CN110526854B - Alpha, beta-unsaturated ketone derivative, preparation method and application thereof as medicine - Google Patents

Alpha, beta-unsaturated ketone derivative, preparation method and application thereof as medicine Download PDF

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CN110526854B
CN110526854B CN201910679937.9A CN201910679937A CN110526854B CN 110526854 B CN110526854 B CN 110526854B CN 201910679937 A CN201910679937 A CN 201910679937A CN 110526854 B CN110526854 B CN 110526854B
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trimethoxyphenyl
methyl
indol
prop
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庄春林
石英
从慧
张万年
黄嘉璇
余建强
徐丽娟
曲卓
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Ningxia Medical University
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Abstract

The application relates to the technical field of medicines, and provides an alpha, beta-unsaturated ketone derivative and a preparation method thereof, wherein the structural general formula is shown as the specificationThe definition of each substituent is shown in the specification, the compound can target microtubulin, has strong inhibition effect on various tumor parents and drug-resistant strains, and can be used for preparing drugs for treating malignant tumors and diseases related to differentiation and proliferation.

Description

Alpha, beta-unsaturated ketone derivative, preparation method and application thereof as medicine
Technical Field
The application relates to the technical field of medicines, in particular to an alpha, beta-unsaturated ketone derivative with microtubule targeting antitumor activity, and a preparation method and application thereof.
Background
Currently, cancer has become a serious health life threatening disease for humans. At present, chemotherapy is still mainly used for treating malignant tumors clinically, but more than half of tumors have obvious drug resistance to traditional chemotherapy drugs. It is estimated by the american cancer society that more than 90% of tumor patients die from varying degrees of resistance, which has become a major cause of clinical chemotherapy failure. Therefore, the development of a novel anti-tumor chemotherapeutic that selectively targets multi-drug resistance has become an urgent need.
In recent years, microtubule-targeted agents have become an important part of anti-tumor drug development. Microtubules are dynamic cytoskeleton consisting of alpha, beta tubulin, which play an important role in various cellular functions, including mitosis. Microtubules exhibit different dynamic behaviors at different phases of the cell cycle, inhibit microtubule dynamics, block the cell cycle, induce apoptosis, and are important therapeutic targets in tumor cells. Tubulin inhibitors such as paclitaxel and vinblastine have been widely used for the treatment of various cancers. However, they show narrow therapeutic window, poor selectivity and multi-drug resistance problems, often due to high expression of p-glycoprotein or multi-drug resistance related proteins. Therefore, there is still a great need to develop a novel targeted microtubule, a highly selective, low-toxic small molecule (Pharm Res (2012) 29:2943-2971).
Chalcone derivatives are important compounds in flavonoids, have simple molecular structures, take 1, 3-diphenylpropenone as a basic skeleton, and have wide biological activities such as anti-tumor, antibacterial, anti-inflammatory, anti-tuberculosis and the like. The novel indolyl chalcone is a novel chalcone derivative discovered by the prior research of the inventor, can obviously improve the anti-tumor activity, and further is used for researching an anti-tumor action mechanism, and the chalcone derivative is discovered to act on beta-tubulin, so that tumor cell apoptosis is effectively induced, and the tumor cell cycle is blocked in the G2/M phase; among them, the representative compound α -methyl substituted indolecalciferone exhibits excellent inhibitory activity against the growth of parent tumor cells and multidrug resistant tumor cells (mol. Pharmaceuticals 2018,15,3892-3900).
Disclosure of Invention
The application aims to provide alpha, beta-unsaturated ketone derivatives with microtubule targeting antitumor activity; the application also aims to provide a preparation method of the alpha, beta-unsaturated ketone derivative; the third object of the application is to provide the application of the alpha, beta-unsaturated ketone derivative.
In order to achieve the above objective, the present application provides a prodrug of an alpha, beta-unsaturated ketone derivative and isomers, salts or solvates thereof.
There is also a need to propose the use of said compounds of formula (I) for the preparation of microtubule inhibitors.
There is also a need for the use of the compounds of formula (I) in the treatment of tumors, including killing of tumor cells, and in the treatment of tumor diseases with multidrug resistance.
The first aspect of the application provides a prodrug of alpha, beta-unsaturated ketone derivatives and isomers, salts or solvates thereof, and the structure is shown as a general formula I:
wherein A, B is selected from the group consisting of saturated, aromatic and heteroaromatic rings, saturated or aromatic and heteroaromatic ring;
R 1 respectively selected from hydrogen and 1 to 7 identical or different C1-C10 alkoxy groups;
R 2 respectively selected from hydrogen, 1-7 identical or different C1-C10 alkyl groups, C1-C10 alkoxy groups, halogen, substituent groups composed of nitrogen and hydrogen elements, substituent groups composed of hydrocarbon and oxygen elements and substituent groups composed of nitrogen and oxygen elements;
R 3 respectively selected from hydrogen and C1-C10 alkyl; and- (CH) s with A being a polycyclic ring 2 ) n -,(n＝1～10)；
Preferably, wherein A, B is independently selected from saturated, aromatic and heteroaromatic rings, saturated or aromatic and heteroaromatic ring;
R 1 respectively selected from the group consisting of hydrogen, trimethoxy, dimethoxy, monomethoxy substituted at different positions on A,
R 2 Respectively selected from the group consisting of hydrogen, methoxy, methyl, fluorine, chlorine, bromine, nitro, amino, carboxyl, which are monosubstituted at different positions on B,
R 3 Selected from hydrogen, methyl, ethyl, and- (CH) s with A being a polycyclic ring 2 ) n -,(n＝1～10)；
Preferably, the method comprises the steps of,
a is selected from
B is selected from
R 1 Respectively selected from the group consisting of hydrogen, trimethoxy, dimethoxy, monomethoxy substituted at different positions on A,
R 2 Respectively selected from the group consisting of hydrogen, methoxy, methyl, fluorine, chlorine, bromine, nitro, amino, carboxyl, which are monosubstituted at different positions on B,
R 3 Respectively selected from hydrogen, methyl, ethyl and-CH forming a six-membered ring with A 2 CH 2 -。
Preferably, the pharmaceutically acceptable salts include acid addition salts of the compounds of formula I with: hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, citric acid, tartaric acid, lactic acid, pyruvic acid, acetic acid, maleic acid or succinic acid, fumaric acid, salicylic acid, phenylacetic acid, mandelic acid.
Preferably, the alpha, beta-unsaturated ketone derivative is selected from one of the following structures:
(E) -2-methyl-3- (4-methyl-1H-indol-3-yl) -1- (3, 4, 5-trimethoxyphenyl) prop-2-en-1-one (1),
(E) -2-methyl-3- (5-methyl-1H-indol-3-yl) -1- (3, 4, 5-trimethoxyphenyl) prop-2-en-1-one (2),
(E) -2-methyl-3- (6-methyl-1H-indol-3-yl) -1- (3, 4, 5-trimethoxyphenyl) prop-2-en-1-one (3),
(E) -2-methyl-3- (7-methyl-1H-indol-3-yl) -1- (3, 4, 5-trimethoxyphenyl) prop-2-en-1-one (4),
(E) -3- (benzo [ b ] thiophen-3-yl) -2-methyl-1- (3, 4, 5-trimethoxyphenyl) prop-2-en-1-one (5),
(E) -3- (5-fluoro-1H-indol-3-yl) -2-methyl-1- (3, 4, 5-trimethoxyphenyl) prop-2-en-1-one (6),
(E) -3- (6-fluoro-1H-indol-3-yl) -2-methyl-1- (3, 4, 5-trimethoxyphenyl) prop-2-en-1-one (7),
(E) -3- (5-chloro-1H-indol-3-yl) -2-methyl-1- (3, 4, 5-trimethoxyphenyl) prop-2-en-1-one (8),
(E) -3- (5-bromo-1H-indol-3-yl) -2-methyl-1- (3, 4, 5-trimethoxyphenyl) prop-2-en-1-one (9),
(E) -1- (3, 5-dimethoxyphenyl) -3- (1H-indol-3-yl) -2-methylpropan-2-en-1-one (10),
(E) -3- (1H-indol-3-yl) -1- (5-methoxypyridin-3-yl) -2-methylpropan-2-en-1-one (11),
(E) -3- (6-methoxy-1H-indol-3-yl) -2-methyl-1- (3, 4, 5-trimethoxyphenyl) prop-2-en-1-one (12),
(E) -2-methyl-3- (5-nitro-1H-indol-3-yl) -1- (3, 4, 5-trimethoxyphenyl) prop-2-en-1-one (13),
(E) -2-methyl-3- (6-nitro-1H-indol-3-yl) -1- (3, 4, 5-trimethoxyphenyl) prop-2-en-1-one (14),
(E) -2-methyl-3- (7-nitro-1H-indol-3-yl) -1- (3, 4, 5-trimethoxyphenyl) prop-2-en-1-one (15),
(E) -3- (6-amino-1H-indol-3-yl) -2-methyl-1- (3, 4, 5-trimethoxyphenyl) prop-2-en-1-one (16),
(E) -2- ((1H-indol-3-yl) methylene) -1- (3, 4, 5-trimethoxyphenyl) butan-1-one (17),
(E) -1- (3, 4-dimethoxyphenyl) -3- (1H-indol-3-yl) -2-methylpropan-2-en-1-one (18),
(E) -3- (1H-indol-3-yl) -1- (3-methoxyphenyl) -2-methylpropan-2-en-1-one (19),
(E) -3- (1H-indol-3-yl) -2-methyl-1-phenylprop-2-en-1-one (20),
(E) -3- (1H-indol-3-yl) -1-phenylprop-2-en-1-one (21),
(E) -2-methyl-3- (1H-pyrrolo [2,3-b ] pyridin-3-yl) -1- (3, 4, 5-trimethoxyphenyl) prop-2-en-1-one (22),
(E) -2-methyl-3- (1H-pyrrolo [3,2-c ] pyridin-3-yl) -1- (3, 4, 5-trimethoxyphenyl) prop-2-en-1-one (23),
(E) -2-methyl-3- (1H-pyrrolo [3,2-b ] pyridin-3-yl) -1- (3, 4, 5-trimethoxyphenyl) prop-2-en-1-one (24),
(E) -2-methyl-3- (1H-pyrrolo [2,3-c ] pyridin-3-yl) -1- (3, 4, 5-trimethoxyphenyl) prop-2-en-1-one (25),
(E) -3- (2-methyl-3-oxo-3- (3, 4, 5-trimethoxyphenyl) prop-1-en-1-yl) -1H-indole-6-carboxylic acid methyl ester (26),
(E) -3- (1H-indol-3-yl) -1- (7-methoxybenzo [ d ] [1,3] dioxol-5-yl) -2-methylpropan-2-en-1-one (27),
(E) -3- (imidazo [1,2-a ] pyridin-3-yl) -2-methyl-1- (3, 4, 5-trimethoxyphenyl) prop-2-en-1-one (28),
(E) -2-methyl-3- (pyrazolo [1,5-a ] pyridin-3-yl) -1- (3, 4, 5-trimethoxyphenyl) prop-2-en-1-one (29),
(E) -2- ((1H-indol-3-yl) methylene) -5-methoxy-3, 4-dihydronaphthalen-1 (2H) -one (30),
(E) -3- (2-methyl-3-oxo-3- (3, 4, 5-trimethoxyphenyl) prop-1-en-1-yl) -1H-indole-6-carboxylic acid (31),
(E) -2-methyl-3- (1H-pyrazol-3-yl) -1- (3, 4, 5-trimethoxyphenyl) prop-2-en-1-one (32),
(E) -2-methyl-3- (1H-pyrrol-3-yl) -1- (3, 4, 5-trimethoxyphenyl) prop-2-en-1-one (33),
(E) -2-methyl-3- (quinolin-3-yl) -1- (3, 4, 5-trimethoxyphenyl) prop-2-en-1-one (34),
(E) -3- (1H-indol-2-yl) -2-methyl-1- (3, 4, 5-trimethoxyphenyl) prop-2-en-1-one (35),
(E) -ethyl 2- (4- (3- (1H-indol-3-yl) -2-methacryloyl) -2, 6-dimethylphenoxy) acetate (36),
(E) -3- (7-amino-1H-indol-3-yl) -2-methyl-1- (3, 4, 5-trimethoxyphenyl) prop-2-en-1-one (37),
(E) -3- (5-amino-1H-indol-3-yl) -2-methyl-1- (3, 4, 5-trimethoxyphenyl) prop-2-en-1-one (38),
In a second aspect, the application provides the use of a compound of formula (I) as defined above for the treatment of neoplastic diseases.
The third aspect of the application provides the use as a microtubule inhibitor antitumor drug against tumor cells. The tumors are HCT-116 (colon cancer cells) and HCT-116/OXA (drug resistant colon cancer cells).
The third aspect of the application provides a preparation method of prodrugs of alpha, beta-unsaturated ketone derivatives and isomers, salts or solvates thereof.
In the present application, "halogen" means fluorine, chlorine, bromine or iodine; "alkyl" refers to a straight or branched chain alkyl group; "Arylheteroaryl" refers to a monocyclic or polycyclic ring system containing one or more heteroatoms selected from N, O, S, the ring system being aromatic, such as pyrrolyl, pyrazolyl, imidazolyl, indolyl, quinolinyl, benzothienyl, pyrrolopyridinyl, and the like; "heterocyclyl" refers to a monocyclic or polycyclic ring system containing one or more heteroatoms selected from N, O, S, such as piperazinyl, piperidinyl, pyrrolidinyl, pyrazolidinyl, and the like.
By adopting the technical scheme, the beneficial effects of the application are as follows:
the alpha, beta-unsaturated ketone derivative and the isomer, salt or solvate thereof have better activity of inhibiting proliferation of tumor cells, and can effectively inhibit proliferation of common tumor cells such as colon cancer, lung cancer, leukemia and the like and drug-resistant tumor cells; the application has simple synthesis, no complicated steps and low synthesis cost.
Detailed Description
The reagents and starting materials used in the present application are commercially available or may be prepared by literature procedures.
The experimental methods, in which specific conditions are not noted in the following examples, are generally conducted under conventional conditions or under conditions recommended by the manufacturer. All raw materials were analytically pure and purchased from manufacturers such as exploration platform, allatin, sigma-Aldrich, etc. without any indication of the synthetic method.
Example 1: (E) Preparation of (E) -2-methyl-3- (4-methyl-1H-indol-3-yl) -1- (3, 4, 5-trimethoxyphenyl) prop-2-en-1-one (1)
Step a: synthesis of 1- (3, 4, 5-trimethoxyphenyl) propan-1-ol.
3,4, 5-trimethoxybenzaldehyde (2 g,10.19 mmol) was added to a reaction vessel at 0deg.C, THF (20 mL) and ethyl magnesium bromide (15 mL) were added after vacuum treatment, reaction was performed for 4h under anaerobic condition, TLC was monitored, diluted with water and ethyl acetate, and washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the organic phase was dried by spin-drying, and the remaining crude product was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1:4) to give compound 1- (3, 4, 5-trimethoxyphenyl) propan-1-ol 2.13g in 94% yield.
Step b: synthesis of 1- (3, 4, 5-trimethoxyphenyl) propan-1-one.
1- (3, 4, 5-trimethoxyphenyl) propan-1-ol (746.6 mg,3.30 mmol) was dissolved in CH at room temperature 2 Cl 2 (10 mL) PCC (1068 mg,4.96 mmol), N was added 2 The reaction was protected, monitored by TLC plate, then diluted with water, CH 2 Cl 2 Extraction, washing with saturated sodium chloride solution, drying with anhydrous sodium sulfate, filtering, spin-drying the organic phase, purifying the remaining crude product by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=5:1) to obtain 690mg of compound 1- (3, 4, 5-trimethoxyphenyl) propan-1-one with a yield of 93.2%.
Step c: (E) -synthesis of 2-methyl-3- (4-methyl-1H-indol-3-yl) -1- (3, 4, 5-trimethoxyphenyl) prop-2-en-1-one.
Intermediate 1- (3, 4, 5-trimethoxyphenyl) propan-1-one (448 mg,2 mmol) was dissolved in toluene (6 mL) of piperidine (0.1 mL), 4-methyl-1H-indole-3-carbaldehyde (156.8 mg,0.8 mmol) was added and reacted at 130℃for 4H, the organic phase was dried by spin-drying, and the remaining crude product was recrystallized from ethanol to give the title compound (E) -2-methyl-3- (4-methyl-1H-indol-3-yl) -1- (3, 4, 5-trimethoxyphenyl) propan-2-en-1-one (1) 230mg, yield 51.3%. 1 H NMR(300MHz,CDCl 3 )δ8.69(s,1H),7.97(s,1H),7.60(d,1H,J＝ 1.2Hz),7.26-7.29(m,1H),7.10-7.16(m,1H),6.89-6.95(m,3H),3.89-3.91(m,9H),2.47(s,3H),2.29(s,3H).MS(ESI):m/z[M+H] + :366.17。
Raw material products such as 4-methyl-1H-indole-3-carbaldehyde and the like can be directly purchased in biological factories, and subsequent raw material obtaining approaches are also known.
The preparation of compounds 2-4 is described in example 1. In the step c, when the compounds 2,3 and 4 are prepared, the '4-methyl-1H-indole-3-formaldehyde' is replaced by '5-methyl-1H-indole-3-formaldehyde', '6-methyl-1H-indole-3-formaldehyde', '7-methyl-1H-indole-3-formaldehyde', and the dosage is unchanged.
Example 2: (E) Preparation of (E) -3- (benzo [ b ] thiophen-3-yl) -2-methyl-1- (3, 4, 5-trimethoxyphenyl) prop-2-en-1-one (5)
Intermediate 1- (3, 4, 5-trimethoxyphenyl) propan-1-one was prepared as described in reference to example 1.
Intermediate 1- (3, 4, 5-trimethoxyphenyl) propan-1-one (4478 mg,2 mmol) was reacted with benzo [ b ]]Thiophene-3-carbaldehyde (162.2 mg,1 mmol) was dissolved in ethanol (8 mL), stirred at room temperature for 30min, then sodium hydroxide (3 mL) was added to complete the reaction, using CH 2 Cl 2 Extracting, washing with saturated sodium chloride solution, drying with anhydrous sodium sulfate, filtering, spin-drying the organic phase, recrystallizing the residual crude product with ethanol to obtain the target compound (E) -3- (benzo [ b)]Thiophen-3-yl) -2-methyl-1- (3, 4, 5-trimethoxyphenyl) prop-2-en-1-one 206.1 mg in 56% yield. 1 H NMR(300MHz,CDCl 3 )δ7.91(s,1H),7.70(d,2H,J＝13.2Hz), 7.44(d,3H,J＝14.1Hz),7.09(s,2H),3.91-3.96(m,9H),2.35(s,3H).MS(ESI):m/z [M+H] + :369.12.
Example 3: (E) Preparation of (E) -3- (5-fluoro-1H-indol-3-yl) -2-methyl-1- (3, 4, 5-trimethoxyphenyl) prop-2-en-1-one (6)
Intermediate 1- (3, 4, 5-trimethoxyphenyl) propan-1-one was prepared as described in reference to example 1.
Intermediate 1- (3, 4, 5-trimethoxyphenyl) propan-1-one(336 mg,1.5 mmol) and 5-fluoro-1H-indole-3-carbaldehyde (81.6 mg,0.5 mmol) were dissolved in ethanol (5 mL), piperidine (0.3 mL) was added, the mixture was stirred at 95℃for 48H, the organic phase was dried by spinning, and the remaining crude product was recrystallized from ethanol to give the title compound (E) -3- (5-fluoro-1H-indol-3-yl) -2-methyl-1- (3, 4, 5-trimethoxyphenyl) prop-2-en-1-one 94.1mg, 51% yield 1 H NMR(300MHz,CDCl 3 )δ8.62(s,1H),7.67(s,1H),7.54(s,1H),7.36(dd, 1H,J＝4.5,8.7Hz),7.20-7.26(m,1H),7.02(s,3H),3.90-3.96(m,9H),2.31(s,3H).MS(ESI):m/z[M+H] + :370.14。
The preparation of compounds 7-8 is described in example 3. Namely: when the compounds 7 and 8 are produced, the compound can be realized by respectively replacing the 5-fluoro-1H-indole-3-formaldehyde with the 6-fluoro-1H-indole-3-formaldehyde and the 5-chloro-1H-indole-3-formaldehyde with the same dosage.
Example 4: (E) Preparation of (E) -3- (5-bromo-1H-indol-3-yl) -2-methyl-1- (3, 4, 5-trimethoxyphenyl) prop-2-en-1-one (9)
Intermediate 1- (3, 4, 5-trimethoxyphenyl) propan-1-one was prepared as described in reference to example 1.
Intermediate 1- (3, 4, 5-trimethoxyphenyl) propan-1-one (4478 mg,2 mmol) was dissolved in PhCH 3 (6 mL) and piperidine (0.12 mL), 5-bromo-1H-indole-3-carbaldehyde (149.2 mg,0.66 mmol) was added to the mixture, the mixture was reacted at 110℃for 4 hours, the organic phase was dried by spinning, and the remaining crude product was recrystallized from ethanol to give 154.7mg of the compound (E) -3- (5-bromo-1H-indol-3-yl) -2-methyl-1- (3, 4, 5-trimethoxyphenyl) prop-2-en-1-one in 54% yield. 1 H NMR(300MHz,CDCl 3 )δ8.61(s,1H),7.70(s,1H),7.62(s,1H),7.53(s,1H), 7.33-7.38(m,2H),7.03(s,2H),3.91-3.97(m,9H),2.30(s,3H)。
Example 5: (E) Preparation of (E) -1- (3, 5-dimethoxyphenyl) -3- (1H-indol-3-yl) -2-methylpropan-2-en-1-one (10)
Intermediate 1- (3, 5-dimethoxyphenyl) propan-1-one was prepared as described in reference to example 1.
Intermediate 1- (3, 5-dimethoxyphenyl) propan-1-one (200 mg,1.03 mmol) and 1H-indole-3-carbaldehyde (49.8 mg,0.323 mmol) were dissolved in ethanol (5 mL), piperidine (0.3 mL) was added, stirred at 95℃for 48H, the organic phase was dried by spin-drying, and the remaining crude product was recrystallized from ethanol to give the title compound (E) -1- (3, 5-dimethoxyphenyl) -3- (1H-indol-3-yl) -2-methylpropan-2-en-1-one 56.1mg, 51% yield. 1 H NMR(300MHz,CDCl 3 )δ8.73(s,1H),7.70(s,1H),7.63(s,1H),7.56(d,1H,J＝7.8 Hz),7.43(d,1H,J＝7.8Hz),7.16-7.21(m,1H,),6.86(s,3H),6.64(s,1H),3.83(s,6H),2.31(s,3H).MS(ESI):m/z[M+H] + :322.14。
Example 6: (E) Preparation of (E) -3- (1H-indol-3-yl) -1- (5-methoxypyridin-3-yl) -2-methylpropan-2-en-1-one (11)
Intermediate 1- (5-methoxypyridin-3-yl) propan-1-one was prepared with reference to example 1.
Intermediate 1- (5-methoxypyridin-3-yl) propan-1-one (200 mg,1.21 mmol) and 1H-indole-3-carbaldehyde (58.5 mg,0.403 mmol) were dissolved in ethanol (5 mL), piperidine (0.3 mL) was added, stirred at 95℃for 48H, the organic phase was dried by spin-drying, and the remaining crude product was recrystallized from ethanol to give the title compound (E) -3- (1H-indol-3-yl) -1- (5-methoxypyridin-3-yl) -2-methylpropan-2-en-1-one 54.3mg, 46% yield. 1 H NMR(300MHz,CDCl 3 )δ8.93(s,1H),8.51(d,2H,J＝18.0Hz),7.67(s,2H),7.53 (d,2H,J＝9.0Hz),7.44(d,1H,J＝9.0Hz),7.30(s,1H),7.15-7.20(m,1H),3.93(s,3H),2.32(s,3H).MS(ESI):m/z[M+H] + :293.13。
Example 7: (E) Preparation of (E) -3- (6-methoxy-1H-indol-3-yl) -2-methyl-1- (3, 4, 5-trimethoxyphenyl) prop-2-en-1-one (12)
Intermediate 1- (3, 4, 5-trimethoxyphenyl) propan-1-one was prepared as described in reference to example 1.
Intermediate 1- (3, 4, 5-trimethoxyphenyl) propan-1-one (336 mg,1.5 mmol) and 6-methoxy-1H-indole-3-carbaldehyde (87.5 mg,0.5 mmol) were dissolved in ethanol (5 mL), piperidine (0.3 mL) was added, stirred at 95℃for 48H, the organic phase was dried by spin-drying, and the remaining crude product was recrystallized from ethanol to give the title compound (E) -3- (6-methoxy-1H-indol-3-yl) -2-methyl-1- (3, 4, 5-trimethoxyphenyl) propan-2-en-1-one 120 mg in 63% yield. 1 H NMR(600MHz,CDCl 3 )δ8.47(s,1H),7.62(s,1H),7.52(d,1H, J＝2.4Hz),7.45(s,1H),7.43(s,1H),7.02(s,1H),6.91(d,1H,J＝2.4Hz),6.85-6.86(dd,1H,J＝2.4,9.0Hz),3.95(s,3H),3.89(s,6H),3.86(s,3H),2.30(d,3H,J＝0.6Hz). MS(ESI):m/z[M+H] + :382.16。
The preparation of compounds 26, 31 is described in example 7. Namely: the same reaction conditions, in the same proportions as in example 7, "1- (3, 4, 5-trimethoxyphenyl) propan-1-one" was reacted with "3-formyl-1H-indole-6-carboxylic acid methyl ester" to give compound 26; "1- (3, 4, 5-trimethoxyphenyl) propan-1-one" and "3-formyl-1H-indole-6-carboxylic acid" gave compound 31.
Example 8: (E) Preparation of (E) -2-methyl-3- (5-nitro-1H-indol-3-yl) -1- (3, 4, 5-trimethoxyphenyl) prop-2-en-1-one (13)
Intermediate 1- (3, 4, 5-trimethoxyphenyl) propan-1-one was prepared as described in reference to example 1.
Intermediate 1- (3, 4, 5-trimethoxyphenyl) propan-1-one (336 mg,1.5 mmol) and 5-nitro-1H-indole-3-carbaldehyde (102.9 mg,0.5 mmol) were dissolved in ethanol (5 mL), piperidine (0.3 mL) was added, stirred at 95℃for 48H, the organic phase was dried by spin-drying, and the remaining crude product was recrystallized from ethanol to give the title compound (E) -2-methyl-3- (5-nitro-1H-indol-3-yl) -1- (3, 4, 5-trimethoxyphenyl) propan-2-en-1-one 84.5mg, 41% yield. 1 H NMR(300MHz,DMSO -d6 )δ12.50(s,1H),8.49(s,1H),8.07-8.13(d, 2H),7.65(d,2H,J＝9.0Hz),7.04(s,2H),3.78-3.84(m,9H),2.23(s,3H). 13 C NMR (150MHz,DMSO -d6 )δ162.66,159.45,156.50,149.49,146.64,138.11,137.52, 134.69,133.86,128.68,128.47,128.24,123.98,121.33,120.19,117.82,116.06,114.97,74.44,67.77,46.02.MS(ESI):m/z[M+H] + :367.17。
The preparation of compounds 14-15 is described in example 8. Namely: when the compounds 14 and 15 are produced, the use of the 6-nitro-1H-indole-3-formaldehyde and the 7-nitro-1H-indole-3-formaldehyde can be realized by replacing the 5-nitro-1H-indole-3-formaldehyde with the same dosage.
Example 9: (E) Preparation of (E) -3- (6-amino-1H-indol-3-yl) -2-methyl-1- (3, 4, 5-trimethoxyphenyl) prop-2-en-1-one (16)
(E) -2-methyl-3- (6-nitro-1H-indol-3-yl) -1- (3, 4, 5-trimethoxyphenyl) prop-2-en-1-one was prepared as in example 8.
(E) -2-methyl-3- (6-nitro-1H-indol-3-yl) -1- (3, 4, 5-trimethoxyphenyl) prop-2-en-1-one (100 mg,0.25 mmol) was dissolved in ethanol/water (5:1) and NH was added 4 Cl (53.9 mg,1 mmol), iron powder (56 mg,1 mmol) was added with stirring, the temperature was raised to 55℃and the reaction was monitored to completion by TLC plates. Filtration through celite, CH 2 Cl 2 Extraction, washing with saturated sodium chloride, drying over anhydrous sodium sulfate, filtering, and spin-drying the organic phase to give the target compound (E) -3- (6-amino-1H-indol-3-yl) -2-methyl-1- (3, 4, 5-trimethoxyphenyl) prop-2-en-1-one 56.6mg, yield 62%. 1 H NMR(300MHz,CDCl 3 )δ11.35(s, 1H),7.54(s,2H),7.08(d,1H,J＝3.0Hz),6.92(s,2H),6.60(d,2H,J＝3.0Hz),6.47-6.48(m,1H),4.89(s,1H),3.77-3.80(m,9H),2.16(s,3H).MS(ESI):m/z[M+H] + : 367.16。
The preparation of compounds 37-38 is described in example 9. Namely: the same reaction conditions, "(E) -2-methyl-3- (7-nitro-1H-indol-3-yl) -1- (3, 4, 5-trimethoxyphenyl) prop-2-en-1-one", and "NH", were used in the same proportions as in example 9 4 Cl and iron powder react to obtain a compound 37; "(E) -2-methyl-)3- (5-nitro-1H-indol-3-yl) -1- (3, 4, 5-trimethoxyphenyl) prop-2-en-1-one and NH 4 Cl, iron powder "to give compound 38.
Example 10: (E) Preparation of (E) -2- ((1H-indol-3-yl) methylene) -1- (3, 4, 5-trimethoxyphenyl) butan-1-one (17)
Intermediate 1- (3, 4, 5-trimethoxyphenyl) butan-1-one was prepared as described in reference to example 1.
Intermediate 1- (3, 4, 5-trimethoxyphenyl) butan-1-one (200 mg,0.84 mmol) and 1H-indole-3-carbaldehyde (40.6 mg,0.28 mmol) were dissolved in ethanol (5 mL), piperidine (0.3 mL) was added, stirred at 95℃for 48H, the organic phase was dried by spin-drying, and the remaining crude product was recrystallized from ethanol to give the title compound (E) -2- ((1H-indol-3-yl) methylene) -1- (3, 4, 5-trimethoxyphenyl) butan-1-one 43.9mg, 43% yield. 1 H NMR(300MHz,CDCl 3 )δ8.60(s,1H),7.64(s,1H),7.54-7.57(m,2H),7.44(d,1H,J ＝8.1Hz),7.30(s,1H),7.16-7.21(m,1H),7.03(s,2H),3.89-3.95(m,9H),2.83(d,2H,J＝7.5Hz),1.59(s,3H).MS(ESI):m/z[M+H]+:366.17。
Example 11: (E) Preparation of (E) -1- (3, 4-dimethoxyphenyl) -3- (1H-indol-3-yl) -2-methylpropan-2-en-1-one (18)
Intermediate 1- (3, 4-dimethoxyphenyl) propan-1-one was prepared as described in reference to example 1.
Intermediate 1- (3, 4-dimethoxyphenyl) propan-1-one (200 mg,1.03 mmol) and 1H-indole-3-carbaldehyde (49.82 mg,0.34 mmol) were dissolved in ethanol (5 mL), piperidine (0.3 mL) was added, the organic phase was dried by spinning under stirring at 95℃for 48H, and the remaining crude product was recrystallized from ethanol to give 57.4mg of the target compound (E) -1- (3, 4-dimethoxyphenyl) -3- (1H-indol-3-yl) -2-methylpropan-2-en-1-one in 52% yield. 1 H NMR(300MHz,CDCl 3 )δ8.72(s,1H),7.57-7.62(m,3H),7.40-7.45(m,3H),7.30(s, 1H),7.16-7.21(m,1H),6.93(d,1H,J＝8.1Hz),3.96(d,6H,J＝13.2Hz),2.32(s,3H).MS(ESI):m/z[M+H]+:322.14。
Example 12: (E) Preparation of (E) -3- (1H-indol-3-yl) -1- (3-methoxyphenyl) -2-methylpropan-2-en-1-one (19)
Intermediate 1- (3-methoxyphenyl) propan-1-one was prepared according to example 1.
Intermediate 1- (3-methoxyphenyl) propan-1-one (200 mg,1.22 mmol) and 1H-indole-3-carbaldehyde (58.94 mg,0.41 mmol) were dissolved in ethanol (5 mL), piperidine (0.3 mL) was added, the mixture was stirred at 95℃for 48H, the organic phase was dried by spinning, and the remaining crude product was recrystallized from ethanol to give the title compound (E) -1- (E) -3- (1H-indol-3-yl) -1- (3-methoxyphenyl) -2-methylpropan-2-en-1-one 54.4mg, 46% yield. 1 H NMR(300MHz,CDCl 3 )δ8.72(s,1H),7.65(d,2H,J＝12.3Hz),7.53(d,1H,J＝ 7.8Hz),7.36-7.44(m,2H),7.26-7.31(m,3H,J＝15.0Hz),7.08-7.20(m,2H),3.86(s,3H),2.31(s,3H).MS(ESI):m/z[M+H]+:292.13。
Example 13: (E) Preparation of (E) -3- (1H-indol-3-yl) -2-methyl-1-phenylprop-2-en-1-one (20)
Intermediate propiophenone was prepared with reference to example 1.
Intermediate propiophenone (200 mg,1.49 mmol) and 1H-indole-3-carbaldehyde (72.12mg,0.50 mmol) were dissolved in ethanol (5 mL), piperidine (0.3 mL) was added, stirred at 95℃for 48H, the organic phase was dried by spinning, and the remaining crude product was recrystallized from ethanol to give the title compound (E) -3- (1H-indol-3-yl) -2-methyl-1-phenylprop-2-en-1-one 74.0mg, 57% yield. 1 H NMR(600MHz,CDCl 3 )δ8.76(s,1H), 7.73-7.75(m,2H),7.62-7.64(m,2H),7.55-7.57(m,1H),7.47-7.52(m,3H),7.42(d, 1H,J＝7.8Hz),7.25-7.28(m,1H),7.15-7.18(m,1H),2.33(s,3H).MS(ESI):m/z[M+H]+:262.12。
Example 14: (E) Preparation of (E) -3- (1H-indol-3-yl) -1-phenylprop-2-en-1-one (21)
Acetophenone (200 mg,1.66 mmol) and 1H-indole-3-carbaldehyde (72.12 mg,0.55 mmol) were dissolved in ethanol (5 mL), piperidine (0.3 mL) was added, stirred at 95℃for 48H, the organic phase was dried by spin, and the remaining crude product was recrystallized from ethanol to give the target compound (E) -3- (1H-indol-3-yl) -1-phenylprop-2-en-1-one 75.5mg, 55% yield. 1 H NMR(300MHz,CDCl 3 )δ8.54(s,1H),8.03-8.14(m, 4H),7.45-7.63(m,6H),7.31-7.34(m,2H).MS(ESI):m/z[M+H]+:248.11。
Example 15: (E) Preparation of (E) -2-methyl-3- (1H-pyrrolo [2,3-b ] pyridin-3-yl) -1- (3, 4, 5-trimethoxyphenyl) prop-2-en-1-one (22)
Intermediate 1- (3, 4, 5-trimethoxyphenyl) propan-1-one was prepared as described in reference to example 1.
Intermediate 1- (3, 4, 5-trimethoxyphenyl) propan-1-one (448 mg,2 mmol) was dissolved in toluene (6 mL), piperidine (0.12 mL), 1H-pyrrolo [2,3-b ] pyridine-3-carbaldehyde (97.32 mg,0.66 mmol) was added and reacted at 110℃for 4H, filtered and recrystallized from ethanol to give compound (E) -2-methyl-3- (1H-pyrrolo [2,3-b ] pyridin-3-yl) -1- (3, 4, 5-trimethoxyphenyl) propan-2-en-1-one 96.2mg in 41% yield.
Preparation of Compounds 23-25 reference example 15. Namely: the same reaction conditions, in the same proportions as in example 15, "1- (3, 4, 5-trimethoxyphenyl) propan-1-one" was reacted with "1H-pyrrolo [3,2-c ] pyridine-3-carbaldehyde" to give compound 23; "1- (3, 4, 5-trimethoxyphenyl) propan-1-one" is reacted with "1H-pyrrolo [3,2-b ] pyridine-3-carbaldehyde" to give compound 24; "1- (3, 4, 5-trimethoxyphenyl) propan-1-one" was reacted with "1H-pyrrolo [2,3-c ] pyridine-3-carbaldehyde" to give compound 25.
Example 16: (E) Preparation of (E) -3- (1H-indol-3-yl) -1- (7-methoxybenzo [ d ] [1,3] dioxol-5-yl) -2-methylpropan-2-en-1-one (27)
Intermediate 1- (7-methoxybenzo [ d ] [1,3] dioxol-5-yl) propan-1-one was prepared according to example 1.
Intermediate 1- (7-methoxybenzo [ d)][1,3]Dioxolen-5-yl) propan-1-one (200 mg,0.96 mmol) and 1H-indole-3-carbaldehyde (46.48 mg,0.32 mmol) were dissolved in ethanol (5 mL), piperidine (0.3 mL) was added, stirred at 95℃for 48H, the organic phase was dried by spinning, and the remaining crude product was recrystallized from ethanol to give the title compound (E) -3- (1H-indol-3-yl) -1- (7-methoxybenzo [ d ]][1,3]Dioxol-5-yl) -2-methylpropan-2-en-1-one 54.8mg, 51% yield. 1 H NMR(300MHz,CDCl 3 )δ8.66(s,1H), 7.59-7.62(m,3H),7.44(d,1H,J＝7.8Hz),7.28-7.31(m,1H),7.17-7.22(m,1H),7.06 (s,1H),6.99(s,1H),6.09(s,2H),3.93(s,3H),2.30(s,3H).MS(ESI):m/z [M+H]+:336.12。
Example 17: (E) Preparation of (E) -3- (imidazo [1,2-a ] pyridin-3-yl) -2-methyl-1- (3, 4, 5-trimethoxyphenyl) prop-2-en-1-one (28)
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Intermediate 1- (7-methoxybenzo [ d ] [1,3] dioxol-5-yl) propan-1-one was prepared according to example 1.
Intermediate 1- (7-methoxybenzo [ d)][1,3]Dioxolan-5-yl) propan-1-one (200 mg,0.89 mmol) with 1,8a dihydroimidazo [1,2-a]Pyridine-3-carbaldehyde (44.05 mg,0.30 mmol) was dissolved in ethanol (5 mL), piperidine (0.3 mL) was added, the mixture was stirred at 95℃for 48h, the organic phase was dried by spinning, and the remaining crude product was recrystallized from ethanol to give the title compound (E) -3- (imidazo [1, 2-a)]Pyridin-3-yl) -2-methyl-1- (3, 4, 5-trimethoxyphenyl) prop-2-en-1-one 53.7mg, 51% yield. 1 H NMR(300MHz,CDCl 3 )δ8.09(s,1H),7.99(d,1H,J＝6.6Hz),7.74(d,1H,J＝9.0Hz),7.32-7.38(m,2H),7.26 (s,1H),6.93-6.99(m,2H),3.89-3.95(m,9H),2.39(s,3H).MS(ESI):m/z [M+H]+:353.15。
Preparation of compound 29 is described in example 17. Namely: the same reaction conditions, "1- (3, 4, 5-trimethoxyphenyl) propan-1-one" and "pyrazolo [1,5-a ] pyridine-3-carbaldehyde" were reacted under the same feed ratios as in example 17 to give compound 29.
Example 18: (E) Preparation of (E) -2- ((1H-indol-3-yl) methylene) -5-methoxy-3, 4-dihydronaphthalen-1 (2H) -one (30)
5-methoxy-3, 4-dihydronaphthalen-1 (2H) -one (200 mg,1.13 mmol) and 1H-indole-3-carbaldehyde (54.92 mg,0.38 mmol) were dissolved in ethanol (5 mL), piperidine (0.3 mL) was added, the organic phase was dried by spinning under stirring at 95℃for 48H, and the remaining crude product was recrystallized from ethanol to give the target compound (E) -2- ((1H-indol-3-yl) methylene) -5-methoxy-3, 4-dihydronaphthalen-1 (2H) -one (30) 59.7mg, yield 52%. 1 H NMR(300MHz,CDCl 3 )δ8.55(s,1H),8.25(s,1H),7.89(d,1H,J＝7.5Hz),7.78 (d,1H,J＝7.8Hz),7.55(s,1H),7.43(d,2H,J＝7.5Hz),7.30-7.35(m,2H),7.04(d,1H,J＝8.1Hz),3.89(s,3H)2.97-3.13(m,4H).MS(ESI):m/z[M+H]+:304.13。
Example 19: (E) Preparation of (E) -2-methyl-3- (1H-pyrazol-3-yl) -1- (3, 4, 5-trimethoxyphenyl) prop-2-en-1-one (32)
Intermediate 1- (3, 4, 5-trimethoxyphenyl) propan-1-one was prepared as described in reference to example 1.
Intermediate 1- (3, 4, 5-trimethoxyphenyl) propan-1-one (336 mg,1.5 mmol) and 1H-pyrazole-3-carbaldehyde (48.0 mg,0.5 mmol) were dissolved in ethanol (5 mL), piperidine (0.3 mL) was added, stirred at 95℃for 48H, dried by spinning, and recrystallized from ethanol to give 66.4mg of the title compound (E) -2-methyl-3- (1H-pyrazol-3-yl) -1- (3, 4, 5-trimethoxyphenyl) propan-2-en-1-one in 44% yield. 1 H NMR(300MHz,CDCl 3 ) δ8.11(s,1H),7.66(s,1H),7.18(s,1H),6.98(s,2H),6.63(s,1H),3.88-3.92(m,9H),2.34(s,3H)。
Example 20: (E) Preparation of (E) -2-methyl-3- (1H-pyrrol-3-yl) -1- (3, 4, 5-trimethoxyphenyl) prop-2-en-1-one (33)
Intermediate 1- (3, 4, 5-trimethoxyphenyl) propan-1-one was prepared as described in reference to example 1.
Intermediate 1- (3, 4, 5-trimethoxyphenyl) propan-1-one (336 mg,1.5 mmol) and 1H-pyrrole-3-carbaldehyde (47.5 mg,0.5 mmol) were dissolved in ethanol (5 mL), piperidine (0.3 mL) was added, stirred at 95℃for 48H, dried by spinning, and recrystallized from ethanol to give 64.5mg of the title compound (E) -2-methyl-3- (1H-pyrrol-3-yl) -1- (3, 4, 5-trimethoxyphenyl) propan-2-en-1-one in 43% yield. 1 H NMR(300MHz,CDCl 3 ) δ8.56(s,1H),7.23(s,1H),7.09(s,1H),6.88-6.92(m,3H),6.52(s,1H),3.88-3.96(m,9H),2.25(s,3H)。
Example 21: (E) Preparation of (E) -2-methyl-3- (quinolin-3-yl) -1- (3, 4, 5-trimethoxyphenyl) prop-2-en-1-one (34)
Intermediate 1- (3, 4, 5-trimethoxyphenyl) propan-1-one was prepared as described in reference to example 1.
Intermediate 1- (3, 4, 5-trimethoxyphenyl) propan-1-one (448 mg,2 mmol) and quinoline-3-carbaldehyde (47.5 mg,1 mmol) were dissolved in ethanol (8 mL), stirred at room temperature for 30min, then sodium hydroxide (3 mL) was added to complete the reaction, using CH 2 Cl 2 Extraction, washing with saturated sodium chloride solution, drying with anhydrous sodium sulfate, filtering, spin-drying the organic phase, and recrystallizing with ethanol to obtain 85.1mg of the target compound (E) -2-methyl-3- (quinolin-3-yl) -1- (3, 4, 5-trimethoxyphenyl) prop-2-en-1-one with a yield of 47%. 1 H NMR(300MHz, CDCl 3 )δ8.97(s,1H),8.29(s,1H),8.18-8.21(m,1H),7.90(d,1H,J＝8.1Hz), 7.78-7.83(m,1H,),7.61-7.66(m,1H),7.28(s,1H),7.07(s,2H),3.91-3.95(m,9H),2.38(s,3H).MS(ESI):m/z[M+H] + :364.15。
Example 22: (E) Preparation of (E) -3- (1H-indol-2-yl) -2-methyl-1- (3, 4, 5-trimethoxyphenyl) prop-2-en-1-one (35)
Intermediate 1- (3, 4, 5-trimethoxyphenyl) propan-1-one was prepared as described in reference to example 1.
Intermediate 1- (3, 4, 5-trimethoxyphenyl) propan-1-one (336 mg,1.5 mmol) and 1H-indole-2-carbaldehyde (72.5 mg,0.5 mmol) were dissolved in ethanol (5 mL), piperidine (0.3 mL) was added, stirred at 95℃for 48H, the organic phase was dried by spin-drying, and the remaining crude product was recrystallized from ethanol to give the title compound (E) -3- (1H-indol-2-yl) -2-methyl-1- (3, 4, 5-trimethoxyphenyl) propan-2-en-1-one 82.5mg, 47% yield. 1 H NMR(300MHz,CDCl 3 )δ8.30(s,1H),7.66(d,1H,J＝7.2Hz),7.38(s,2H),7.20 (s,2H),6.97(s,2H),6.89(s,1H),3.89-3.94(m,9H),2.43(s,3H)。
Example 23: (E) Preparation of ethyl-2- (4- (3- (1H-indol-3-yl) -2-methacryloyl) -2, 6-dimethylphenoxy) acetate (36)
The synthetic route is as follows:
step a: synthesis of 4- ((tert-butyldimethylsilyl) oxy) -3, 5-dimethoxybenzaldehyde.
4-hydroxy-3, 5-dimethoxybenzaldehyde (10 g,54.89 mmol) and imidazole (14.95g,219.6 mmol) were dissolved in DMF (100 mL), TBSCl (16.55 g,109.8 mmol) was added at 0deg.C, TLC monitored to completion, quenched with water, extracted with ethyl acetate, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the dried organic phase was spun-dried and the remaining crude product purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=10:1) to give compound 4- ((tert-butyldimethylsilyl) oxy) -3, 5-dimethoxybenzaldehyde 11.37g in 70% yield.
Steps b and c refer to steps a and b in example 1.
Step d Synthesis of 1- (4-hydroxy-3, 5-dimethoxyphenyl) propan-1-one.
1- (4- ((t-Butyldimethylsilanyloxy) -3, 5-dimethoxyphenyl) propan-1-one (2.32 g,7.15 mmol) was dissolved in THF (30 mL) and TBAF (7.5 mL) was added at 0deg.C, N 2 The reaction was carried out for 2h under protection, TLC was monitored to complete reaction, quenched with water, extracted with ethyl acetate, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the organic phase was dried by spin-drying, and the remaining crude product was purified by column chromatography on silica gel (eluent: petroleum ether/ethyl acetate=1:1) to give compound 1- (4-hydroxy-3, 5-dimethoxyphenyl) propan-1-one 1.34g in 89% yield.
Step e, synthesizing the ethyl 2- (2, 6-dimethoxy-4-propionylphenoxy) acetate.
1- (4-hydroxy-3, 5-dimethoxyphenyl) propan-1-one (266 mg,1.27 mmol), potassium carbonate (351.9 mg,2.55mmol), ethyl 2-bromoacetate (425.1 mg,2.55 mmol) were dissolved in DMF (6 mL), TLC monitored to completion of the reaction, quenched with water, extracted with ethyl acetate, washed with sodium chloride, dried over anhydrous sodium sulfate, and purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=10:1) to give compound 2- (2, 6-dimethoxy-4-propionylphenoxy) ethyl acetate 296.2mg in 79% yield.
Step f (E) -Synthesis of ethyl 2- (4- (3- (1H-indol-3-yl) -2-methacryloyl) -2, 6-dimethylphenoxy) acetate.
Intermediate 2- (2, 6-dimethoxy-4-propionylphenoxy) ethyl acetate (460 mg,1.55 mmol) and 1H-indole-3-carbaldehyde (75.1 mg,0.5 mmol) were dissolved in ethanol (10 mL), piperidine (0.6 mL) was added, stirred at 95℃for 48H, the organic phase was dried by spin-drying, and the remaining crude product was recrystallized from ethanol to give the title compound (E) -2- (4- (3- (1H-indol-3-yl) -2-methacryloyl) -2, 6-dimethylphenoxy) ethyl acetate 100.7 mg in 46% yield. 1 H NMR(300MHz,CDCl 3 )δ8.61(s,1H),7.66(s,2H),7.57(s,1H), 7.43(s,1H),7.21(s,2H),7.01(s,1H),4.70-4.74(m,2H),4.30(d,2H,J＝7.2Hz),3.87-3.90(m,6H),2.31(s,3H),1.25(s,3H)。
Example 24: in vitro antitumor Activity test of the Compounds of the application
The in vitro antitumor activity of the synthesized compounds and part of the intermediates of the application was tested by using CellTiter-Blue method.
The experimental method comprises the following steps: HCT-116 (colon cancer cells), HCT-116/OXA (drug resistant colon cancer cells) were incubated with RPMI+10% FBS+1% diabodies.
Sample liquid preparation: dissolving with DMSO to obtain 50 μm mother solution. Then diluted with 1% dmso-containing medium (three-fold or five-fold dilution) to finally prepare a series of gradient concentration solutions.
4000-8000 cells are added into each well of a 96-well plate, and the plate is placed at 37 ℃ and 5% CO 2 After incubation in the incubator for 24 hours, the sample solution and the control solution were added, respectively, and the mixture was allowed to act at 37℃for 72 hours at 200. Mu.L/well. 20 mu L of CellTiter-Blue (fluorescent Blue cell active kit) solution is added into each hole, the OD value of 570/590nm is measured by a full-automatic enzyme-labeled instrument (manufactured by the manufacturer Labsystems Dragon) after 0.5-1 hour of action, and half inhibition concentration IC is calculated 50 。
Data were analyzed using GraphPad Prism software, and compound IC was finally measured 50 Values.
The compounds of the present application were subjected to in vitro antitumor activity studies according to the above in vitro antitumor activity test methods:
2 tumor cell lines are selected to study the in vitro anti-tumor activity of the target compound: HCT-116 (colon cancer cells), HCT-116/OXA (drug resistant colon cancer cells). The activity test is carried out by adopting the CellTiter-Blue method, and the results show that the compound has better anti-tumor activity on colon cancer and drug-resistant cell lines thereof, and particularly has better anti-tumor activity on drug-resistant leukemia cells. Among the most active derivatives there are mainly 2: compounds 6 and 7, IC 50 The values were all below 10 nM. However, the activity of the compounds without methoxy substitution on the benzene ring is obviously reduced, such as compounds 20 and 21; after the bromine substitution and the carboxyl substitution on the indole ring, the activity is also obviously reduced, such as compounds 9 and 31.
TABLE 1 IC of target compounds for colon cancer (HCT-HCT) and drug resistant colon cancer (HCT-116/OXA) cells 50 Value of
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In conclusion, the compound and the salts thereof can be used for preparing anti-tumor drugs.
While the preferred embodiments of the present application have been described in detail, the present application is not limited to the embodiments, and various equivalent modifications and substitutions can be made by those skilled in the art without departing from the spirit of the present application, and these equivalent modifications and substitutions are intended to be included in the scope of the present application as defined in the appended claims.

Claims (2)

1. An alpha, beta-unsaturated ketone derivative is characterized in that: the alpha, beta-unsaturated ketone derivative is selected from one of the following structures:
(E) -2-methyl-3- (5-methyl-1H-indol-3-yl) -1- (3, 4, 5-trimethoxyphenyl) prop-2-en-1-one (2),
(E) -2-methyl-3- (7-methyl-1H-indol-3-yl) -1- (3, 4, 5-trimethoxyphenyl) prop-2-en-1-one (4),
(E) -3- (benzo [ b ] thiophen-3-yl) -2-methyl-1- (3, 4, 5-trimethoxyphenyl) prop-2-en-1-one (5),
(E) -3- (5-fluoro-1H-indol-3-yl) -2-methyl-1- (3, 4, 5-trimethoxyphenyl) prop-2-en-1-one (6),
(E) -3- (6-fluoro-1H-indol-3-yl) -2-methyl-1- (3, 4, 5-trimethoxyphenyl) prop-2-en-1-one (7),
(E) -3- (5-chloro-1H-indol-3-yl) -2-methyl-1- (3, 4, 5-trimethoxyphenyl) prop-2-en-1-one (8),
(E) -2-methyl-3- (6-nitro-1H-indol-3-yl) -1- (3, 4, 5-trimethoxyphenyl) prop-2-en-1-one (14),
(E) -2-methyl-3- (7-nitro-1H-indol-3-yl) -1- (3, 4, 5-trimethoxyphenyl) prop-2-en-1-one (15),
(E) -3- (6-amino-1H-indol-3-yl) -2-methyl-1- (3, 4, 5-trimethoxyphenyl) prop-2-en-1-one (16),
(E) -2-methyl-3- (1H-pyrrolo [2,3-b ] pyridin-3-yl) -1- (3, 4, 5-trimethoxyphenyl) prop-2-en-1-one (22),
(E) -2-methyl-3- (1H-pyrrolo [3,2-b ] pyridin-3-yl) -1- (3, 4, 5-trimethoxyphenyl) prop-2-en-1-one (24).
2. The use of an alpha, beta-unsaturated ketone derivative according to claim 1 for the preparation of a medicament for the treatment of colon cancer and drug-resistant colon cancer.
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