CN105061342A - 1,2,4-triazole based disulfide compound and preparation method thereof - Google Patents
1,2,4-triazole based disulfide compound and preparation method thereof Download PDFInfo
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- CN105061342A CN105061342A CN201510567864.6A CN201510567864A CN105061342A CN 105061342 A CN105061342 A CN 105061342A CN 201510567864 A CN201510567864 A CN 201510567864A CN 105061342 A CN105061342 A CN 105061342A
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
- C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
- C07D249/10—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D249/12—Oxygen or sulfur atoms
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Abstract
The invention provides a 1,2,4-triazole based disulfide compound of which the chemical structural formula is shown by a formula in the description. A preparation method of the compound comprises the steps of: taking ethanol as a solvent, and preparing the compound by performing reaction between 3-phenyl-4-amino-5-mercapto-1,2,4-triazole and an mercapto-isothiourea hydrochloride in the presence of sodium hydrogen carbonate, wherein the compound is used for preparing antitumor pharmaceutical compositions. The invention has the advantages that a series of the 1,2,4-triazole based disulfide compounds are prepared for the first time according to a new drug design theory and a new drug design method, the structure is determined by virtue of an infrared spectrum, a nuclear magnetic resonance hydrogen spectrum and a high-resolution mass spectrum, the proliferation inhibition activity of the compounds to human cervical cancer cells Hela, human hepatocellular carcinoma cells SMMC-7721 and human lung cancer cells A549 is tested by a CCK-8 method, and a result shows that the compounds have a relatively good effect of inhibiting tumor cell proliferation and have a potential application prospect.
Description
Technical field
The present invention relates to medical art, particularly a kind of disulfide compound based on 1,2,4-triazole and preparation method thereof.
Background technology
Malignant tumour is one of disease of serious threat human health, therefore, finds the concern that new treatment means and target are subject to people day by day.Trx (thioredoxin, Trx) is a kind of small molecules multifunctional protein being generally expressed in various biological tissues organ.Trx (Trx), thioredoxin reductase (thioredoxinreductase, TrxR) and nicotinoyl VITAMIN B4 dinucleotide phosphoric acid (NADPH) constitute Trx (Trx) system jointly.Research display, the relation of Trx system and tumour is very close, affects the process of the generation of tumour, development, propagation, differentiation, even can as of a clinical prognosis index.Trx has become the large focus in oncomolecularbiology research in the world, is an oncotherapy novel targets having clinical meaning, see: document 1) Arn é rESJ, HolmgrenA.Eur.J.Biochem.2000,267,6102; Document 2) KirkpatrickD, KuperusM, DowdeswellM, etal.Biochem.Pharmacol.1998,55,987; Document 3) TanQ, LiJ, YinHW, etal.InvestNewDrugs2010,28,205; Document 4) XingFX, LiSL, GeXY, etal.OralOncol.2008,44,963; Document 5) UrigS, BeckerK.Semin.CancerBiol.2006,16,452; Document 6) HeJ, LiDD, XiongK, etal.Bioorg.Med.Chem.2012,20,3816.
In the state of the art, the targeted anticancer medicine entering the thioredoxin system of clinical study in the world only has three kinds: motexafin gadolinium, 1-methyl-propyl-2-imidazolyl disulfide and Ethaselen, see: document 7) LiDD, TaoZW.TianjinPharmacy2014,26,64.The motexafin gadolinium (Motexafingadolinium) of Canada PharmacyclicsInc research and development, is a kind of cancer therapy drug with porphyrin ring similar structures, carries out the clinical study of III phase at present; 1-methyl-propyl-2-imidazolyl disulfide (PX-12) of ProlXPharmaceuticals company of U.S. research and development, is a kind of cancer therapy drug with disulfide structure, carries out the clinical study of II phase at present; The Ethaselen (Ethaselen) of Peking University's research and development, is a kind of cancer therapy drug with Benzisoelenazolone structure, has completed the clinical study of I phase at present.Wherein, PX-12 is the representative molecule of disulfide class anticancer compound, also be first disulfide class anticancer compound entering clinical study in the world, see: document 8) RamanathanRK, AbbruzzeseJ, DragovichT, etal.CancerChemother.Pharmacol.2011,67,503; Document 9) BakerAF, AdabKN, RaghunandN, etal.InvestNewDrugs2013,31,631.Research shows, the disulfide linkage in PX-12 is the critical active region that this drug molecule and thioredoxin reductase and Trx react.It can cause the activity decrease of thioredoxin reductase and Trx and trigger the antitumous effect of its molecular targeted property, see: document 10) YouBR, ShinHR, ParkWH.Int.J.Oncol.2014,44,301; Document 11) ShinHR, YouBR, ParkWH.Oncol.Lett.2013,6,1804.Above-mentioned report has important directive significance to being sought performance better disulfide kind anti-cancer drugs thing by structure of modification.
Former achievements shows: 1,2,4-triazole class derivative has the multiple biological activitys such as anticancer, antibacterial, anti-oxidant, see: document 12) KamalA, KhanMNA, SrikanthYVV.etal.Chem.Biol.DrugDes.2009,73,687; Document 13) MurtyMSR, RamKR, RaoRV, etal.Lett.DrugDes.Discov.2012,9,276; Document 14) KheraMK, CliffeIA, MathurT, etal.Bioorg.Med.Chem.Lett.2011,21,2887; Document 15)
e, KaraaliN, Y1lmazF, etal.Arch.Pharm.Chem.LifeSci.2013,346,556.And the heterocycle of different activities or group are incorporated on 1,2,4-triazole parent nucleus, can have an impact to its biological activity, therefore, become the new focus of azole compounds research.
Based on this conception, by certain reaction formation, achieve the split of 1,2,4-triazole and disulfide, then adopt CCK-8 method to measure the proliferation inhibition activity of such compound on tumor cell, to finding the better compound of anti-tumor activity.
[summary of the invention]
The object of the invention is for solving cancer therapy drug of less types and lack technology of preparing problem, a kind of disulfide compound based on 1,2,4-triazole and preparation method thereof is provided, this disulfide compound has good antitumour activity, is the good potential cancer therapy drug of a class.
Technical scheme of the present invention:
A kind of disulfide compound based on 1,2,4-triazole, its chemical structural formula is as follows:
In structural formula: R
1for the aromatic group of C1-6 alkyl, C3-8 cycloalkyl or C5-14, wherein aromatic group can replace by the group of 1-3 hydroxyl, nitro, halogen atom, cyano group, C1-6 alkoxyl group or C1-6 alkyl, or by C1-6 alkyl, C1-6 alkyl sulphonyl and C1-6 alkyl-carbonyl one or two group replace amino replace, described halogen atom is fluorine, chlorine, bromine or iodine atom;
R
2for C1-6 alkyl, the aromatic group of benzyl group or C5-14, wherein benzyl group can by 1-3 hydroxyl, nitro, halogen atom, cyano group, the group of C1-6 alkoxyl group or C1-6 alkyl replaced, or by C1-6 alkyl, the amino that one or two group in C1-6 alkyl sulphonyl and C1-6 alkyl-carbonyl replaces replaced, aromatic group can by 1-3 hydroxyl, nitro, halogen atom, cyano group, the group of C1-6 alkoxyl group or C1-6 alkyl replaced, or by C1-6 alkyl, the amino that one or two group in C1-6 alkyl sulphonyl and C1-6 alkyl-carbonyl replaces replaced, described halogen atom is fluorine, chlorine, bromine or iodine atom.
A kind of described preparation method based on the disulfide compound of 1,2,4-triazole, take ethanol as solvent, under sodium bicarbonate exists, carry out reaction by 3-phenyl-4-amino-5-sulfydryl-1,2,4-triazole and sulfydryl isothiuronium salts hydrochlorate and prepare, step is as follows:
1) 3-phenyl-4-amino-5-sulfydryl-1,2,4-triazole, sulfydryl isothiuronium salts hydrochlorate and ethanol are mixed and stirred, at 0-10 DEG C, instill concentration is 4wt% sodium bicarbonate aqueous solution, and stirring reaction 6-8h obtains muddy shape reaction solution;
2) by above-mentioned reaction solution after suction filtration, washing, take volume ratio as the ethanol-water mixture recrystallization of 1:1, obtained target compound.
Described sulfydryl isothiuronium salts hydrochlorate is second sulfydryl isothiuronium salts hydrochlorate, positive third sulfydryl isothiuronium salts hydrochlorate, positive fourth sulfydryl isothiuronium salts hydrochlorate, positive penta sulfydryl isothiuronium salts hydrochlorate or Benzylmercapto isothiuronium salts hydrochlorate; The mol ratio of 3-phenyl-4-amino-5-sulfydryl-1,2,4-triazole and sulfydryl isothiuronium salts hydrochlorate is 1:1-1.3; The amount ratio of 3-phenyl-4-amino-5-sulfydryl-1,2,4-triazole and ethanol is 1mmol:5-8mL; The mol ratio of sodium bicarbonate and 3-phenyl-4-amino-5-sulfydryl-1,2,4-triazole is 1.2-1.5:1.
The synthetic route of this preparation method is schematically as follows:
A kind of described application based on the disulfide compound of 1,3,4-oxadiazole, for the preparation of antitumor medicine composition, comprises anti-cervical cancer (Hela), liver cancer (SMMC-7721) and lung cancer (A549).
The invention has the beneficial effects as follows: the present invention is according to new drug design Theories and methods, prepare series 1 first, 2, the disulfide compound of 4-triazole, and confirm structure by infrared spectra, proton nmr spectra and high resolution mass spectrum etc., the proliferation inhibition activity of this compounds to human body cervical carcinoma cell Hela, human hepatoma cell SMMC-7721 and Human Lung Cancer cell A549 is tested with CCK-8 method, result shows: such compound on tumor cell proliferation has good inhibition, has potential application prospect.
Embodiment
Embodiment 1:
A kind of preparation method based on the disulfide compound of 1,2,4-nitrogen triazole, the described disulfide compound based on 1,2,4-nitrogen triazole is ethyl (3-phenyl-4-amino-1,2,4-nitrogen triazole-5-base) disulfide, its chemical formula chemical structural formula is as follows:
Preparation method take ethanol as solvent, and under sodium bicarbonate exists, carry out reaction by 3-phenyl-4-amino-5-sulfydryl-1,2,4-triazole and second sulfydryl isothiuronium salts hydrochlorate and prepare, step is as follows:
1) in 50mL round-bottomed flask, by 0.48g (2.5mmol) 3-phenyl-4-amino-5-sulfydryl-1,2,4-triazole, 0.47g (2.7mmol) second sulfydryl isothiuronium salts hydrochlorate and 20mL ethanol mix and stir, at 5 DEG C, instill 7mL, concentration is 4wt% sodium bicarbonate aqueous solution, stirring reaction 7h, obtains muddy shape reaction solution;
2) by above-mentioned reaction solution after suction filtration, washing, take volume ratio as the ethanol-water mixture recrystallization of 1:1, obtained target compound ethyl (3-phenyl-4-amino-1,2,4-nitrogen triazole-5-base) disulfide 0.33g, yield 50.3%, fusing point 120.8-122.5 DEG C.This obtained product is established and is numbered a.
Embodiment 2:
A kind of preparation method based on the disulfide compound of 1,2,4-nitrogen triazole, the described disulfide compound based on 1,2,4-nitrogen triazole is n-propyl (3-phenyl-4-amino-1,2,4-nitrogen triazole-5-base) disulfide, its chemical structural formula is as follows:
Preparation method is substantially the same manner as Example 1, and difference is: sulfydryl isothiuronium salts hydrochlorate used is positive third sulfydryl isothiuronium salts hydrochlorate, and the target compound of preparation is n-propyl (3-phenyl-4-amino-1,2,4-nitrogen triazole-5-base) disulfide.This obtained product is established and is numbered b.
Embodiment 3:
A kind of preparation method based on the disulfide compound of 1,2,4-nitrogen triazole, the described disulfide compound based on 1,2,4-nitrogen triazole is normal-butyl (3-phenyl-4-amino-1,2,4-nitrogen triazole-5-base) disulfide, its chemical structural formula is as follows:
Preparation method is substantially the same manner as Example 1, and difference is: sulfydryl isothiuronium salts hydrochlorate used is positive fourth sulfydryl isothiuronium salts hydrochlorate, and the target compound of preparation is normal-butyl (3-phenyl-4-amino-1,2,4-nitrogen triazole-5-base) disulfide.This obtained product is established and is numbered c.
Embodiment 4:
A kind of preparation method based on the disulfide compound of 1,2,4-nitrogen triazole, the described disulfide compound based on 1,2,4-nitrogen triazole is n-pentyl (3-phenyl-4-amino-1,2,4-nitrogen triazole-5-base) disulfide, its chemical structural formula is as follows:
Preparation method is substantially the same manner as Example 1, and difference is: sulfydryl isothiuronium salts hydrochlorate used is positive penta sulfydryl isothiuronium salts hydrochlorate, and the target compound of preparation is n-pentyl (3-phenyl-4-amino-1,2,4-nitrogen triazole-5-base) disulfide.This obtained product is established and is numbered d.
Embodiment 5:
A kind of preparation method based on the disulfide compound of 1,2,4-nitrogen triazole, the described disulfide compound based on 1,2,4-nitrogen triazole is benzyl (3-phenyl-4-amino-1,2,4-nitrogen triazole-5-base) disulfide, its chemical structural formula is as follows:
Preparation method is substantially the same manner as Example 1, and difference is: sulfydryl isothiuronium salts hydrochlorate used is Benzylmercapto isothiuronium salts hydrochlorate, and the target compound of preparation is benzyl (3-phenyl-4-amino-1,2,4-nitrogen triazole-5-base) disulfide.This obtained product is established and is numbered e.
Product anti-tumor biological body outer screening test obtained by above embodiment:
Product samples dissolves with DMSO, and Test compound concentrations is 5 × 10
-5mol/L, chemicals treatment 48 hours, adopts CCK-8 method to measure series compound to the proliferation inhibition rate of human body cervical carcinoma cell (Hela), human hepatoma cell (SMMC-7721) and Human Lung Cancer cell (A549).
Detected result:
1) physical data of product
as table 1shown in:
table 1
2) high resolution mass spectrum (HRMS) [M+H] of product
+peak value
as table 2shown in:
table 2
3) infrared spectra (IR) data of product
as table 3shown in:
table 3
4) product proton nmr spectra (
1hNMR) data
as table 4shown in:
table 4
5) proliferation inhibition rate of product
as table 5shown in:
table 5
Detected result shows: such compound on tumor cell proliferation has good inhibition, have to be applied to and prepare antitumor medicine composition, comprise the prospect of anti-cervical cancer (Hela), liver cancer (SMMC-7721) and lung cancer (A549).
Foregoing, it is only representative embodiment of the present invention, not any type of restriction is done to the present invention, every above embodiment is done according to technical spirit of the present invention any simple modification, equivalent variations and modification, all still belong in the scope of technical solution of the present invention.
Claims (4)
1. one kind based on the disulfide compound of 1,2,4-triazole, it is characterized in that: chemical structural formula is as follows:
In structural formula: R
1for the aromatic group of C1-6 alkyl, C3-8 cycloalkyl or C5-14, wherein aromatic group can replace by the group of 1-3 hydroxyl, nitro, halogen atom, cyano group, C1-6 alkoxyl group or C1-6 alkyl, or by C1-6 alkyl, C1-6 alkyl sulphonyl and C1-6 alkyl-carbonyl one or two group replace amino replace, described halogen atom is fluorine, chlorine, bromine or iodine atom;
R
2for C1-6 alkyl, the aromatic group of benzyl group or C5-14, wherein benzyl group can by 1-3 hydroxyl, nitro, halogen atom, cyano group, the group of C1-6 alkoxyl group or C1-6 alkyl replaced, or by C1-6 alkyl, the amino that one or two group in C1-6 alkyl sulphonyl and C1-6 alkyl-carbonyl replaces replaced, aromatic group can by 1-3 hydroxyl, nitro, halogen atom, cyano group, the group of C1-6 alkoxyl group or C1-6 alkyl replaced, or by C1-6 alkyl, the amino that one or two group in C1-6 alkyl sulphonyl and C1-6 alkyl-carbonyl replaces replaced, described halogen atom is fluorine, chlorine, bromine or iodine atom.
2. one kind
as claimbased on the preparation method of the disulfide compound of 1,2,4-triazole described in 1, it is characterized in that: take ethanol as solvent, under sodium bicarbonate exists, by 3-phenyl-4-amino-5-sulfydryl-1,2,4-triazole and sulfydryl isothiuronium salts hydrochlorate carry out reaction to be prepared, and step is as follows:
1) 3-phenyl-4-amino-5-sulfydryl-1,2,4-triazole, sulfydryl isothiuronium salts hydrochlorate and ethanol are mixed and stirred, at 0-10 DEG C, instill concentration is 4wt% sodium bicarbonate aqueous solution, and stirring reaction 6-8h obtains muddy shape reaction solution;
2) by above-mentioned reaction solution after suction filtration, washing, take volume ratio as the ethanol-water mixture recrystallization of 1:1, obtained target compound.
3.
according to claimbased on 1 described in 2,2, the preparation method of the disulfide compound of 4-triazole, is characterized in that: described sulfydryl isothiuronium salts hydrochlorate is second sulfydryl isothiuronium salts hydrochlorate, positive third sulfydryl isothiuronium salts hydrochlorate, positive fourth sulfydryl isothiuronium salts hydrochlorate, positive penta sulfydryl isothiuronium salts hydrochlorate or Benzylmercapto isothiuronium salts hydrochlorate; The mol ratio of 3-phenyl-4-amino-5-sulfydryl-1,2,4-triazole and sulfydryl isothiuronium salts hydrochlorate is 1:1-1.3; The amount ratio of 3-phenyl-4-amino-5-sulfydryl-1,2,4-triazole and ethanol is 1mmol:5-8mL; The mol ratio of sodium bicarbonate and 3-phenyl-4-amino-5-sulfydryl-1,2,4-triazole is 1.2-1.5:1.
4. one kind
as claimbased on the application of the disulfide compound of 1,2,4-triazole described in 1, it is characterized in that: for the preparation of antitumor medicine composition, comprise anti-cervical cancer (Hela), liver cancer (SMMC-7721) and lung cancer (A549).
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106957275A (en) * | 2017-04-17 | 2017-07-18 | 天津理工大学 | The triazole compound of 2 alkyl-dithio, 5 substituted benzene urea groups 1,2,4 and its application |
| CN110128360A (en) * | 2019-06-28 | 2019-08-16 | 天津理工大学 | Two thio 1,2,4- nitrogen triazole class compounds and its preparation method and application |
| CN113461625A (en) * | 2021-07-02 | 2021-10-01 | 天津理工大学 | Preparation method and application of disulfide compound based on 1,2, 4-azotriazole |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103965140A (en) * | 2014-05-12 | 2014-08-06 | 天津理工大学 | 1,3,4-thiadiazole-based disulfide compound and preparation method and application thereof |
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- 2015-09-08 CN CN201510567864.6A patent/CN105061342A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103965140A (en) * | 2014-05-12 | 2014-08-06 | 天津理工大学 | 1,3,4-thiadiazole-based disulfide compound and preparation method and application thereof |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106957275A (en) * | 2017-04-17 | 2017-07-18 | 天津理工大学 | The triazole compound of 2 alkyl-dithio, 5 substituted benzene urea groups 1,2,4 and its application |
| CN110128360A (en) * | 2019-06-28 | 2019-08-16 | 天津理工大学 | Two thio 1,2,4- nitrogen triazole class compounds and its preparation method and application |
| CN113461625A (en) * | 2021-07-02 | 2021-10-01 | 天津理工大学 | Preparation method and application of disulfide compound based on 1,2, 4-azotriazole |
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