CN109456312A - 1,2,3- its synthetic method of triazole tubulin polymerization inhibitor and application - Google Patents
1,2,3- its synthetic method of triazole tubulin polymerization inhibitor and application Download PDFInfo
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- CN109456312A CN109456312A CN201811267408.XA CN201811267408A CN109456312A CN 109456312 A CN109456312 A CN 109456312A CN 201811267408 A CN201811267408 A CN 201811267408A CN 109456312 A CN109456312 A CN 109456312A
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- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D249/04—1,2,3-Triazoles; Hydrogenated 1,2,3-triazoles
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Abstract
The invention discloses a new class of 1,2,3- triazole compound, their preparation method and its in the application of tubulin polymerization inhibitor, belong to anti-tumor drug chemical field.The present invention is simple and efficient, and environmentally protective has synthesized such 1,2,3- triazole compounds.It has the following structure general formula:Such Compound ira vitro anticancer activity is experiments have shown that all have certain inhibiting effect to kinds of tumor cells PC3, HepG2, MGC803, while having significant inhibiting effect to the polymerization of tubulin.Compound (6c) is better than anti-tumor drug colchicin and anti-tumor drug 5 FU 5 fluorouracil to the activity of three kinds of cancer cells, compound (6a, 6b, 6c, 6g, anti-tumor drug 5 FU 5 fluorouracil 6j) is better than to the activity of three kinds of cancer cells, can be used as the candidate further developed or lead compound, applied to preparing anti-tumor drug.
Description
Technical field
The present invention relates to anti-tumor drug chemical fields, and in particular to a kind of novel 1,2,3- triazole compound, it
Preparation method and its application as a new class of anti-tumor drug lead compound.
Background technique
Micro-pipe is the important component of most of eukaryotic cells skeletons, is maintaining cellular morphology, is keeping cell interior knot
Play an important role in the order of structure, and with intracellular matter transportation, cell movement, cell differentiation and development and cell
The vital movements such as schizogamy are closely related.The important physiological action of tubulin (Tubulin) makes it in tumor area
As important target spot.The colchicin mitosis capable of inhibiting cell as tubulin polymerization inhibitor, there is antitumor work
With, but toxicity is big, uses less.
Summary of the invention
It is an object of that present invention to provide the novel 1,2,3- triazole chemical combination that a kind of anti-tumor activity is better than colchicin
Object.
It is another object of the present invention to provide one kind to be simple and efficient, environmentally protective 1,2,3- triazole of synthesizing new
The method for closing object.
Another object of the present invention is to seek the anti-tumor target of the compound, it was demonstrated that compound is tubulin polymerization
Inhibitor.
The novel 1,2,3- triazole compound of one kind of the present invention has following general formula:
Specially compound shown in 6a~6l:
Novel 1,2,3- triazole compound of the present invention is mainly made through the following steps:
(1) preparation method of compound (4):
In solvent, by 3,4,5- trimethoxy-anilines (1), 4- methoxyl group benzyl chloride is stirred to react under alkaline condition, and chloroethene is added
Acyl chloride reaction obtains compound (4), and alkali compounds used is sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, phosphoric acid
One of sodium, ten phosphate dihydrate sodium, potassium phosphate, saleratus, sodium bicarbonate；Solvent used is ethyl alcohol, methanol, N, N- bis-
One of methylformamide, dimethyl sulfoxide, tetrahydrofuran, dioxane, methylene chloride or in which any two kinds of mixture；
Reaction carries out between 0-80 DEG C.
(2) preparation method of compound (5):
In solvent, compound (4) and Sodium azide are stirred to react under alkaline condition, obtain compound (5)；Alkaline chemical combination used
Object is sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium phosphate, ten phosphate dihydrate sodium, potassium phosphate, saleratus, carbonic acid
One of hydrogen sodium；Solvent used is ethyl alcohol, methanol, N,N-dimethylformamide, dimethyl sulfoxide, tetrahydrofuran, dioxy
One of six rings, methylene chloride or in which any two kinds of mixture；Reaction carries out between 60-120 DEG C.
(3) preparation method of general formula (6a~6l):
In solvent, compound (5) reacts in the presence of cupric sulfate pentahydrate and sodium ascorbate with substituted alkynyl compound, used
Solvent is one of acetone, acetonitrile, ethyl alcohol, methanol, isopropanol, tetrahydrofuran, distilled water or in which two or three any
Mixture；Reaction carries out between 25-80 DEG C.
The invention has the advantages that 1, such Compound ira vitro anticancer activity experiments have shown that kinds of tumor cells PC3, HepG2,
MGC803 etc. all has certain inhibiting effect, while having significant inhibiting effect to the polymerization of tubulin.Especially chemical combination
Object (6c) is better than anti-tumor drug colchicin and anti-tumor drug 5- to the activity of tri- kinds of cancer cells of PC3, HepG2, MGC803
Fluorouracil, compound (6a, 6b, 6c, 6g, 6j) are better than antineoplastic to the activity of tri- kinds of cancer cells of PC3, HepG2, MGC803
Object 5 FU 5 fluorouracil can be used as the candidate further developed or lead compound, applied to preparing anti-tumor drug.2, it synthesizes
Method is simple and efficient, environmentally protective, high income, up to 80% or more.
Detailed description of the invention
Fig. 1 is the compound 6c of various concentration to Tubulin polymerization inhibiting activity figure, wherein 1- blank control, 2- colchicum
Alkali, 3-1uM compound 6c, 4-2uM compound 6c, 5-4uM compound 6c.
Specific embodiment
It is as follows for embodiment for the present invention is better described:
Preparation (1) prepare compound (4) of 1 general formula of embodiment (6a~6l):
(1) at room temperature, in alcohol solvent, 3,4,5- trimethoxy-aniline (1), 4- methoxyl group benzyl chloride, sodium carbonate stirring is added instead
It answers, chloracetyl chloride is then added and reacts to obtain compound (4)；
(2) prepare compound (5):
In alcohol solvent, potassium phosphate, compound (4) and Sodium azide is added, 60 DEG C are stirred to react, and obtain compound (5)；
(3) prepare compound (6a~6l): compound (5) (1.93g, 5mmol) and different alkynyl compounds (6mmol) are added
10mL acetone/water (5ml/5ml) dissolution, is eventually adding cupric sulfate pentahydrate (1mmol) and sodium ascorbate (0.5mmol), room temperature
It is stirred overnight.TLC monitors reaction process, to which distilled water after reaction, is added into system, then with dichloroethanes extraction 6
It is secondary, then be stripped dichloroethanes phase 3 times, each 10mL with saturated salt solution, last organic phase is dry with anhydrous magnesium sulfate, filters out sulphur
Dichloroethanes is distilled off in sour magnesium, filtrate decompression.Gained crude product silicagel column column chromatographic isolation and purification, petroleum ether/acetic acid second
Ester=8:1 elution, obtains compound (6a~6l) respectively.
Compound (6a):1H NMR(400MHz,DMSO-d6)δ8.3(s,1H),7.7(d,1H),7.7(d,1H),7.4(d,
1H),7.4(t,1H),7.2(d,2H),6.9(d,2H),6.6(s,2H),6.2(s,1H),5.5(s,2H),5.2(s,2H),4.8
(s, 2H), 3.7 (s, 9H), 3.7 (s, 3H) yields 81%.
Compound (6b):1H NMR(400MHz,DMSO-d6)δ8.2(s,1H),8.0(d,1H),7.7(d,1H),7.2(dd,
3H),7.0(dd,1H),6.9(d,2H),6.6(s,2H),6.3(d,1H),5.3(s,2H),5.2(s,2H),4.8(s,2H),
3.7 (s, 9H), 3.7 (s, 3H) yields 86%.
Compound (6c):1H NMR(400MHz,DMSO-d6)δ8.2(s,1H),7.7(d,1H),7.2(dd,3H),7.1(dd,
1H),6.9(d,2H),6.6(s,2H),6.2(d,1H),5.30(s,2H),5.2(s,2H),4.8(s,2H),3.7(s,9H),
3.7 (s, 3H), 2.4 (d, 3H) yields 85%.
Compound (6d):1H NMR(400MHz,DMSO-d6)δ8.1(s,1H),7.3(dd,2H),7.2(d,2H),7.1(d,
2H), 7.0 (t, 1H), 6.9 (d, 2H), 6.6 (s, 2H), 5.2 (d, 4H), 4.8 (s, 2H), 3.7 (s, 9H), 3.7 (s, 3H) are received
Rate 83%.
Compound (6e):1H NMR(400MHz,DMSO-d6)δ8.0(d,2H),7.9(d,1H),7.6–7.3(m,2H),7.1
(d,2H),6.9(d,2H),6.6(s,2H),5.1(s,2H),4.8(s,2H),4.7(s,2H),3.7(d,9H),3.7(s,3H).
Yield 89%.
Compound (6f):1H NMR(400MHz,DMSO-d6)δ7.9(s,1H),7.2(d,2H),6.8(d,2H),6.6(s,
2H), 5.1 (s, 2H), 4.8 (s, 2H), 4.4 (s, 2H), 4.2 (t, 2H), 3.7 (s, 9H), 3.7 (s, 3H), 3.5 (t, 2H) are received
Rate 90%.
Compound (6g):1H NMR(400MHz,DMSO-d6)δ8.1(s,1H),7.8–7.6(m,2H),7.5–7.2(m,2H),
7.1(d,2H),6.9(d,2H),6.6(s,2H),5.1(s,2H),4.8(s,2H),4.7(s,2H),3.7(d,9H),3.7(s,
3H) yield 92%.
Compound (6h):1H NMR(400MHz,DMSO-d6)δ7.99(s,1H),7.6–7.3(m,10H),7.1(d,2H),6.9
(d, 2H), 6.6 (s, 2H), 5.1 (s, 2H), 4.8 (s, 2H), 4.9 (s, 2H), 3.7 (d, 9H), 3.7 (s, 3H) yields 93%.
Compound (6i):1H NMR(400MHz,DMSO-d6)δ9.6(s,1H),8.0(s,1H),7.1(d,2H),6.9(d,
2H), 6.6 (s, 2H), 5.1 (s, 2H), 4.8 (s, 2H), 4.7 (s, 2H), 3.7 (d, 9H), 3.7 (s, 3H) yields 80%.
Compound (6j):1H NMR(400MHz,DMSO-d6)δ8.0(s,1H),7.1(d,2H),6.9(d,2H),6.6(s,
2H), 5.1 (s, 2H), 4.8 (s, 2H), 4.6 (s, 2H), 3.9 (s, 3H), 3.7 (d, 9H), 3.7 (s, 3H) yields 86%.
Compound (6k):1H NMR(400MHz,DMSO-d6)δ7.9(s,1H),7.6(dd,2H),7.4(d,1H),7.1(t,
3H),7.0(t,1H),6.8(d,2H),6.6(s,2H),6.4(d,1H),5.5(s,2H),5.1(s,2H),4.8(s,2H),3.7
(s, 3H), 3.7 (s, 6H), 3.6 (s, 3H) yields 80%.
Compound (6l):1H NMR(400MHz,DMSO-d6)δ8.1(t,1H),7.8(s,1H),7.7(d,2H),7.4(d,
2H),7.1(d,2H),6.9(d,2H),6.6(s,2H),5.1(s,2H),4.8(s,2H),4.0(d,2H),3.7(s,9H),3.7
(s, 3H), 2.4 (s, 3H) yields 96%.
The antitumor cytolytic activity of 2 above compound of embodiment:
Screening compound used therefor is to be synthesized by the present invention, purify and obtain；Stock sample solution: it weighs 1-2mg sample and is placed in 2mL
In EP pipe, solution then is configured to DMSO, and 4 DEG C of preservations are placed, and utilize culture medium dilution according to required concentration when experiment.It takes pair
The cell in number growth period after digestion counts, adjusts cell density with culture medium, is seeded to 96 holes with the 4000-5000 hole cell/
In plate, every 150 μ L of hole discards culture medium, drug (50 μ g/mL, 100 μ g/ that addition has been diluted with culture medium after culture for 24 hours
ML), each concentration sets 6 multiple holes, separately sets blank control group and negative control group.After drug effect 72h, 20 μ are added in every hole
LMTT continues after cultivating 4h, sucks liquid, be added the DMSO of 150mL, shaken well, the place microplate reader 490nm detection absorbance
Value calculates inhibiting rate, and calculation formula is as follows: inhibiting rate (%)=(1- administration group absorbance value/blank group absorbance value) ×
Inhibiting rate is greater than 50% sample when 100%, 50 μ g/mL, resets concentration and carries out dusting cover.Test result uses SPSS software
Calculate IC50Value and related coefficient.Experimental result is shown in Table 1.
The IC of 1 compound of table inhibition tumor cell strain50Value
aEach numerical value indicates that variance analysis: p < 0.05,5-Fu:5- fluorine urine are phonetic with average value ± standard deviation (mean ± SD)
Pyridine, Colchicine: colchicin
The Tubulin polymerization inhibiting activity of 3 compound 6c of embodiment measures:
The tubulin of extraction is resuspended in in ice-cold G-PEM buffer (80mM PIPES pH 5.9,5mM MgCl2,1mM
EGTA, 1mMATP, 5% (v/v) glycerol), take 100ul to add in 96 orifice plates comprising 100ul compound 6c, tubulin
0uM, 1uM, 2uM, tetra- gradients of 4uM is arranged in final concentration of 5.6g/L, drug concentration, and sample mixes well, spectrophotometer inspection
The polymerization of micrometer tubulin is spaced 5min, amounts to 60min, IC50Value was calculated at 30 minutes using GraphPad software.Change
Close the IC of the tubulin polymerization inhibitory activity of object 6c50Value is 2.17 μM, illustrates that compound 6c can actually combine tubulin,
Inhibit its polymerization, the result is shown in Figure 1.
Claims (4)
1.1,2,3- triazole compounds, which is characterized in that structural formula of compound is as follows:
2. as described in claim 11, the application of 2,3- triazole compounds in medicine preparation, which is characterized in that by it
Anti-tumor drug or tubulin polymerization inhibitor are used to prepare as active constituent.
3. as claimed in claim 21, the application of 2,3- triazole compounds in medicine preparation, which is characterized in that described
Anti-tumor drug is anti-gastric cancer, liver cancer or anti-prostate cancer.
4. preparing as described in claim 11, the method for 2,3- triazole compounds, which is characterized in that including following step
It is rapid:
(1) prepare compound (4):
In solvent, by 3,4,5- trimethoxy-anilines (1), 4- methoxyl group benzyl chloride is stirred to react under alkaline condition, and chloroethene is added
Acyl chloride reaction obtains compound (4)；Alkali compounds used is sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, phosphoric acid
One of sodium, ten phosphate dihydrate sodium, potassium phosphate, saleratus, sodium bicarbonate；Solvent used is ethyl alcohol, methanol, N, N- bis-
One of methylformamide, dimethyl sulfoxide, tetrahydrofuran, dioxane, methylene chloride or in which any two kinds of mixture；
Reaction carries out between 0-80 DEG C；
(2) prepare compound (5):
In solvent, compound (4) and Sodium azide are stirred to react under alkaline condition, obtain compound (5)；Alkali compounds used
It is sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium phosphate, ten phosphate dihydrate sodium, potassium phosphate, saleratus, bicarbonate
One of sodium；Solvent used is ethyl alcohol, methanol, N,N-dimethylformamide, dimethyl sulfoxide, tetrahydrofuran, dioxy six
One of ring, methylene chloride or in which any two kinds of mixture；Reaction carries out between 60-120 DEG C；
(3) prepare compound 6a~6l:
In solvent, compound (5) reacts in the presence of cupric sulfate pentahydrate and sodium ascorbate from different substituted alkynyl compounds, i.e.,
Obtain object；Solvent used is one of acetone, acetonitrile, ethyl alcohol, methanol, isopropanol, tetrahydrofuran, distilled water or in which appoints
The mixture that two or three of meaning；Reaction carries out between 25-80 DEG C.
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111747882A (en) * | 2020-07-30 | 2020-10-09 | 北京中医药大学 | Indole NEDD8 activating enzyme inhibitor, preparation method thereof and application thereof in antitumor drugs |
| CN111848498A (en) * | 2020-07-30 | 2020-10-30 | 北京中医药大学 | Piperidine and 2, 6-piperiddione colchicine site inhibitor and preparation method and application thereof |
| CN113999211A (en) * | 2021-11-23 | 2022-02-01 | 郑州大学 | Indazole skeleton derivatives containing 1,2, 3-triazole and having specific activity of resisting prostate cancer |
| WO2022198777A1 (en) * | 2021-03-22 | 2022-09-29 | 苏州大学 | Application of triazole compound in preparation of antitumor drugs |
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| WO2007014198A1 (en) * | 2005-07-25 | 2007-02-01 | Synta Pharmaceuticals Corp. | 1, 2, 3 -triazoles inhibitors of tubulin polymerization for the treatment of poliferative disorders |
| CN107011227A (en) * | 2017-05-03 | 2017-08-04 | 郑州大学 | Nitrine beta-lactam Small-molecule probe based on tubulin and its preparation method and application |
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2018
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| WO2007014198A1 (en) * | 2005-07-25 | 2007-02-01 | Synta Pharmaceuticals Corp. | 1, 2, 3 -triazoles inhibitors of tubulin polymerization for the treatment of poliferative disorders |
| CN107011227A (en) * | 2017-05-03 | 2017-08-04 | 郑州大学 | Nitrine beta-lactam Small-molecule probe based on tubulin and its preparation method and application |
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111747882A (en) * | 2020-07-30 | 2020-10-09 | 北京中医药大学 | Indole NEDD8 activating enzyme inhibitor, preparation method thereof and application thereof in antitumor drugs |
| CN111848498A (en) * | 2020-07-30 | 2020-10-30 | 北京中医药大学 | Piperidine and 2, 6-piperiddione colchicine site inhibitor and preparation method and application thereof |
| CN111848498B (en) * | 2020-07-30 | 2021-08-20 | 北京中医药大学 | Piperidine and 2, 6-piperiddione colchicine site inhibitor and preparation method and application thereof |
| CN111747882B (en) * | 2020-07-30 | 2021-08-20 | 北京中医药大学 | Indole NEDD8 activating enzyme inhibitor, preparation method thereof and application thereof in antitumor drugs |
| WO2022198777A1 (en) * | 2021-03-22 | 2022-09-29 | 苏州大学 | Application of triazole compound in preparation of antitumor drugs |
| CN113999211A (en) * | 2021-11-23 | 2022-02-01 | 郑州大学 | Indazole skeleton derivatives containing 1,2, 3-triazole and having specific activity of resisting prostate cancer |
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