CN109206399B - Tertiary amide tubulin polymerization inhibitor and preparation method and application thereof - Google Patents

Tertiary amide tubulin polymerization inhibitor and preparation method and application thereof Download PDF

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CN109206399B
CN109206399B CN201811267864.4A CN201811267864A CN109206399B CN 109206399 B CN109206399 B CN 109206399B CN 201811267864 A CN201811267864 A CN 201811267864A CN 109206399 B CN109206399 B CN 109206399B
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tubulin polymerization
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tertiary amide
sodium
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张雁冰
张赛扬
付冬君
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Zhengzhou University
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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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • 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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    • 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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    • 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
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    • 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

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Abstract

The invention discloses a novel tertiary amide tubulin polymerization inhibitor, a preparation method thereof and application thereof in medicaments of gastric cancer, prostatic cancer, breast cancer and the like, belonging to the field of antitumor drug chemistry. The invention is simple, efficient, green and environment-friendly, and synthesizes a novel tubulin polymerization inhibitor. It has the following structural general formula:

Description

Tertiary amide tubulin polymerization inhibitor and preparation method and application thereof
Technical Field
The invention relates to the field of antitumor drug chemistry, in particular to novel tertiary amide tubulin polymerization inhibitors, a preparation method thereof and application thereof as a novel antitumor drug lead compound.
Background
Microtubules are important components of most eukaryotic cytoskeletons and are closely related to vital activities such as substance transportation in cells, cell movement, differentiation and development of cells, division and propagation of cells and the like. The important physiological role of Tubulin (Tubulin) makes it an important target in the tumor field. Colchicine as tubulin polymerization inhibitor can inhibit mitosis of cells, has anti-tumor effect, but has high toxicity, and is rarely used at present. There is a need to develop new anti-tumor targeted drugs.
Disclosure of Invention
The invention aims to provide a novel tertiary amide tubulin polymerization inhibitor with good antitumor activity.
Another object of the present invention is to provide a simple, efficient, environmentally friendly method for synthesizing novel tertiary amide tubulin polymerization inhibitors.
In order to achieve the purpose of the invention, the novel class of tertiary amide tubulin polymerization inhibitor compounds has the following general formula:
Figure GDA0002602720480000011
R1hydrogen, chlorine, methoxy and methyl which are mono-substituted or multi-substituted at different positions; preferably, R is1Is polysubstituted methoxyl.
Figure GDA0002602720480000012
Is a benzene ring, a halogen, a methoxyl, a C1-5 alkyl monosubstituted benzene ring or a benzene ring monosubstituted by amino, methoxyl, a halogen monosubstituted benzothiophene ring, a naphthalene ring, a C1-3 alkyl monosubstituted or polysubstituted pyridine ring, a quinazoline ring and a benzimidazole ring. Preferably:
Figure GDA0002602720480000021
is benzene ring, halogen, methoxy, methyl, isobutyl monosubstituted benzene ring or benzene ring disubstituted by amino, methoxy, halogen monosubstituted benzothiophene ring, naphthalene ring, methyl monosubstituted pyridine ring.
R2Is a thiophene ring, a benzene ring mono-substituted with methoxy or halogen. Halogen is preferably: F.
the novel tertiary amide tubulin polymerization inhibitor compound is mainly prepared by the following steps:
Figure GDA0002602720480000022
(1) a process for the preparation of compound (I):
in a solvent, stirring and reacting an aryl substituted methylene chloride compound and different substituted anilines under an alkaline condition to obtain a compound I. The alkaline compound is one of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium phosphate, potassium bicarbonate and sodium bicarbonate; the solvent is one or a mixture of any two of ethanol, methanol, acetone, tetrahydrofuran, dioxane and dichloromethane; the reaction is carried out at 60-120 ℃.
(2) A process for producing the compound (II):
in the solvent, the compound (I) and the substituted acetyl chloride compound are stirred and react under the alkaline condition to obtain a compound II. The alkaline compound is one of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium phosphate dodecahydrate, potassium phosphate, potassium bicarbonate and sodium bicarbonate; the solvent is one of ethanol, methanol, N-dimethylformamide, dimethyl sulfoxide, tetrahydrofuran, dioxane and dichloromethane or a mixture of any two of the ethanol, the methanol, the N, N-dimethylformamide, the dimethyl sulfoxide, the tetrahydrofuran, the dioxane and the dichloromethane; the reaction is carried out at a temperature of between 0 and 70 ℃.
The invention has the advantages that: 1. the compound has a certain inhibiting effect on various tumor cells PC3, MCF7 and MGC803 as shown in an in-vitro anticancer activity test, and has a remarkable inhibiting effect on polymerization of tubulin. The activity of the compounds (IId, IIe, IIg, IIi, IIm, IIo, IIp, IIq and IIr) on three cancer cells is superior to that of the antitumor drug 5-fluorouracil. Can be used as a candidate or lead compound for further development and applied to preparing antitumor drugs. 2. The synthesis method is simple and efficient, green and environment-friendly, and has high yield which is more than 75%.
Detailed Description
To better illustrate the invention, the following examples are given:
EXAMPLE 1 preparation of general formula (II)
(1) A process for the preparation of compound (I):
in an ethanol solvent, at the temperature of 60-120 ℃, the methylene chloride compound substituted by aryl and the aniline substituted by different aryl are stirred and react under the condition of sodium hydroxide to obtain a compound I.
(2) A process for producing the compound (II):
compound (I) (5mmol) and the variously substituted acetyl chloride compound (5mmol) were dissolved by addition of 15mL of acetone and the reaction was stirred at 80 ℃. TLC monitors the reaction progress, after the reaction is finished, distilled water is added into the system, then dichloroethane is used for extraction for 3 times, the dichloroethane phase is extracted by saturated saline solution for 2 times, 20mL each time, finally the organic phase is dried by anhydrous magnesium sulfate, the magnesium sulfate is filtered, and the dichloroethane is removed by vacuum distillation of the filtrate. And (3) separating and purifying the obtained crude product by using a silica gel column chromatography, and eluting with petroleum ether/ethyl acetate (9: 1) to obtain different compounds (II).
Figure GDA0002602720480000031
A white solid, a solid which is,1h NMR (400MHz, DMSO) 7.4-7.1 (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). The yield is 78%.
Figure GDA0002602720480000032
A white solid, a solid which is,1h NMR (400MHz, DMSO)7.4(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%.
Figure GDA0002602720480000041
A white solid, a solid which is,1h NMR (400MHz, DMSO) 7.5-7.3 (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%.
Figure GDA0002602720480000042
A white solid, a solid which is,1h NMR (400MHz, DMSO)7.5(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%.
Figure GDA0002602720480000043
A white solid, a solid which is,1H NMR(400MHz,CDCl3)7.1–7.0(m,3H),6.8(dd,1H),6.7(d,2H),6.6(d1H),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%.
Figure GDA0002602720480000044
A white solid, a solid which is,1h NMR (400MHz, DMSO)7.4(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). The yield is 80%.
Figure GDA0002602720480000051
A white solid, a solid which is,1h NMR (400MHz, DMSO)7.4(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%.
Figure GDA0002602720480000052
A yellow solid, which is a solid,1h NMR (400MHz, DMSO) 7.4-7.3 (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.), 86% yield.
Figure GDA0002602720480000053
A yellow solid, which is a solid,1h NMR (400MHz, DMSO)7.4(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%.
Figure GDA0002602720480000054
A white solid, a solid which is,1h NMR (400MHz, DMSO) 7.5-7.2 (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). The yield was 82%.
Figure GDA0002602720480000061
A yellow solid, which is a solid,1H NMR(400MHz,CDCl3)7.1(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) · yield 88%.
Figure GDA0002602720480000062
A white-yellow solid, and a white-yellow solid,1h NMR (400MHz, DMSO)8.0(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%.
Figure GDA0002602720480000063
A yellow solid, which is a solid,1h NMR (400MHz, DMSO) 8.0-7.8 (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%.
Figure GDA0002602720480000064
A white solid, a solid which is,1H NMR(400MHz,CDCl3)7.5(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) · yield 82%.
Figure GDA0002602720480000071
A white solid, a solid which is,1H NMR(400MHz,CDCl3)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%.
Figure GDA0002602720480000072
Yellow solid, yield: 33%.1H NMR(400MHz,CDCl3) 7.2-7.1 (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%.
Figure GDA0002602720480000073
A white-yellow solid, and a white-yellow solid,1H NMR(400MHz,CDCl3)7.1(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%.
Figure GDA0002602720480000074
A white solid, a solid which is,1H NMR(400MHz,CDCl3)7.1(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%.
Example 2 determination of the antitumor activity of the above-mentioned compounds:
the compounds used in the screening are synthesized and purified by the invention, the sample stock solution is prepared by weighing 1-2mg of sample and placing the sample in a 2mL EP tube, then DMSO is used for preparing solution, the solution is stored and placed at 4 ℃, the cells in logarithmic growth phase are diluted by a culture medium during the experiment according to the required concentration, after digestion and counting, the cell density is adjusted by the culture medium, 5000 cells/hole with 4000 plus are inoculated into a 96-well plate, 150 mu L of each hole is obtained, after 24h of culture, the culture medium is discarded, the medicaments (50 mu g/mL and 100 mu g/mL) diluted by the culture medium are added, 6 multiple holes are arranged at each concentration, a blank control group and a negative control group are additionally arranged, after 72h of medicament action, 20 mu LMTT is added into each hole, after 4h of continuous culture, the liquid is sucked, 150mL of DMSO is added, the mixture is uniformly oscillated, the absorbance value is detected at 490nm of an enzyme labeling instrument, the inhibition rate is calculated by adopting the formula that (1-administration group absorbance value) is × 100%, when 50 mu g/blank value is continuously cultured, the absorbance rate is increased, when 50 mu g/mL of the concentration is more than 50% of the SPSS50Values and correlation coefficients. The results are shown in Table 1.
TABLE 1 IC inhibition of tumor cell lines by compounds50Value of
Figure GDA0002602720480000081
Figure GDA0002602720480000091
aEach value is expressed as mean ± standard deviation (mean ± SD), analysis of variance: p is a radical of<0.05.5-Fu: 5-fluorouracil.
And (4) conclusion: the activity of the compounds (IId, IIe, IIg, IIi, IIm, IIo, IIp, IIq and IIr) on three cancer cells is superior to that of the antitumor drug 5-fluorouracil. Can be used as a candidate or lead compound for further development and applied to preparing antitumor drugs.
Example 3 determination of the Tubulin polymerization inhibitory Activity of Compound IId:
the extracted tubulin was resuspended in ice-cold G-PEM buffer (80mM PIPES pH 5.9,5mM MgCl)21mM EGTA,1mM ATP, 5% (v/v) glycerol), 100ul of the mixture is added into a 96-well plate containing 100ul of compound IId, the final concentration of the tubulin is 5.6g/L, the concentration of the drug is set to four gradients of 0uM, 1uM, 2uM and 4uM, the sample is fully mixed, the polymerization of the tubulin is detected by a spectrophotometer at intervals of 5min, the total time is 60min, and IC is detected by the spectrophotometer50Values were calculated at 30 minutes using GraphPad software. And (4) conclusion: the enzymatic activity of compound IId on microtubules was less than 3 uM.

Claims (4)

1. A class of tertiary amide tubulin polymerization inhibitors, selected from the group consisting of:
Figure FDA0002625259730000011
Figure FDA0002625259730000021
2. the use of a class of tertiary amide tubulin polymerization inhibitors of claim 1 in the preparation of a medicament, wherein the class is used as an active ingredient in the preparation of an anti-neoplastic drug or tubulin polymerization inhibitor.
3. The use of a class of tertiary amide tubulin polymerization inhibitors of claim 2 for the preparation of a medicament, wherein said antineoplastic agent is against gastric, prostate or breast cancer.
4. A method of preparing a class of tertiary amide tubulin polymerization inhibitors as claimed in claim 1, comprising the steps of:
Figure FDA0002625259730000022
(1) a process for the preparation of compound (I):
in a solvent, stirring and reacting an aryl substituted methylene chloride compound and different substituted anilines under an alkaline condition to obtain a compound I; the alkaline compound is one of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium phosphate, potassium bicarbonate and sodium bicarbonate; the solvent is one or a mixture of any two of ethanol, methanol, acetone, tetrahydrofuran, dioxane and dichloromethane; the reaction is carried out at 60-120 ℃;
(2) a process for producing the compound (II):
in a solvent, stirring and reacting a compound (I) and a substituted acetyl chloride compound under an alkaline condition to obtain a compound II; the alkaline compound is one of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium phosphate dodecahydrate, potassium phosphate, potassium bicarbonate and sodium bicarbonate; the solvent is one of ethanol, methanol, N-dimethylformamide, dimethyl sulfoxide, tetrahydrofuran, dioxane and dichloromethane or a mixture of any two of the ethanol, the methanol, the N, N-dimethylformamide, the dimethyl sulfoxide, the tetrahydrofuran, the dioxane and the dichloromethane; the reaction is carried out at 0-70 ℃;
Figure FDA0002625259730000031
is composed of
Figure FDA0002625259730000032
R1Is methoxy substituted at the 3,4,5 position;
R2is composed of
Figure FDA0002625259730000033
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