CN106117172A - Naphtho-[1,2 b] furan 4,5 diketone 2 sulfonic acid and salt thereof are in the application prepared on antitumor drug - Google Patents

Naphtho-[1,2 b] furan 4,5 diketone 2 sulfonic acid and salt thereof are in the application prepared on antitumor drug Download PDF

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CN106117172A
CN106117172A CN201610435360.3A CN201610435360A CN106117172A CN 106117172 A CN106117172 A CN 106117172A CN 201610435360 A CN201610435360 A CN 201610435360A CN 106117172 A CN106117172 A CN 106117172A
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naphtho
furan
diketone
sulfonic acid
salt
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CN106117172B (en
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刘苏友
罗志勇
马大友
龙丽君
邹自征
刘丽君
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Central South University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/92—Naphthofurans; Hydrogenated naphthofurans

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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The invention discloses naphtho-[1,2 b] furan 4,5 diketone 2 sulfonic acid and salt thereof is at the application prepared on antitumor drug, naphtho-[1,2 b] chemical structural formula of furan 4,5 diketone 2 sulfonic acid is as shown in logical formula (I):Wherein: R1, R2、R3、R4Separately selected from hydrogen, halogen；R5Independently selected from hydrogen, halogen, 15 carbon alkyl, aryl.The invention has the beneficial effects as follows, by the structural modification to parent compound so that the water solublity of compound improves, and has more preferable anti-tumor activity simultaneously.

Description

Naphtho-[1,2-b] furan-4,5-diketone-2-sulfonic acid and salt thereof are anti-in preparation Application on tumour medicine
Technical field
The present invention relates to naphtho-[1,2-b] furan-4,5-diketone-2-sulfonic acid and antitumor drug prepared by salt On application, belong to field of antineoplastic medicaments.
Background technology
Naphtho-[1,2-b] furan-4,5-diketone (NFD) is that lapacho wood belongs to active component important during lapacho wood section derives, Chiu etc. in hepatoma carcinoma cell HCC, Hep3B, HepG2 and Huh-7, the antiproliferative activity simultaneously measured, find compound N FD energy Suppress this type of tumor cell proliferation and induce its apoptosis (Cancer Letters, 2010,295 (1): 92-99)；Tsai etc. are at breast Adenocarcinoma cell MDA-MB-231 carries out active suppression test, finds that NFD may be by suppressing the cell pathway resistance of Src mediation Disconnected MDA-MB-231 cell invasion and transfer, and do not affect apoptosis or growth retardation (Molecular and Cellular Biochemistry,2014,387(1-2):101-111)；Tsai etc. find the breast cancer cell MDA-of NFD suppression HGF induction MB-231 migrating and attacking, it may be possible to suppression tyrosine kinase c-Met phosphorylation, controls the activation of PI3K Yu Akt, negative regulation (NF) activity of-kB and MMP-9, thus migrate at breast cancer cell and reach intervention effect (Clinical and in early days Experimental Pharmacology and Physiology(2014)41,716–726).Hsieh etc. select epidermal growth The factor (EGF), as the inducer of breast cancer cell MDA-MB-231, finds c-Jun and c-Fos that NFD can suppress EGF to mediate Protein level, the phosphorylation level of negative regulation EFGR, PI3K/Akt, reduce the expression of MMP-9 and activity, reach to suppress tumor Cell invasion and the effect (Toxicology in Vitro, 2013,27 (1): 1-10) of migration.It is appreciated that in suppression During EGF induction MDA-MB-231 invasion and attack and migration, NFD there is no obvious cytotoxicity.But we send out under study for action The water solublity of existing NFD is very poor, the most insoluble in water, affects its druggability, and its activity needs to be improved further activity
Summary of the invention
The present invention, based on natural product naphtho-[1,2-b] furan-4, the structure of 5-diketone (NFD), by structural modification, sends out An existing naphtho-[1,2-b] that class activity is good, water solublity is high-furan-4,5-diketone-2-sulfonic acid.
The technical scheme is that, it is provided that a kind of naphtho-[1,2-b] furan-4,5-diketone-2-sulfonic acid and The most acceptable salt, described naphtho-[1,2-b] furan-4, the chemical structural formula such as formula of 5-diketone-2-sulfonic acid (I) shown in:
Wherein:
R1、R2、R3、R4Separately selected from hydrogen, halogen；
R5Independently selected from hydrogen, halogen, 1-5 carbon alkyl, aryl.
Further, described R1, R2、R3、R4It is hydrogen.
Further, described R5For hydrogen or methyl.
Further, the cation in described salt is selected from alkali metal ion, alkaline-earth metal ions, ammonium ion.
Further, chemical structural formula is:
The present invention provides naphtho-[1,2-b] furan-4,5-diketone-2-sulfonic acid further and pharmaceutically may be used The preparation method of the salt accepted, it is characterised in that naphtho-[1,2-b] furan-4, the preparation method of 5-diketone-2-sulfonic acid As follows: in naphtho-[1,2-b] furan-4, the acetic acid of 5-derovatives and the mixed solution of acetic anhydride, add the vinegar of concentrated sulphuric acid , there is sulfonating reaction in acid diluent, the response time is 0.5-24h, and reaction temperature is-10 DEG C～100 DEG C；Reaction completely, adjusts pH To 4-5；Column chromatography for separation the most available naphtho-[1,2-b] furan-4,5-diketone-2-sulfonic acid.
Further, by naphtho-[1,2-b] furan-4,5-diketone-2-sulfonic acid reacts with alkali generation acid-base neutralization Obtain its corresponding sulfonate.
Further, described naphtho-[1,2-b] furan-4,5-diketone-2-sulfonic acid and pharmaceutically can connecing The salt being subject to is preferably breast carcinoma in the application prepared on antitumor drug, tumor.
Present disclosure relates to naphtho-[1,2-b] furan-4,5-diketone-2-sulfonic acid and pharmaceutically can connect The salt being subject to, its structural formula is respectively logical formula (I) and logical formula (II)；Logical formula (I) and the preparation method of logical formula (II) compound.
Shown in the following reaction scheme of its preparation method
A): alph-halogenated ketone or aldehyde, KI, KOH；b):H2SO4,(AcO)2O,AcOH；C): alkali
The first step is reacted: this step reaction cyclization, with commercially available 2 hydroxy naphthalene quinone (A) as raw material, according to literature method (Toxicology in Vitro, 2013,27 (1): 1-10) and alph-halogenated ketone or aldehyde reaction, prepare intermediate B, instead Ying Zhong, adds potassium iodide or sodium iodide, can improve response speed.Finally give compound B.
Second step reacts: this step sulfonating reaction, and compound B, in acetic acid and acetic anhydride mixed solvent, occurs sulfonated reaction, Obtain corresponding sulfonic acid (I).Post isolated sterling.Eluent is the mixing system of methanol and ethyl acetate.Acetic acid and acetic anhydride Ratio 1:1～5, the ratio of concentrated sulphuric acid and compound B is 1:1～3, and reaction temperature is 0-50 DEG C.Acetic acid and acetic anhydride optimal Ratio 1:1～2, the ratio of concentrated sulphuric acid and compound B is 1:1～1.5, and reaction temperature is 0 degree to 25 degree.Ratio is volume Ratio.
Three-step reaction: salt-forming reaction.In organic solvent, sulfonic acid (I) and inorganic base or organic base generation acid-base neutralization Reaction, obtains the sulfonate of logical formula (II).Conventional inorganic base have Lithium hydrate, sodium hydroxide, potassium hydroxide, calcium hydroxide, Ammonium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, lithium carbonate, Feldalat NM, Feldalat KM, Sodium ethylate, potassium ethoxide, Sodium tert-butoxide, potassium tert-butoxide；Conventional organic base is primary amine, secondary amine, tertiary amine, aminoacid.Inorganic base is preferably hydroxide Sodium, potassium hydroxide, calcium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate,.
Choose tumor cell line, by tumor promotion screening technique, pressing down of the compound on tumor cell of the mensuration present invention System activity.The compound of the present invention has more preferable anti-tumour cell proliferative activity than natural parent compound, and its activity is it 3-5 times of precursor structure naphtho-[1,2-b] furan-4,5-diketone (NFD).
The invention has the beneficial effects as follows, by the structural modification to parent compound so that the water solublity of compound is notable Improve, wherein compound 4,5-dioxo-4,5-dihydro-naphtho-[1,2-b] furan-2-sulfonic acid and compound 3-methyl-4,5- The dissolubility in water of dioxo-4,5-dihydro-naphtho [1,2-b] furan-2-sulfonic acid is more than 20mg/mL, compound 4,5-bis- Oxo-4,5-dihydro-naphtho [1,2-b] furan-2-sodium sulfonate and 3-methyl-4,5-dioxo-4,5-dihydro-naphtho [1,2-b] The dissolubility of furan-2-sulfonic acid is all higher than 50mg/mL.There is more preferable anti-tumor activity simultaneously.
Detailed description of the invention
Below in conjunction with specific embodiment, invention is expanded on further.It will be appreciated that these embodiments are merely to illustrate the present invention Rather than restriction the scope of the present invention.
Example 1
The preparation of naphtho-[1,2-b] furan-4,5-diketone
Single neck bottle adds 2-Chloro-1-ethanal 3.64mL, concentrated hydrochloric acid 1mL, stand-by after 40 DEG C of heat-activated.2 hydroxy 1,4 naphthoquinone (lawsone) 0.13g (0.75mmol), 2-Chloro-1-ethanal 0.26mL (1.6mmol), potassium iodide 25mg (0.15mmol), the potassium hydroxide of 1mol/L is molten After liquid 1.5mL is partly dissolved, 80 DEG C of backflows, after TLC detection raw material is wholly absent, stopped reaction, add water 30mL dilution, with two Chloromethanes extractive reaction liquid (50mL × 3), merges organic layer addition anhydrous sodium sulfate and is dried, be spin-dried for solvent, cross column purification (PE/ EA=15:1), red solid B1120mg, productivity 14% are obtained.mp 213-215℃,1H NMR(500MHz,CDCl3)δ8.12(d, J=7.7Hz, 1H), 7.77 (dd, J=11.6,5.9Hz, 1H), 7.69 (td, J=7.6,1.2Hz, 1H), 7.54 (d, J= 2.0Hz, 1H), 7.51 (td, J=7.6,1.1Hz, 1H), 6.90 (d, J=2.0Hz, 1H).
Example 2
The preparation of 4,5-dioxo-4,5-dihydro-naphtho-[1,2-b] furan-2-sulfonic acid
Under condition of ice bath, single neck bottle adds compound naphtho-[1,2-b] furan-4,5-diketone 20mg (0.1mmol), mixes Closing solution 3mL (acetic acid: acetic anhydride=3:4) and dissolve completely, add the acetic acid diluent of concentrated sulphuric acid 40 μ L (0.1mmol), room temperature is anti- Should overnight after, TLC monitoring reaction completely, stopped reaction, add saturated sodium carbonate solution and adjust pH value to be 7.6, the water being spin-dried in solvent, Add ethanol 0.2mL to dissolve, cross column purification (MeOH/EA=1:4), obtain red brown solid 12mg, productivity 40%.mp 229-240 ℃,1H NMR(400MHz,D2O) δ 7.81 (d, J=7.7Hz, 1H), 7.62 7.57 (m, 2H), 7.42 (m, 1H), 7.02 (s, 1H)；13C NMR(125MHz,D2O)δ180.3,175.3,161.6,154.2,136.3,131.6,130.1,128.5,126.7, 123.2,120.2,108.6；HRMS(ESI)m/z[M+H]+calcd.For C12H6O6S,277.9885,found:279.1597.
Example 3
The preparation of 3-methyl naphtho-[1,2-b] furan-4,5-diketone
Tube sealing adds HNQ 125mg (0.72mmol), bromacetone 150mg (1mmol), ammonium acetate 56mg (0.72mmol), toluene 10mL dissolve completely, under the conditions of lucifuge, after 120 DEG C of tube sealing backflow 24h, and stopped reaction, it is spin-dried for first Benzene, after the hydrochloric acid solution of residue 1mol/L dissolves, adds water 30mL dilution, adds dichloromethane extraction (50mL × 3), close And organic layer adds anhydrous sodium sulfate and is dried, it is spin-dried for solvent, crosses column purification (PE/EA=15:1), obtain red solid 10mg, productivity 6%.mp 168-169℃1H NMR (500MHz, DMSO) δ 7.92 (d, J=7.6Hz, 1H), 7.72 7.71 (m, 3H), 7.53 (td, J=7.5,1.4Hz, 1H), 2.19 (d, J=1.1Hz, 3H).
Example 4
The preparation of 3-methyl-4,5-dioxo-4,5-dihydro-naphtho [1,2-b] furan-2-sulfonic acid
Under condition of ice bath, single neck bottle adds 3-methyl naphtho-[1,2-b] furan-4 of example 3 gained, 5-diketone 22mg (0.1mmol), mixed solution 3mL (acetic acid/acetic anhydride=1:2) dissolves completely, and the acetic acid adding concentrated sulphuric acid 40 μ L (0.1mmol) is dilute Release liquid, room temperature reaction overnight after, TLC monitoring reaction completely, stopped reaction, add saturated sodium carbonate solution and adjust pH value to be 7.6, be spin-dried for Water in solvent, adds ethanol 0.2mL and dissolves, cross column purification (MeOH/EA=1:5), obtain red brown solid 414mg, productivity 48%.mp 185-186℃,1H NMR(500MHz,D2O) δ 7.74 (d, J=7.7Hz, 1H), 7.58 (t, J=7.5Hz, 1H), 7.51 (d, J=7.6Hz, 1H), 7.40 (t, J=7.6Hz, 1H), 2.26 (s, 3H)；13C NMR(125MHz,D2O)δ180.0, 175.5,159.5,149.4,136.4,131.3,130.0,128.0,126.4,122.9,121.7,120.0,22.4.
Example 5
The preparation of 4,5-dioxo-4,5-dihydro-naphtho [1,2-b] furan-2-sodium sulfonate
Under condition of ice bath, single neck bottle adds the 4 of example 2 gained, 5-dioxo-4,5-dihydro-naphtho [1,2-b] furan- 2-sulfonic acid 28mg (0.1mmol), adds 1mL ethanol and dissolves, add 0.1mmol Sodium ethylate, be stirred at room temperature 1 hour, be spin-dried for solvent, Add ether, have solid to separate out, filter, obtain product.EI-MS:277 (M-Na)+。
Example 6
The preparation of 3-methyl-4,5-dioxo-4,5-dihydro-naphtho [1,2-b] furan-2-sodium sulfonate
Under condition of ice bath, single neck bottle adds 3-methyl-4 of example 4 gained, 5-dioxo-4,5-dihydro-naphtho [1,2- B] furan-2-sulfonic acid 29mg (0.1mmol), add 1mL ethanol and dissolve, add 0.1mmol sodium hydroxide, be stirred at room temperature 1 hour, Partial solvent is removed in rotation, adds ether, has solid to separate out, and filters, obtains product.EI-MS:291 (M-Na)+。
Antitumor activity of compound is tested
Experimental technique
1. collecting logarithmic (log) phase MCF-7 Breast Cancer Cell, adjust concentration of cell suspension, every hole adds 100 μ L, and bed board makes to be measured Cell adjust density to 4000 every holes, (edge hole is filled with aseptic PBS).
2. in 5% carbon dioxide, hatch for 37 DEG C, be paved with (96 hole flat underside) at the bottom of hole to cell monolayer, add Concentraton gradient Medicine, in principle, get final product dosing, or two hours, or time half a day after cell attachment, at bed board noon before that day, on next day Noon dosing.5-7 Concentraton gradient, every hole 100 μ L, if 3-5 multiple hole.
3., in 5% carbon dioxide, hatch 16-48h for 37 DEG C, observation of cell growing state under inverted microscope.
4. every hole adds 20 μ L MTT solution (5mg/mL, i.e. 0.5%MTT), continues to cultivate 4h.If medicine and MTT can Reaction, can first be centrifuged and discard culture fluid afterwards, after carefully rushing 2-3 time with PBS, adds the culture fluid containing MTT.
5. terminate cultivating, carefully suck culture fluid in hole.
6. every hole adds 100 μ L dimethyl sulfoxide, puts low-speed oscillation 10min on shaking table, makes crystal fully dissolve.At enzyme The light absorption value in each hole is measured at connection immune detector 490nm.
The most simultaneously arrange zeroing hole (culture medium, MTT, dimethyl sulfoxide), control wells (cell, same concentrations medicine molten Solve medium, culture fluid, MTT, dimethyl sulfoxide)
8. each multiple hole OD value is averaged, calculate cell survival rate and suppression ratio
Survival rate=medicine group OD value averages/and matched group OD value averages × 100%
Suppression ratio=100%-survival rate
Test concentrations according to each compound and the suppression ratio of correspondence thereof, calculate the IC of this compound50Value.
Test result
Compound structure and the IC to human breast cancer MCF-7 cell's strain shown in table 1 formula of the present invention I50Value compound pair MCF-7 cell (breast carcinoma) inhibitory activity is as shown in table 1:
The structure of table 1 compound and anti-tumor activity thereof

Claims (9)

1. naphtho-[1,2-b] furan-4,5-diketone-2-sulfonic acid and the most acceptable salt, its feature Being, described naphtho-[1,2-b] furan-4, the chemical structural formula of 5-diketone-2-sulfonic acid is as shown in logical formula (I):
Wherein: R1, R2、R3、R4Separately selected from hydrogen, halogen；R5Independently selected from hydrogen, halogen, 1-5 carbon alkyl, aryl.
2. naphtho-[1,2-b] furan-4,5-diketone-2-sulfonic acid as claimed in claim 1 and pharmaceutically can connecing The salt being subject to, it is characterised in that described R1, R2、R3、R4It is hydrogen.
3. naphtho-[1,2-b] furan-4,5-diketone-2-sulfonic acid as claimed in claim 1 and pharmaceutically can connecing The salt being subject to, it is characterised in that described R5For hydrogen or methyl.
4. naphtho-[1,2-b] furan-4,5-diketone-2-sulfonic acid as claimed in claim 1 and pharmaceutically can connecing The salt being subject to, it is characterised in that the cation in described salt selected from alkali metal ion, alkaline-earth metal ions, ammonium ion, quaternary amine from Son.
5. naphtho-[1,2-b] furan-4,5-diketone-2-sulfonic acid as claimed in claim 1 and medically can connecing The salt being subject to, it is characterised in that chemical structural formula is:
6. naphtho-[1,2-b] furan-4,5-diketone-2-sulfonic acid described in an any one of claim 1-5 and The preparation method of pharmaceutically acceptable salt, it is characterised in that naphtho-[1,2-b] furan-4,5-diketone-2-sulfonic acid Preparation method is as follows: in naphtho-[1,2-b] furan-4, the acetic acid of 5-derovatives and the mixed solution of acetic anhydride, add dense , there is sulfonating reaction in the acetic acid diluent of sulphuric acid, the response time is 0.5-24h, and reaction temperature is-10 DEG C～100 DEG C；React Entirely, pH to 4-5 is adjusted；Column chromatography for separation the most available naphtho-[1,2-b] furan-4,5-diketone-2-sulfonic acid.
7. method as claimed in claim 6, it is characterised in that by naphtho-[1,2-b] furan-4,5-diketone-2-sulfonic acid derives Thing reacts to obtain its corresponding sulfonate with alkali generation acid-base neutralization.
8. naphtho-[1,2-b] furan-4,5-diketone-2-sulfonic acid described in any one of claim 1-5 and in pharmacy Upper acceptable salt is in the application prepared on antitumor drug.
Apply the most as claimed in claim 8, it is characterised in that described tumor is breast carcinoma.
CN201610435360.3A 2016-06-17 2016-06-17 The application of naphtho- [1,2-b] furans -4,5- diketone -2- sulfonic acids and its salt on preparing antitumor drug Expired - Fee Related CN106117172B (en)

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