CN109206399A - Three-level amide tubulin polymerization inhibitor and its preparation method and application - Google Patents
Three-level amide tubulin polymerization inhibitor and its preparation method and application Download PDFInfo
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- CN109206399A CN109206399A CN201811267864.4A CN201811267864A CN109206399A CN 109206399 A CN109206399 A CN 109206399A CN 201811267864 A CN201811267864 A CN 201811267864A CN 109206399 A CN109206399 A CN 109206399A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
- C07D333/24—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C233/00—Carboxylic acid amides
- C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C233/16—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms
- C07C233/24—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring
- C07C233/29—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring having the carbon atom of the carboxamide group bound to an acyclic carbon atom of a carbon skeleton containing six-membered aromatic rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
- C07C235/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton
- C07C235/32—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton containing six-membered aromatic rings
- C07C235/38—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton containing six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a six-membered aromatic ring
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
- C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
- C07D333/54—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
- C07D333/60—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
Abstract
The invention discloses a kind of novel three-level amide tubulin polymerization inhibitor, their preparation method and its applications in the drugs such as gastric cancer, prostate cancer, breast cancer, belong to anti-tumor drug chemical field.The present invention is simple and efficient, a kind of novel tubulin polymerization inhibitor of environmentally protective synthesis.It has the following structure general formula:
Description
Technical field
The present invention relates to anti-tumor drug chemical fields, and in particular to a kind of novel three-level amide tubulin polymerization inhibits
Agent, their 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, with intracellular matter transportation, cell movement, thin
The vital movements such as the differentiation and development of born of the same parents and cell division breeding are closely related.The important physiology of tubulin (Tubulin) is made
With so that it becomes important target spot in tumor area.Colchicin is capable of inhibiting cell as tubulin polymerization inhibitor
Mitosis, have antitumor action, but toxicity is big, use less.New antitumoral target drug is urgently developed at present.
Summary of the invention
It is an object of that present invention to provide the good novel three-level amide tubulin polymerization inhibitor of a kind of anti-tumor activity.
It is another object of the present invention to provide one kind to be simple and efficient, environmentally protective synthesizing new three-level amide tubulin
The method of polymerization inhibitor.
Purpose to realize the present invention, the novel three-level amide tubulin polymerization inhibitor class compound of one kind of the present invention have
Following general formula:
R1For hydrogen, different location is monosubstituted or polysubstituted chlorine, methoxyl group, methyl；It is preferred that: R1For polysubstituted methoxyl group.
For phenyl ring, halogen, methoxyl group, the monosubstituted phenyl ring of C1-5 alkyl or by amino, the polysubstituted phenyl ring of methoxyl group, halogen
Mono-substituted benzothiophene ring, naphthalene nucleus, C1-3 alkyl be monosubstituted or polysubstituted pyridine ring, quinazoline ring, benzimidazole ring.It is excellent
Choosing:For phenyl ring, the monosubstituted phenyl ring of halogen, methoxyl group, methyl, isobutyl group or by amino, the disubstituted phenyl ring of methoxyl group, halogen
The mono-substituted benzothiophene ring of element, naphthalene nucleus, the mono-substituted pyridine ring of methyl base.
R2For thiphene ring, phenyl ring, by methoxyl group or the mono-substituted phenyl ring of halogen.Halogen is preferred: F.
Novel three-level amide tubulin polymerization inhibitor class compound of the present invention is mainly made through the following steps:
(1) preparation method of compound (I):
In solvent, the METHYLENE CHLORIDE compound that aromatic radical is replaced, the aniline that difference replaces is stirred to react under alkaline condition
Compound I.Alkali compounds used is sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium phosphate, potassium phosphate, carbonic acid
One of hydrogen potassium, sodium bicarbonate；Solvent used is ethyl alcohol, in methanol, acetone, tetrahydrofuran, dioxane, methylene chloride
One of or in which any two kinds of mixture；Reaction carries out between 60-120 DEG C.
(2) preparation method of compound (II):
In solvent, compound (I) and the acetyl chlorine compound replaced are stirred to react under alkaline condition, obtain compound II.It is used
Alkali compounds be sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium phosphate, ten phosphate dihydrate sodium, potassium phosphate, carbonic acid
One of hydrogen potassium, sodium bicarbonate；Solvent used is ethyl alcohol, methanol, N,N-dimethylformamide, dimethyl sulfoxide, tetrahydro
One of furans, dioxane, methylene chloride or in which any two kinds of mixture；Reaction carries out between 0-70 DEG C.
The invention has the advantages that 1, such Compound ira vitro anticancer activity experiments have shown that its to kinds of tumor cells PC3, MCF7,
MGC803 all has certain inhibiting effect, while having significant inhibiting effect to the polymerization of tubulin.Compound (IId,
IIe, IIg, IIi, IIm, IIo, IIp, IIq, IIr) anti-tumor drug 5 FU 5 fluorouracil is better than to the activity of three kinds of cancer cells.It can
As the candidate or lead compound further developed, applied to preparing anti-tumor drug.2, synthetic method is simple and efficient, green
Colour circle is protected, high income, up to 75% or more.
Specific embodiment
It is as follows for embodiment for the present invention is better described:
Embodiment 1 leads to the preparation of formula (II)
(1) preparation method of compound (I):
In alcohol solvent, at a temperature of 60-120 DEG C, the METHYLENE CHLORIDE compound that aromatic radical is replaced, the aniline that difference replaces is in hydrogen
Compound I is stirred to react to obtain under sodium oxide molybdena item.
(2) preparation method of compound (II):
15mL acetone solution is added in compound (I) (5mmol) and different substituted acetyl chlorine compounds (5mmol), 80 is Celsius
Degree is stirred to react.Then TLC monitoring reaction process is extracted to which distilled water after reaction, is added into system with dichloroethanes
3 times, then be stripped dichloroethanes phase 2 times, each 20mL with saturated salt solution, last organic phase is dry with anhydrous magnesium sulfate, filters out
Dichloroethanes is distilled off in magnesium sulfate, filtrate decompression.Gained crude product silicagel column column chromatographic isolation and purification, petroleum ether/acetic acid
Ethyl ester=9:1 elution, obtains different compounds (II).
White solid.1H NMR(400MHz,DMSO)δ7.4–7.1(m,6H),6.9(dd,1H),6.8(d,1H),6.4(s,
2H), 4.9 (s, 2H), 3.7 (s, 2H), 3.6 (d, 9H), yield 78%.
White solid.1H NMR(400MHz,DMSO)δ7.4(d,1H),7.3(dd,2H),7.1(t,2H),7.0–6.9(m,
1H), 6.7 (d, 1H), 6.4 (s, 2H), 4.8 (s, 2H), 3.7 (s, 2H), 3.7 (s, 3H), 3.6 (s, 6H), yield 82%.
White solid.1H NMR(400MHz,DMSO)δ7.5–7.3(m,3H),7.2(d,2H),7.00–6.8(m,1H),
6.7 (d, 1H), 6.4 (s, 2H), 4.8 (s, 2H), 3.8 (s, 2H), 3.7 (d, 9H), yield 76%.
White solid.1H NMR(400MHz,DMSO)δ7.5(d,2H),7.4(d,1H),7.2(d,2H),7.0–6.8(m,
1H), 6.7 (s, 1H), 6.4 (s, 2H), 4.8 (s, 2H), 3.7 (s, 2H), 3.6 (s, 9H), yield 79%.
White solid.1H NMR(400MHz,CDCl3)δ7.1–7.0(m,3H),6.8(dd,1H),6.7(d,2H),6.6
(d, 1H), 6.0 (s, 2H), 4.7 (s, 2H), 3.8 (s, 3H), 3.7 (s, 3H), 3.6 (s, 2H), 3.5 (s, 6H), yield 79%.
White solid.1H NMR(400MHz,DMSO)δ7.4(dd,2H),7.1(t,3H),6.9(dd,1H),6.8(d,
1H), 6.5 (s, 2H), 4.9 (s, 2H), 3.8 (s, 2H), 3.7 (d, 9H), yield 80%.
White solid.1H NMR(400MHz,DMSO)δ7.4(d,1H),7.1(s,4H),6.9(dd,1H),6.7(d,1H),
6.4 (s, 2H), 4.8 (s, 2H), 3.7 (s, 2H), 3.6 (d, 9H), 2.3 (s, 3H), yield 90%.
Yellow liquid.1H NMR(400MHz,DMSO)δ7.4–7.3(m,1H),7.3(d,2H),7.1(d,2H),7.0–
6.9(m,1H),6.9(dd,1H),6.4(s,2H),4.8(s,2H),3.7(s,2H),3.6(s,3H),3.6(s,6H),1.2(s,
9H), yield 86%.
Yellow liquid.1H NMR(400MHz,DMSO)δ7.4(dd,1H),6.9(dd,1H),6.7(d,1H),6.6(d,
1H),6.5(s,1H),6.4(s,2H),6.3(dd,1H),4.7(s,2H),4.6(s,2H),3.7(s,3H),3.6(s,2H),
3.6 (s, 3H), 3.5 (s, 6H), yield 80%.
White solid.1H NMR(400MHz,DMSO)δ7.5–7.2(m,4H),7.1(d,1H),6.9(dd,1H),6.7(d,
1H), 6.4 (s, 2H), 4.9 (s, 2H), 3.8 (s, 2H), 3.6 (s, 9H), yield 82%.
Yellow liquid.1H NMR(400MHz,CDCl3)δ7.1(dd,2H),6.9(d,2H),6.9(d,1H),6.8(dd,
1H), 6.7 (d, 1H), 6.0 (s, 2H), 4.7 (s, 2H), 3.8 (s, 3H), 3.6 (s, 2H), 3.5 (s, 6H), 2.2 (s, 3H) are received
Rate 88%.
White solid.1H NMR(400MHz,DMSO)δ8.0(d,1H),7.8(d,1H),7.6(s,1H),7.5–7.2(m,
2H),7.0–6.8(m,1H),6.7(d,1H),6.3(s,2H),5.1(s,2H),3.7(s,2H),3.6(s,3H),3.5(s,
6H), yield 76%.
Yellow liquid.1H NMR(400MHz,DMSO)δ8.0–7.8(m,3H),7.7(s,1H),7.5–7.4(m,4H),
7.0-6.8 (m, 2H), 6.5 (s, 2H), 5.0 (s, 2H), 3.8 (s, 2H), 3.6 (d, 9H), yield 79%.
White solid.1H NMR(400MHz,CDCl3)δ7.5(t,1H),7.1(dd,2H),7.0(d,1H),6.8(dd,
1H), 6.7 (d, 1H), 6.3 (s, 2H), 4.9 (s, 2H), 3.8 (s, 3H), 3.7 (s, 2H), 3.6 (s, 6H), 2.4 (s, 3H) are received
Rate 82%.
White solid.1H NMR(400MHz,CDCl3) δ 7.0 (t, J=8.2Hz, 3H), 6.7 (t, J=5.7Hz, 2H),
6.7 (dd, J=8.2,1.9Hz, 1H), 6.6-6.5 (m, 2H), 5.9 (s, 2H), 4.7 (s, 2H), 3.8 (s, 3H), 3.7 (s,
3H), 3.6 (s, 3H), 3.5 (s, 6H), 3.4 (s, 2H), yield 88%.
Yellow liquid, yield:33%.1H NMR(400MHz,CDCl3)δ7.2–7.1(m,3H),7.0(d,2H),6.9
(d,2H),6.7(d,2H),5.9(s,2H),4.7(s,2H),3.8(s,3H),3.7(s,3H),3.5(s,6H),3.4(s,
2H), yield 86%.
White solid.1H NMR(400MHz,CDCl3)δ7.1(d,2H),6.9(d,2H),6.8–6.6(m,4H),5.9(s,
2H), 4.7 (s, 2H), 3.8 (s, 3H), 3.7 (d, 6H), 3.5 (s, 6H), 3.3 (s, 2H), yield 80%.
White solid.1H NMR(400MHz,CDCl3)δ7.1(d,2H),6.9(dd,2H),6.8(t,2H),6.7(d,
2H), 5.9 (s, 2H), 4.7 (s, 2H), 3.8 (s, 3H), 3.7 (s, 3H), 3.6 (s, 6H), 3.4 (s, 2H), yield 76%.
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 is phonetic with average value ± standard deviation (mean ± SD)
Pyridine
Conclusion: compound (IId, IIe, IIg, IIi, IIm, IIo, IIp, IIq, IIr) is to the activity of three kinds of cancer cells better than anti-
Tumour medicine anti-tumor drug 5 FU 5 fluorouracil.It can be used as the candidate further developed or lead compound, be applied to preparation
Anti-tumor drug.
The measurement of the Tubulin polymerization inhibiting activity of 3 compound IIe of embodiment:
The tubulin of extraction is resuspended in ice-cold G-PEM buffer (80mM PIPES pH 5.9,5mM MgCl2,1mM
EGTA, 1mM ATP, 5% (v/v) glycerol), take 100ul to add in 96 orifice plates comprising 100ul compound IIId, micro-pipe
Final concentration of protein is 5.6g/L, and 0uM, 1uM, 2uM, tetra- gradients of 4uM is arranged in drug concentration, and sample mixes well, spectrophotometric
The polymerization of meter detection tubulin, is spaced 5min, amounts to 60min, IC50Value was calculated at 30 minutes using GraphPad software
It arrives.Conclusion: compound IIId is less than 3uM to the enzymatic activity of micro-pipe.
Claims (6)
1. a kind of three-level amide tubulin polymerization inhibitor, which is characterized in that have structure shown in general formula II:
R1For hydrogen or different location is monosubstituted or polysubstituted chlorine, methoxyl group, methyl；
For phenyl ring, halogen, methoxyl group, the monosubstituted phenyl ring of C1-5 alkyl or by amino, the polysubstituted phenyl ring of methoxyl group, halogen
Mono-substituted benzothiophene ring, naphthalene nucleus, C1-3 alkyl is monosubstituted or polysubstituted pyridine ring, quinazoline ring, benzimidazole ring；
R2For thiphene ring, phenyl ring, by methoxyl group or the mono-substituted phenyl ring of halogen.
2. three-level amide tubulin polymerization inhibitor as described in claim 1, which is characterized in that R1For polysubstituted methoxy
Base；For phenyl ring, the monosubstituted phenyl ring of halogen, methoxyl group, methyl, isobutyl group or by amino, the disubstituted phenyl ring of methoxyl group, halogen
The mono-substituted benzothiophene ring of element, naphthalene nucleus, the mono-substituted pyridine ring of methyl base；R2For thiphene ring, phenyl ring is mono- by methoxyl group or F
Substituted phenyl ring.
3. three-level amide tubulin polymerization inhibitor as claimed in claim 2, which is characterized in that select following compound:
4. a kind of three-level amide tubulin polymerization inhibitor as described in one of claim 1-3 in medicine preparation
Using, which is characterized in that it is used to prepare anti-tumor drug or tubulin polymerization inhibitor as active constituent.
5. the application of one kind three-level amide tubulin polymerization inhibitor as claimed in claim 4 in medicine preparation, special
Sign is that the anti-tumor drug is the drug of anti-gastric cancer, prostate cancer or breast cancer.
6. the method for preparation a kind of three-level amide tubulin polymerization inhibitor as claimed in claim 1 or 2, feature exist
In, comprising the following steps:
(1) preparation method of compound (I):
In solvent, the METHYLENE CHLORIDE compound that aromatic radical is replaced, the aniline that difference replaces is stirred to react under alkaline condition
Compound I；Alkali compounds used is sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium phosphate, potassium phosphate, carbonic acid
One of hydrogen potassium, sodium bicarbonate；Solvent used is ethyl alcohol, in methanol, acetone, tetrahydrofuran, dioxane, methylene chloride
One of or in which any two kinds of mixture；Reaction carries out between 60-120 DEG C；
(2) preparation method of compound (II):
In solvent, compound (I) and the acetyl chlorine compound replaced are stirred to react under alkaline condition, obtain compound II；It is used
Alkali compounds be sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium phosphate, ten phosphate dihydrate sodium, potassium phosphate, carbonic acid
One of hydrogen potassium, sodium bicarbonate；Solvent used is ethyl alcohol, methanol, N,N-dimethylformamide, dimethyl sulfoxide, tetrahydro
One of furans, dioxane, methylene chloride or in which any two kinds of mixture；Reaction carries out between 0-70 DEG C；
R1Or R2It is consistent with claims 1 or 2 statement.
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Cited By (2)
| 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 |
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2018
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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 |
| 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 |
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