4，7.7Hz，1H)，7.72(d，J＝7.7Hz，1H)，8.08(d，J＝7.7Hz，1H).
EIMS(m/z)：284，238，210，182.
Synthesizing of compound 24:
Remove that (1.826g 9.5mmol) replaces outside the methyl aceto acetate, with the method synthetic compound thing 24 (895mg, productive rate 41%) identical with synthetic compound 22 with ethyl benzoylacetate.
1H?NMR(300MHz，CDCl
3)δ?1.40(t，J＝7.2Hz，3H)，4.43(q，J＝7.2Hz，2H)，7.45-7.55(m，4H)，7.70(dd，J＝7.6，7.6Hz，1H)，7.83(d，J＝7.7Hz，1H)，7.86-7.91(m，2H)，8.12(d，J＝7.7Hz，1H).
EIMS(m/z)：346，318，302，246，189.
Synthesizing of compound 26:
Remove that (2.111g 9.5mmol) replaces outside the methyl aceto acetate, with the method synthetic compound thing 26 (853mg, productive rate 36%) identical with synthetic compound 22 with 4-anisoyl ethyl acetate.
1HNMR(300MHz，CDCl
3)δ1.40(t，J＝7.2Hz，3H)，3.83(s，3H)，4.41(q，J＝7.1Hz，2H)，6.98(m，2H)，7.49(dd，J＝7.7，7.5Hz，1H)，7.68(dd，J＝7.4，7.6Hz，1H)，7.80(d，J＝7.5Hz，1H)，7.86(m，2H)，8.10(d，J＝7.6Hz，1H).
EIMS(m/z)：376，348，332，304，276，261.
Compound 28:
Remove that (1.236g 9.5mmol) replaces outside the methyl aceto acetate, with the method synthetic compound thing 28 (673mg, productive rate 42%) identical with synthetic compound 22 with methyl ethyl diketone.
1H?NMR(300MHz，CDCl
3)δ2.60(s，3H)，2.72(s，3H)，7.5(dd，J＝7.7，8.0Hz，1H)，7.68(dd，J＝7.8，7.5Hz，1H)，7.75(d，J＝7.7Hz，1H)，8.09(d，J＝7.9Hz，1H).
EIMS(m/z)：254，184，128.
Compound 30:
Remove that (1.541g 9.5mmol) replaces outside the methyl aceto acetate, with the method synthetic compound thing 30 (418mg, productive rate 21%) identical with synthetic compound 22 with benzoyl acetone.
1H?NMR(300MHz，CDCl
3)δ2.50(s，3H)，7.41-7.61(m，4H)，7.68(dd，J＝7.6，7.3Hz，1H)，7.78(d，J＝7.7Hz，1H)，7.84(m，1H)，8.09(d，J＝7.3Hz，1H).
EIMS(m/z)：318，316，260，212，105.
Embodiment 5
Reaction scheme is schematically as follows:
A. compound 32 is synthetic: in flask, add compound 21 (150mg, 0.555mmol) and LiAlH
4(84mg, 2.22mmol), logical nitrogen adds exsiccant THF 10mL, back flow reaction 2h.Carefully add the shrend reaction of going out, ethyl acetate extraction merges organic phase, successively washing, saturated sodium-chloride wash, anhydrous magnesium sulfate drying.Filter, concentrate the crude product of compound 31, not purified, directly carry out oxidation.Except that replacing the compounds 21, synthesized red solid compound 32 (101mg, productive rate 75%) with the method identical with synthetic compound 22 with compound 31.
1H?NMR(300MHz，CDCl
3)δ2.38(s，3H)，3.70(brs，1H)，4.59(s，2H)，7.46(dd，J＝7.4，7.5Hz，1H)，7.62-7.69(m，2H)，8.06(d，J＝8.4Hz，1H).
B. compound 33 is synthetic: (100mg 0.413mmol), is dissolved in the 2mL pyridine, adds the 1.5mL aceticanhydride, and room temperature reaction spends the night, pours in the water, and ethyl acetate extraction merges organic phase, and washing, saturated sodium-chloride are washed, anhydrous magnesium sulfate drying with compound 32.Column chromatography (sherwood oil: ethyl acetate=15: 1) get dark red solid 33 (100mg, productive rate 85%).
1H?NMR(300MHz，CDCl
3)δ2.04(s，3H)，2.42(s，3H)，5.12(s，2H)，7.43(dd，J＝7.0，7.3Hz，1H)，7.58-7.66(m，2H)，8.03(d，J＝7.5Hz，1H).
EIMS(m/z)：284，242，224，196。
C. compound 39 is synthetic: (200mg 0.689mmol) is dissolved in the mixed solvent of 15mL methyl alcohol and 3mL acetic acid, adds 40mg 10%Pd/C, leads to hydrogen, and room temperature reaction spends the night with compound 34.Filter, steam except that behind most of solvent, thin up, ethyl acetate extraction merges organic phase, and washing, saturated sodium-chloride are washed, anhydrous magnesium sulfate drying.Simple column chromatography (sherwood oil: ethyl acetate=15: 1) get oily liquids 39 (179mg, productive rate 95%).
1H?NMR(300MHz，CDCl
3)δ2.50(s，3H)，6.95(s，1H)，7.36(dd，J＝7.4，7.6Hz，1H)，7.50(m，3H)，7.63(dd，J＝7.0，8.1Hz，1H)，7.87(d，J＝8.0Hz，1H)，8.24(d，J＝8.4Hz，1H)，8.33(d，J＝8.3Hz，1H)。
D. compound 40 is synthetic: remove that (100mg 0.365mmol) replaces outside the compound 21, with the method synthetic compound 40 (80mg, 76%) identical with synthetic compound 22 with compound 39.
1H?NMR(300MHz，CDCl
3)δ2.54(s，3H)，7.39-7.53(m，4H)，7.62-7.73(m，3H)，7.77(d，J＝7.6Hz，1H)，8.06(d，J＝7.8Hz，1H).
EIMS(m/z)：288，260，231，203.
E. compound 35: remove that (184mg 0.555mol) replaces outside the compound 21, uses the method identical with synthetic compound 32 to synthesize compound 35 (91mg, 75%) with compound 23.
1H?NMR(300MHz，CDCl
3)δ4.80(s，2H)，7.42-7.56(m，4H)，7.60-7.71(m，3H)，7.78(d，J＝7.6Hz，1H)，8.08(d，J＝7.6Hz，1H).
F. compound 37: remove that (133mg 0.555mol) replaces outside the compound 21, uses the method identical with synthetic compound 32 to synthesize compound 37 (88mg, 77%) with compound 27.
1H?NMR(300MHz，CDCl
3)δ1.48(d，J＝6.7Hz，3H)，4.79(m，1H)，7.45(dd，J＝7.0，7.8Hz，1H)，7.61-7.68(m，2H)，8.05(d，J＝7.5Hz，1H).
G. compound 38: remove that (106mg 0.413mmol) replaces outside the compound 32, uses the method identical with synthetic compound 33 to synthesize compound 38 (47mg, 85%) with compound 37.
1H?NMR(300MHz，CDCl
3)δ1.64(d，J＝6.7Hz，1H)，2.07(s，3H)，2.48(s，3H)，6.03(q，J＝6.8Hz，1H)，7.45(dd，J＝7.7，8.6Hz，1H)，7.60-7.70(m，2H)，8.05(d，J＝7.7Hz，1H).
EIMS(m/e)：298，256，238，214.
Embodiment 6
Reaction scheme is schematically as follows:
A. compound 42 is synthetic: (1g 3.6mmol) is dissolved in 50mL acetone, adds K with compound 41
2CO
3(0.995g 7.2mmol), stirred 10 minutes, and the adding ethyl bromoacetate (0.48mL, 4.32mmol), back flow reaction 3h.Steam most of solvent, thin up, ethyl acetate extraction merges organic phase, and washing, saturated sodium-chloride water solution are washed, anhydrous magnesium sulfate drying.Column chromatography (sherwood oil: ethyl acetate=30: 1) get colourless oil liquid 42 (1.286g, productive rate 98%).
1H?NMR(300MHz，CDCl
3)δ1.21(t，J＝7.2Hz，3H)，3.98(s，3H)，4.18(q，J＝7.2Hz，2H)，4.50(s，2H)，6.74(s，1H)，7.46(m，2H)，7.55-7.65(m，3H)，7.91(m，2H)，8.42(m，2H).
B. compound 43 is synthetic: (587mg 1.611mmol), adds 33mL ethanol and 455mg KOH, room temperature reaction 2h to add compound 42 in flask.Solvent evaporated adds 16.4mL water, uses the dilute hydrochloric acid acidifying, 80 ℃ of reaction 2h.Ethyl acetate extraction merges organic phase, and washing, saturated sodium-chloride water solution are washed, anhydrous magnesium sulfate drying.Column chromatography (sherwood oil: ethyl acetate=50: 1) get pale yellow oily liquid body 43 (331mg, productive rate 75%).
1H?NMR(300MHz，CDCl
3)δ4.04(s，3H)，7.16(s，1H)，7.44(m，1H)，7.55(m，3H)，7.70(m，3H)，7.88(s，1H)，8.33(d，J＝8.1Hz，1H)，8.39(d，J＝8.4Hz，1H).
C. compound 45 is synthetic: (300mg 1.09mmol) is dissolved in 30mL exsiccant CH with compound 43
2Cl
2, be cooled to 0 ℃, add 5.49mL 1M BBr
3CH
2Cl
2Solution, 0 ℃ of reaction 4h.Pour in the saturated sodium-chloride water solution, tell organic phase, water CH
2Cl
2Extraction merges organic phase, and saturated sodium-chloride water solution is washed, anhydrous magnesium sulfate drying.Solvent evaporated is dissolved in 40mL exsiccant CH
2Cl
2, (891mg, 2.19mmol), room temperature reaction spends the night to add 12-I-5 (Dess-Martin, oxygenant can be according to document J.Am.Chem.Soc.1991,113,7277-7287 is synthetic).Add rare NaOH aqueous solution, stirred 10 minutes, tell organic phase, water CH
2Cl
2Extraction merges organic phase, washing, and saturated sodium-chloride water solution is washed, anhydrous magnesium sulfate drying.Column chromatography (sherwood oil: ethyl acetate=20: 1) get red solid 45 (149mg, productive rate 50%).
1H?NMR(300MHz，CDCl
3)δ7.37-7.46(m，3H)，7.51(d，J＝7.6Hz，1H)，7.64(s，1H)，7.66-7.73(m，3H)，7.78(d，J＝7.7Hz，1H)，8.10(d，J＝7.8Hz，1H).
EIMS(m/e)：274，246，218，189.
Embodiment 7
Synthetic route is as follows:
Compound 46 synthetic: in flask, add compound 2 (373mg, 1.0mmol), phenylo boric acid (146mg, 1.2mmol) and PdCl
2(PPh
3)
2(21mg, 0.03mmol), logical nitrogen adds Et
3N and 10mL DMF, 100 ℃ of reactions are spent the night.Be cooled to room temperature, pour in the water, ethyl acetate extraction merges organic phase, washing, and saturated sodium-chloride water solution is washed, anhydrous magnesium sulfate drying.Column chromatography (sherwood oil: ethyl acetate=30: 1) get red-purple solid 46 (196mg, productive rate 80%).
1H?NMR(300MHz，CDCl
3)δ1.25(s，6H)，1.65(m，2H)，1.80(m，2H)，2.24(s，3H)，3.18(t，J＝6.8Hz，2H)，7.36-7.82(m，7H).
EIMS(m/e)：370，355，337，294，279，261，233.
Embodiment 8
Synthetic route is as follows:
A. compound 48 is synthetic: (1g, 3.16mmol) and 1.143gNaOAc, in the mixed solvent of 10mL and 10mL HOAc, slight boiling condition is reaction 48h down for compound 47.Thin up, ethyl acetate extraction merges organic phase, washing, saturated sodium-chloride water solution is washed, anhydrous magnesium sulfate drying.Column chromatography (sherwood oil: ethyl acetate=100: 1) get colourless oil liquid 48 (566mg, productive rate 60%).
1H?NMR(300MHz，CDCl
3)δ1.45(t，J＝7.0Hz，3H)，1.58(t，J＝6.9Hz，3H)，2.60(s，3H)，4.21(q，J＝6.8Hz，2H)，4.46(q，J＝7.1Hz，2H)，6.80(s，1H)，7.60(m，2H)，8.37(m，2H).
B. compound 50 is synthetic: (500mg, 1.676mmol), logical nitrogen adds exsiccant 30mL CH to add compound 49 in flask
2Cl
2, be cooled to 0 ℃, add the BBr of 8.38mL1M
3CH
2Cl
2Solution, 0 ℃ of reaction 4h.Pour in the saturated sodium-chloride, tell organic phase, water CH
2Cl
2Extraction merges organic phase, and saturated sodium-chloride water solution is washed, anhydrous magnesium sulfate drying.Solvent evaporated is dissolved among the 25mL HOAc, adds HNO
310,65 ℃ of reaction 30min.In entry, filter red solid 50 (357mg, productive rate 75%).
1H?NMR(300MHz，CDCl
3)δ1.40(t，J＝6.9Hz，3H)，2.60(s，3H)，4.40(q，J＝7.1Hz，2H)，7.53(dd，J＝8.8Hz，7.6Hz，1H)，7.69(dd，J＝7.6Hz，7.6Hz，1H)，7.89(d，J＝7.7Hz，1H)，8.09(d，J＝7.7Hz，1H).
EIMS(m/e)：284，256，228，184.
Biological activity:
(1). compound on molecular level to the IC of Cdc25A, Cdc25B
50(μ g/ml):
The goal gene of recombination human source Cdc25A (residues 336～523) and Cdc25B (residues 351-540) all is implemented on the pGEX-KG carrier, changes escherichia coli expression bacterial strain BL21 (DE over to
3) pLysS, the broken born of the same parents of IPTG abduction delivering are after glutathione agarose affinity chromatography column purification obtains gst fusion protein, cut respectively via zymoplasm and obtain target protein Cdc25A and Cdc25B after discharging GST and purifying.Through 12%SDS-PAGE glue isolation identification, its purity all reaches more than 90%.Further analyze its zymologic property (K
m, k
Cat), all with the natural of bibliographical information (Mol.Pharmacol.61:720-728,2002) or recombinant protein is consistent.
Measure the inhibition activity of following compound to Cdc25A and Cdc25B respectively, it is 50mM Tris-HCl (8.0/9.0) that Cdc25A and Cdc25B survey the reaction system of living, 1mM EDTA, 2mM DTT, 50mM NaCl, 120nM Cdc25A/50nM Cdc25B, 20 μ M OMFP; The application of sample of reaction system is in proper order: earlier the DMSO/ compound is added in 96 orifice plates, then enzyme is added and survey live body system, start enzymatic reaction after adding the substrate buffer solution mixing at last, put into Flexstation II 384 (Molecular Devices) immediately, in room temperature, the variation (RFU/sec) of the fluorescence intensity of detection of dynamic exciting light 485nm, emission light 538nm within 2 minutes.The mean value of initial velocity of reaction that has only DMSO as 100% enzymic activity, is mapped to sample concentration with the relative reactivity under the different inhibitor concentration,, draw IC through formula fitting
50Value.
Table 1: compound suppresses active (IC to Cdc25A, Cdc25B
50: μ M)
aCompound number is that compound is numbered in specification sheets embodiment in the table.
bIC
50Value is three independently mean values of experimental data
cNA: do not suppress active, IC
50＞20 μ g/mL.
The compound structure numbering is as follows:
Compare with Tanshinone II A, the Cdc25 of the most of analogue of synthetic of the present invention suppresses activity all large increase, and the enzyme inhibition activity that 7 compounds are wherein arranged is less than 1 μ M; Discovery do not have A ring compound exhibits stronger Cdc25 suppress active; Bromine, phenyl and formyl radical are introduced in 2-position at compound, and its Cdc25 suppresses activity and do not significantly improve; Introduce the amine methyl by the Mannich reaction, bigger improvement is all arranged except that compound 18 and 16; In order to investigate macoradical, synthesized compound 45 (comparing), but obviously do not changed with compound 3 to its bioactive influence; In order to investigate compound 2-bit substituent to its bioactive influence, introduced different substituting groups in its 2-position with the 3-position, when the 3-position was carboxylicesters, no matter the 2-position was methyl (22), phenyl (24) or p-methoxyphenyl (26), and its Cdc25 activity is very weak; But when carboxylic acid ester groups when 2-position (50), better active; When we introduced acyl group in its 3-position, the compound (28) that ethanoyl replaces had shown very weak enzyme inhibition activity, and is active preferably but the compound (30) that benzoyl replaces has shown; The unfavorable compound of activity reduced to have obtained 3-be the compound (32,35,37) that methylol replaces, its biological activity has had and has significantly improved; Hydroxyl in the compound is carried out acetylize, to its active not influence, compound may be to enter the first hydrolysis in back in the body, then brings into play its enzyme inhibition activity.
(2) compound is to the toxicity test of tumour cell:
The utilization mtt assay detects cell survival rate, is about to be grown in the A549 cell of logarithmic phase, in 96 orifice plates respectively with 3.0 * 10
3/ well inoculation, each compound is established six concentration gradients, and each concentration is established three multiple holes, contains the substratum of 100 μ l in every hole, places CO
2Cultivated 72 hours for 37 ℃ in the incubator, add the 5mg/ml MTT of 40 μ l.37 ℃ hatch 4 hours after, inhale and to abandon supernatant, add the DMSO dissolving of 100 μ l, use SpectraMAX 340 to survey 550nm (L1) absorbance values, reference wavelength 690nm (L2) maps (L1-L2) value to the inhibitor different concns, get IC through formula fitting
50
Table 2: compound is to tumour cell A549 inhibition of proliferation effect (IC
50: μ M):
aIC
50Value is three independently mean values of experimental data
The present invention has selected active five the best compounds of protein phosphatase Cdc25 have been carried out the cytotoxicity test, has all shown very strong anti tumor activity in vitro.Has good DEVELOPMENT PROSPECT.
Claims (5)
1. a class has the aphthofurans o-quinone compound of structure shown in following formula A or the A1:
R wherein
1Be H, C
1～C
10Alkyl, contain two keys or triple-linked C
1～C
10Alkyl, contain the C of hydroxyl
1～C
10Alkyl, aromatic base or benzyl;
R
2Be H, C
1～C
10Straight or branched alkyl, contain the C of hydroxyl or alkoxyl group
1～C
10Alkyl, C
1～C
10Straight or branched alkoxyl group, contain the C of fat acyloxy or fragrant acyloxy
1～C
10Alkyl, contain the C of halogen
1～C
10Alkyl, replacement or unsubstituted aromatic base, C
1～C
10Acyloxy, C
1～C
10Alkene oxygen base, C
1～C
10Alkylthio, fatty acyl group, aromaticacyl radical, carboxylic acid ester groups, halogen, amido or amine alkyl;
R
3Be H, C
1～C
10Straight or branched alkyl, contain the C of hydroxyl or alkoxyl group
1～C
10Alkyl, C
1～C
10Straight or branched alkoxyl group, contain the C of fat acyloxy or fragrant acyloxy
1～C
10Alkyl, contain halogen C
1～C
10Alkyl, replacement or unsubstituted aromatic base, C
1～C
10Acyloxy, C
1～C
10Alkene oxygen base, C
1～C
10Alkylthio, fatty acyl group, aromaticacyl radical, carboxylic acid ester groups, halogen, amido or amine alkyl, wherein said substituting group is cycloalkyl, cyclenes, aromatic ring, five yuan or hexa-member heterocycle;
And work as R
2During for methyl, R
3Be not hydrogen.
2. aphthofurans o-quinone compound according to claim 1 is characterized in that:
R
1Be H, (CH
3)
2CCHCH
2-, (CH
3)
2CCH (CH
2)
2-, (CH
3)
2CCH (CH
2)
3-, CH
3-, CH
3CH
2-, CH
3(CH
2)
2-, CH
3(CH
2)
3-, CH
3(CH
2)
4-, CH
3(CH
2)
5-, HOCH
2-, HOCH
2CH
2-, HOCH
2(CH
2)
2-, HOCH
2(CH
2)
3-, CH
2CHCH
2-, CH
2CH (CH
2)
2-, CH
2CH (CH
2)
3-, C
6H
5-or C
6H
5CH
2-;
R
2Be H, CH
3-, CH
3CH
2-, HOCH
2-, CH
3CH (OH)-, CH
3OCH
2-, CH
3CH
2OCH
2-, H
2NCH
2-, Me
2NCH
2-, Et
2NCH
2-, Et
2NCH
2CH
2-,
CH
3CO-, PhCO-, 4-OMe-PhCO-, COOEt ,-CH
2OCOCH
3,-CH (OCOCH
3) CH
3Or Ph-;
R
3Be H, Br, CH
3-, CH
3CH
2-, HOCH
2-, HOCH
2CH
2-, CH
3OCH
2-, CH
3CH
2OCH
2-, H
2NCH
2-, Me
2NCH
2-, Me
2N-, Et
2NCH
2-, Et
2NCH
2CH
2-,
-CHO, Ph-, 4-OMe-Ph-or COOEt.
3. aphthofurans o-quinone compound according to claim 1 and 2 is characterized in that this compound is:
4. preparation method as each described aphthofurans o-quinone compound of claim 1～3, described aphthofurans o-quinone compound is synthetic by following route:
Route 1: preparation R
3Aphthofurans o-quinone compound for bromine:
Do not have the aphthofurans o-quinone compound (general structure A2 and A3) of replacement from the 2-position, in HOAc, carry out bromination and obtain target product (general structure B and B1), wherein R
1And R
2Described with claim 1;
Route 2: preparation R
3Aphthofurans o-quinone compound for formyl radical
The aphthofurans o-quinone compound (general structure A2 and A3) that does not have replacement from the 2-position, at first reduce, obtain bisnaphthol (general structure C and C1), directly carry out two methyl-etherifieds then and obtain intermediate (general structure D and D1), obtain compound (general structure E and E1) by the Vilsmeier reaction then, use BBr then
3Demethylation directly carries out oxidation subsequently and obtains target compound (general structure G and G1) in air;
Route 3: preparation R
3Aphthofurans o-quinone compound for the amine methyl
The aphthofurans o-quinone compound (general structure A2 and A3) that does not have replacement from the 2-position obtains target compound H and H1 by the Mannich reaction;
R wherein
4Be C
1～C
10Amino or N-heterocyclic radical that alkyl replaces, described heterocycle are the piperazine or the morphine quinoline of tetramethyleneimine, piperidines, N replacement;
Route 4: preparation R
2Aphthofurans o-quinone compound for acyl group or carboxylic acid ester groups
By at ZnCl
2Under the catalysis, the acyl acetic acid ester reaction that direct and corresponding acyl group ketone of corresponding naphthoquinones (general structure I and I1) or alkyl or aromatic base replace obtains naphthols intermediate (general structure J, J1, L and L1), obtains target product (general structure K, K1, M and M1) with concentrated nitric acid oxidation then in acetic acid;
Substituent R wherein
6And R
7Be C independently of one another
1～C
10Alkyl, C
1～C
10Contain two keys or triple-linked alkyl, replacement or unsubstituted aryl;
Route 5: preparation R
2The aphthofurans o-quinone compound of the alkyl that replaces for hydroxyl
Be raw material with intermediate (general structure J, J1, L and L1) respectively, obtain intermediate (N, N1, Q and Q1), obtain target compound (P, P1, R and R1) with nitric acid oxidation then by reduction;
Substituent R wherein
6And R
7Definition the same;
The compound (general structure P, P1, R and R1) that obtains is carried out esterification and etherificate has obtained other target compound; Esterification products can react in pyridine with corresponding acid anhydrides or acyl chlorides and obtain; The etherificate product can obtain with corresponding alkyl halide reaction in the presence of alkali;
R wherein
8, R
9Be C independently of one another
1～C
10Alkyl, C
1～C
10Contain two keys or triple-linked alkyl or replacement or unsubstituted aryl;
Route 6: preparation R
3Aphthofurans o-quinone compound for carboxylic acid ester groups, alkyl
(general structure U and U1) is raw material with corresponding acyl group naphthols, with bromoacetic acid or bromacetate reaction, has ShiShimonoseki ring at sodium-acetate then, obtains intermediate (general structure W and W1), reoxidizes and obtains target compound (general structure Y and Y1); Intermediate (general structure X and X1) also can be reduced to intermediate X a and X1a earlier and reoxidize and obtain target product (general structure Xb and X1b); To compounds X b with X1b carries out acidylate or alkylation can obtain product (general structure Xc, Xd, X1c and X1d); R wherein
10, R
11Be C independently of one another
1～C
10Alkyl, C
1～C
10Contain two keys or triple-linked alkyl or replacement or unsubstituted aryl;
The compound that part 2-position alkyl replaces can obtain with corresponding acid reaction by the compound of 2-bromo:
5. prevent and/or treat application in the medicine of tumour as each described aphthofurans o-quinone compound of claim 1～3 in preparation.
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2007
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