CN102643247A - Disulfide compound as well as preparation method and application thereof - Google Patents
Disulfide compound as well as preparation method and application thereof Download PDFInfo
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Abstract
The invention belongs to the fields of organic chemistry and pharmaceutical chemistry and particularly relates to novel disulfide compounds shown as a formula I as well as a synthetic method and application of the novel disulfide compounds. The disulfide compounds have strong inhibiting function for various tumor cells and can be used as pilot compounds for researching novel tumor-resisting medicaments or can be used as medicaments for treating various clinically-general multiple cancers. The formula I is shown as the description.
Description
Technical field
The invention belongs to organic chemistry and pharmaceutical chemistry field.Particularly, the present invention relates to have novel disulfide compound and the new synthetic method and the purposes of anti-tumor activity.This compounds has had strong inhibitory effects to kinds of tumor cells, can be used as one type of lead compound of developing new antitumor drug, also maybe be as the medicine of various clinical common multiple cancers.
Technical background
The mortality ratio that malignant tumour causes is ranked second of all disease deaths, is only second to cardiovascular and cerebrovascular diseases.The antitumor drug ubiquity toxic side effect of using clinically is big, is prone to produce shortcomings such as resistance.Therefore seek better efficacy, toxic side effect is lower, and the wider medicine of antitumor spectra is the target that Pharmaceutical Chemist is sought.
Disulfide compound demonstrates many-sided good biological activity, like antibiotic, antimycotic, cytotoxicity, arrestin kinase c etc.Can promote glucose and amino acid metabolism in the brain like the disulfide compound pyritinol; Improve the whole body assimilation; Strengthen the carotid artery flow amount; The improvement of symptoms such as thereby the alliteration that is widely used in cerebral concussion syndromes, cerebral trauma sequela, encephalitis and meningitis sequela clinically is painful, dizziness, insomnia, memory are concentrated, emotional change also can be used for cerebral arteriosclerosis, senile dementia etc.Another disulfide compound PX-12 is the former protein inhibitor of novel thioredoxin, and sulphur hydrogen reduction protein inhibitor is one type of medicine with antitumour activity, and PX-12 is about to get into II phase clinical study at present, and PX-12 is that first gets into such clinical medicine.Kirkpatrick etc. discover that the alkyl imidazole disulfide compound has good inhibition activity to mouse mastopathy cell EMT6.Up to the present, the relevant bioactive research of disulfide compound is also rare.
The synthetic of relevant disulfide compound mainly obtained by the reaction between two kinds of mercaptan in the past, and used alkyl sulfhydryl has stench, all can work the mischief to human body and environment.The compound method that the present invention uses has been avoided the use of alkyl sulfhydryl, is a kind of compound method safely and effectively.
Summary of the invention
The purpose of this invention is to provide one type of disulfide compound, its general formula is following formula 1:
Formula 1
Wherein:
X is NH, O or S;
R
1Be the C1-C5 alkyl;
R
2Be hydrogen, C1-C5 alkyl, C1-C5 alkoxyl group or nitro.
Preferably, the disulfide compound shown in the said formula 1 is specially:
Ethyl-(2-benzoxazole) disulfide (1a),
Ethyl-(2-[4-morpholinodithio) disulfide (1b),
Ethyl-(5-methoxyl group-2-[4-morpholinodithio) disulfide (1c),
Ethyl-(2-benzoglyoxaline) disulfide (1d),
Ethyl-(5-methyl-2-benzoglyoxaline) disulfide (1e),
Ethyl-(5-nitro-2-benzoglyoxaline) disulfide (1f),
Normal-butyl-(2-benzoxazole) disulfide (1g),
Normal-butyl-(2-[4-morpholinodithio) disulfide (1h),
Normal-butyl-(5-methoxyl group-2-[4-morpholinodithio) disulfide (1i),
Normal-butyl-(2-benzoglyoxaline) disulfide (1j),
Normal-butyl-(5-methyl-2-benzoglyoxaline) disulfide (1k), or
Normal-butyl-(5-nitro-2-benzoglyoxaline) disulfide (1l).
Another object of the present invention provides the compound method of the disulfide compound shown in the formula 1, can realize through following steps:
Wherein X, R
1And R
2Definition the same; X
1Be chlorine, bromine or iodine.
(1) compound I obtains compound I I with the Sulfothiorine reaction in protic solvent; Temperature of reaction is 60-100 ℃; Reaction times is 1-5 hour, is preferably 2 hours.
(2) under alkaline condition, in protic solvent, compound I I and compound III reaction production 1 compound; Temperature of reaction is that room temperature extremely refluxes, and carries out in room temperature usually; Reaction times is 0.5-3 hour.
In step (1) and (2), said protic solvent is methanol-water, alcohol-water or Virahol-water.
In the step (2), the alkali that said alkaline condition uses is sodium hydroxide or Pottasium Hydroxide.
Another object of the present invention provides the application of the disulfide compound shown in the formula 1 in the preparation antitumor drug, the particularly application in the medicine of preparation treatment colorectal carcinoma and lymphatic cancer.Preliminary pharmacological evaluation finds that they to various tumor cell strains, comprise that HCT-116, L5178 γ all have good vitro inhibition proliferation function.IC to above-mentioned tumor cell line
50Between 1-14 μ g/mL, show that its antitumor spectra is wider, be expected in the anticancer disease drug of preparation, to use.
Characteristics of the present invention are to be starting raw material with the halogenated alkyl thing, through and the Sulfothiorine reaction generate alkyl sodium (potassium) thiosulfate, again under alkaline condition with sulfhydryl heterocycle compound reaction generation disulfide compound.The compound that makes has better antitumor activity, and anti-sulphur spectrum is wider.The used raw material of the present invention is wide material sources not only, are easy to preparation, and reaction conditions is gentle, and each goes on foot the yield height, and is simple to operate, and production cost is low, is suitable for suitability for industrialized production.
Embodiment
Following embodiment is that explanation is of the present invention, rather than limits the present invention by any way.
Embodiment 1, ethylenebis dithiocarbamate Preparation of sodium:
Get the 10mmol iodoethane, 2.48g five water Sulfothiorine mix with 25mL 75% ethanol-water solution, reflux 2 hours, through detecting the Sulfothiorine completely dissolve, cooling directly is used for next step reaction.
The preparation of embodiment 2, ethyl-(2-benzoxazole) disulfide (1a)
Get 1.51g 2-mercaptobenzoxazole, mix, drip 30%KOH and after solid all dissolves, pour in the above-mentioned ethylenebis dithiocarbamate metabisulfite solution with 10mL water; Continue to stir 30min in room temperature; The most ethanol of pressure reducing and steaming, ether extraction, dried over mgso; Filtering and concentrating, resistates obtains colorless oil through silica gel column chromatography (eluent is sherwood oil and ether).Yield 75%.
1H-NMR(CDCl
3)，δ(ppm)：1.43(t，3H，CH
3)，3.02(q，2H，CH
2)，7.30(m，2H，ArH)，7.50(m，1H，ArH)，7.68(m，H，ArH)；ESI-Mass：211.9(M+1)
+.
The preparation of embodiment 3, ethyl-(2-[4-morpholinodithio) disulfide (1b)
With reference to embodiment 2, just change the 2-mercaptobenzoxazole into 2-mercaptobenzothiazole.Product is a colorless oil, yield 70%;
1H-NMR (CDCl
3), δ (ppm): 1.41 (t, 3H, CH
3), 2.98 (q, 2H, CH
2), 7.30 (m, 2H, ArH), 7.42 (m, H, ArH), 7.79 (dd, H, ArH), 7.86 (dd, H, ArH); ESI-Mass:227.9 (M+1)
+.
The preparation of embodiment 4, ethyl-(5-methoxyl group-2-[4-morpholinodithio) disulfide (1c)
With reference to embodiment 2, just change the 2-mercaptobenzoxazole into 5-methoxyl group-2-mercaptobenzothiazole.Product is a colorless oil, yield 72%;
1H-NMR (CDCl
3), δ (ppm): 1.41 (t, 3H, CH
3), 2.97 (q, 2H, CH
2), 3.86 (s, 3H, CH
3O), 6.96 (dd, H, ArH), 7.36 (d, H, ArH), 7.63 (d, H, ArH), ESI-Mass:257.9 (M+1)
+.
The preparation of embodiment 5, ethyl-(2-benzoglyoxaline) disulfide (1d)
With reference to embodiment 2, just change the 2-mercaptobenzoxazole into 2-mercaptobenzimidazole.Product is a white solid, yield 70%.
1H-NMR(CD
3OD)，δ(ppm)：1.33(t，3H，CH
3)，2.93(q，2H，CH
2)，7.22(m，2H，ArH)，7.51(m，2H，ArH)，ESI-Mass：210.9(M+1)
+.
The preparation of embodiment 6, ethyl-(5-methyl-2-benzoglyoxaline) disulfide (1e)
With reference to embodiment 2, just change the 2-mercaptobenzoxazole into 5-methyl-2-mercaptobenzimidazole.Product is a colorless oil, yield 73%.
1H-NMR(CDCl
3)，δ(ppm)：1.34(t，3H，CH
3)，2.45(s，3H，CH
3)，2.88(q，2H，CH
2)，7.05(d，H，ArH)，7.32(s，H，ArH)，7.44(d，H，ArH)，ESI-Mass：224.9(M+1)
+.
The preparation of embodiment 7, ethyl-(5-nitro-2-benzoglyoxaline) disulfide (1f).
With reference to embodiment 2, just change the 2-mercaptobenzoxazole into 5-nitro-2-mercaptobenzimidazole.Obtain yellow solid, yield 65%.
1H-NMR(CDCl
3)，δ(ppm)：1.40(t，3H，CH
3)，2.95(q，2H，CH
2)，7.60(d，H，ArH)，8.19(d，H，ArH)，8.48(s，H，ArH)，ESI-Mass：256.0(M+1)
+.
The preparation of embodiment 8, normal-butyl Sulfothiorine:
With reference to embodiment 1, just replace iodoethane with bromination of n-butane, make the normal-butyl hypo solution.
The preparation of embodiment 9, normal-butyl-(2-benzoxazole) disulfide (1g)
Get 1.51g 2-mercaptobenzoxazole, mix, drip 30%KOH and after solid all dissolves, pour in the above-mentioned normal-butyl hypo solution with 10mL water; Continue to stir 30min, the most ethanol of pressure reducing and steaming, ether extraction in room temperature; Dried over mgso; Filtering and concentrating, resistates obtains colorless oil, yield 80% through silica gel column chromatography (eluent is sherwood oil and ether).
1H-NMR(CDCl
3)，δ(ppm)：0.92(t，3H，CH
3)，1.45(m，2H，CH
2)，1.75(m，2H，CH
2)，3.00(t，2H，CH
2)，7.30(m，2H，ArH)，7.49(m，1H，ArH)，7.68(m，H，ArH)，ESI-Mass：239.9(M+1)
+.
The preparation of embodiment 10, normal-butyl-(2-[4-morpholinodithio) disulfide (1h):
With reference to embodiment 9, just change the 2-mercaptobenzoxazole into 2-mercaptobenzothiazole, product is a colourless liquid, yield 83%.
1H-MR(CDCl
3)，δ(ppm)：0.93(t，3H，CH
3)，1.42(m，2H，CH
2)，1.75(m，2H，CH
2)，2.97(t，2H，CH
2)，7.32(m，H，ArH)，7.44(m，1H，ArH)，7.83(m，2H，ArH)，ESI-Mass：256.0(M+1)
+.
The preparation of embodiment 11, normal-butyl-(5-methoxyl group-2-[4-morpholinodithio) disulfide (1i)
With reference to embodiment 9, just change the 2-mercaptobenzoxazole into 5-methoxyl group-2-mercaptobenzothiazole, product is a colourless liquid, yield 85%.
1H-MR(CDCl
3)，δ(ppm)：0.92(t，3H，CH
3)，1.44(m，2H，CH
2)，1.75(m，2H，CH
2)，2.96(t，2H，CH
2)，3.86(s，3H，CH
3O)，6.97(dd，H，ArH)，7.36(d，1H，ArH)，7.65(d，H，ArH)，ESI-Mass：286.0(M+1)
+.
The preparation of embodiment 12, normal-butyl-(2-benzoglyoxaline) disulfide (1j)
With reference to embodiment 9, just change the 2-mercaptobenzoxazole into 2-mercaptobenzimidazole, product is a white solid, yield 77%.
1H-MR(CD
3OD)，δ(ppm)：0.86(t，3H，CH
3)，1.39(m，2H，CH
2)，1.68(m，2H，CH
2)，2.89(t，2H，CH
2)，7.21(m，2H，ArH)，7.50(m，2H，ArH)，ESI-Mass：239.0(M+1)
+.
The preparation of embodiment 13, normal-butyl-(5-methyl-2-benzoglyoxaline) disulfide (1k):
With reference to embodiment 9, just change the 2-mercaptobenzoxazole into 5-methyl-2-mercaptobenzimidazole, product is a colourless liquid, yield 74%.
1H-NMR(CDCl
3)，δ(ppm)：0.86(t，3H，CH
3)，1.36(m，2H，CH
2)，1.65(m，2H，CH
2)，2.45(s，3H，CH
3)，2.84(t，2H，CH
2)，7.05(d，H，ArH)，7.32(s，H，ArH)，7.44(d，1H，ArH)，ESI-Mass：253.0(M+1)
+.
The preparation of embodiment 14, normal-butyl-(5-nitro-2-benzoglyoxaline) disulfide (11):
With reference to embodiment 9, just change the 2-mercaptobenzoxazole into 5-nitro-2-mercaptobenzimidazole, product is a yellow solid, yield 71%.
1H-NMR(CDCl
3)，δ(ppm)：0.88(t，3H，CH
3)，1.40(m，2H，CH
2)，1.68(m，2H，CH
2)，2.90(t，2H，CH
2)，7.60(d，J＝7.8Hz，H，ArH)，8.18(d，J＝7.8Hz，H，ArH)，8.47(s，1H，ArH)，ESI-Mass：284.0(M+1)
+.
Embodiment 15, anti-tumor biological testing method:
Experiment all comes from the biological article collecting center (ATCC) of USS with tumour cell.
The utilization mtt assay detects cell survival rate, and the cell that is about to be grown in logarithmic phase is through 0.01% trysinization, and counting is with 2.0 * 10
3The cell density in/hole is seeded in 96 orifice plates 100 milliliters, places 5%CO
237 ℃ of overnight cultures in the incubator.Each compound is provided with six concentration gradients, and each concentration is established three multiple holes, and each concentration joins respectively in the corresponding aperture, 5%CO
2Cultivated 72 hours in 37 ℃ of incubators; Adding 20 milliliters 5mg/mL MTT.37 ℃ hatches to inhale after 3 hours and abandons supernatant; The DMSO dissolving that adds 100 milliliters uses SpectraMAX340 to survey 550nm (L1) absorbance value, reference wavelength 690nm (L2); (L1-L2) value is obtained IC to the effect of suppressor factor different concns through Graphpad Prism 4 software matches
5012 compounds of institute's synthetic are to the IC of different tumor lines
50(μ g/mL) value is seen table 1.
Table 1
NT: do not detect.
Can find out that from last table 1 12 all compounds all have certain inhibition active to tumor cell line, wherein suppress active higher with X during for NH, alkyl chain is little for activity influence.Wherein the inhibition activity with 11 couples of L5178 γ of compound is the strongest, its IC
50Reach 1.5 μ g/mL.Generally speaking, this compounds has the good antitumor application prospect.
Claims (7)
1. the disulfide compound shown in one type of following formula 1:
Formula 1
Wherein:
X is NH, O or S;
R
1Be the C1-C5 alkyl;
R
2Be hydrogen, C1-C5 alkyl, C1-C5 alkoxyl group or nitro.
2. disulfide compound according to claim 1, wherein, said disulfide compound is specially:
Ethyl-(2-benzoxazole) disulfide,
Ethyl-(2-[4-morpholinodithio) disulfide,
Ethyl-(5-methoxyl group-2-[4-morpholinodithio) disulfide,
Ethyl-(2-benzoglyoxaline) disulfide,
Ethyl-(5-methyl-2-benzoglyoxaline) disulfide,
Ethyl-(5-nitro-2-benzoglyoxaline) disulfide,
Normal-butyl-(2-benzoxazole) disulfide,
Normal-butyl-(2-[4-morpholinodithio) disulfide,
Normal-butyl-(5-methoxyl group-2-[4-morpholinodithio) disulfide,
Normal-butyl-(2-benzoglyoxaline) disulfide,
Normal-butyl-(5-methyl-2-benzoglyoxaline) disulfide, or
Normal-butyl-(5-nitro-2-benzoglyoxaline) disulfide.
3. the preparation method of the described disulfide compound of claim 1 is characterized in that, this method may further comprise the steps:
Wherein X, R
1And R
2Definition with claim 1; X
1Be chlorine, bromine or iodine;
(1) compound I obtains compound I I with the Sulfothiorine reaction in protic solvent; Temperature of reaction is 60-100 ℃; Reaction times is 1-5 hour;
(2) under alkaline condition, in protic solvent, compound I I and compound III reaction production 1 compound; Temperature of reaction is that room temperature is to refluxing; Reaction times is 0.5-3 hour.
4. preparation method according to claim 3 is characterized in that, in said step (1) and (2), said protic solvent is methanol-water, alcohol-water or Virahol-water.
5. preparation method according to claim 3 is characterized in that, in the said step (2), the alkali that said alkaline condition uses is sodium hydroxide or Pottasium Hydroxide.
6. the described disulfide compound of claim 1 is in the purposes of preparation in the antitumor drug.
7. purposes according to claim 6 is characterized in that, described tumour is colorectal carcinoma or lymphatic cancer.
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Cited By (4)
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|---|---|---|---|---|
| CN105017352A (en) * | 2015-07-02 | 2015-11-04 | 广东药学院 | Indole alkaloid glycoside and application thereof |
| CN105130864A (en) * | 2015-07-27 | 2015-12-09 | 扬州大学 | Diselenide synthesizing method |
| CN109053841A (en) * | 2018-08-30 | 2018-12-21 | 浙江大学 | The bis- sulphur of 6- replace -2 '-deoxyguanosine class compounds and its preparation method and application |
| CN113880777A (en) * | 2021-09-22 | 2022-01-04 | 贵州大学 | Preparation method and application of quinazolinone derivatives containing disulfide structures |
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| US6552060B1 (en) * | 1997-08-11 | 2003-04-22 | Prolx Pharmaceuticals, Inc. | Asymmetric disulfides and methods of using same |
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Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105017352A (en) * | 2015-07-02 | 2015-11-04 | 广东药学院 | Indole alkaloid glycoside and application thereof |
| CN105017352B (en) * | 2015-07-02 | 2017-08-22 | 广东药科大学 | A kind of indole alkaloid glucoside and its application |
| CN105130864A (en) * | 2015-07-27 | 2015-12-09 | 扬州大学 | Diselenide synthesizing method |
| CN105130864B (en) * | 2015-07-27 | 2016-09-21 | 扬州大学 | A kind of method synthesizing diselenide |
| CN109053841A (en) * | 2018-08-30 | 2018-12-21 | 浙江大学 | The bis- sulphur of 6- replace -2 '-deoxyguanosine class compounds and its preparation method and application |
| CN109053841B (en) * | 2018-08-30 | 2020-11-17 | 浙江大学 | 6-disulfur substituted-2' -deoxyguanosine compound and preparation method and application thereof |
| CN113880777A (en) * | 2021-09-22 | 2022-01-04 | 贵州大学 | Preparation method and application of quinazolinone derivatives containing disulfide structures |
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Application publication date: 20120822 |