CN110305061B

CN110305061B - Potential antitumor drug compound structure

Info

Publication number: CN110305061B
Application number: CN201910729997.7A
Authority: CN
Inventors: 顾海宁
Original assignee: Hangzhou Xinbenli Pharmaceutical Co ltd
Current assignee: Hangzhou Xinbenli Pharmaceutical Co ltd
Priority date: 2019-08-08
Filing date: 2019-08-08
Publication date: 2020-12-22
Anticipated expiration: 2039-08-08
Also published as: CN110305061A

Abstract

The invention discloses a novel compound structure of a potential antitumor drug. The potential antitumor drug compound is 7-chloro-1-cyclopropyl-6-fluoro-3- (2,4, 6-trimethylbenzenesulfenyl) quinolin-4 (1H) -one, and the structural formula is shown in a formula 5. The invention has simple and feasible synthetic route and easily obtained raw materials, and can be applied to the synthesis of similar compounds; the results of preliminary biological activity tests show that the novel compound shows excellent tumor cell inhibitory activity, is a potential antitumor drug and has great significance for developing new antitumor drugs.

Description

Potential antitumor drug compound structure

Technical Field

The invention belongs to the technical field of organic synthesis and chemical medicine preparation, and relates to a novel structure of a potential antitumor drug compound, in particular to a novel compound 7-chloro-1-cyclopropyl-6-fluoro-3- (2,4, 6-trimethylbenzenesulfenyl) quinolin-4 (1H) -one.

Technical Field

The document reports that the quinolone compounds break through the traditional antibacterial concept and have new progress in the aspects of plasmodium resistance, inflammation resistance, tumor resistance and the like. Vandekerckhove et al reported that halogenated 4-quinolones and derivatives thereof have excellent anti-plasmodium activity in 2014, and the structures of the halogenated 4-quinolones and the derivatives are shown as the following formulas:

formula 1 halo 4-quinolones and derivatives thereof

Nilsen et al reported that 4(1H) -quinolone-3-alkyl derivatives are an excellent class of antimalarials.

Carbostyril-3-alkyl derivatives of formula 2

The Chern and Harris research groups reported that 3-heteroaromatic quinolones can inhibit topoisomerase I and tyrosine kinase, respectively, and have potential antitumor activity.

Formula 33-heteroaromatic carbostyril derivatives

Rajput team studies found that compounds of the formula have anti-inflammatory activity.

Novel quinolone structural derivatives of formula 4

The novel quinolone derivative has the advantages that the novel quinolone derivative is structurally creative with the original quinolone antibacterial drugs, other alkyl, aryl, aromatic heterocyclic rings and other structures are mainly introduced to the 3-position to replace the traditional carboxyl structure, great breakthrough is made in the aspect of biological activity, multiple functions of resisting tumors, inflammation, plasmodium and acetylcholine can be achieved, and a good foundation is laid for the research and development of new drugs.

However, the new quinolone derivative has not yet achieved the effect expected by researchers, and is not much superior to the drugs commonly used on the market in terms of biological activity, and the research and development of the drugs with higher activity is the trend of new drug development at present and is also the technical difficulty to be solved. Subject groups such as Caucasian J.2016 (11, 360-366) further studied and developed a series of novel quinolone derivatives, the most active compound in HepG2 (human hepatoma cell) activity test is 7-chloro-1-ethyl-6-fluoro-3- (4-methylphenylsulfanyl) quinolin-4 (1H) -one, and the half-inhibitory rate IC of the quinolone derivatives₅₀The value was 3.05 uM.

In order to overcome the defect of low biological activity of the existing drugs, the invention prepares the target product 7-chloro-1-cyclopropyl-6-fluoro-3- (2,4, 6-trimethylthiophenyl) quinoline-4 (1H) -ketone in one step by taking quinolone-3-carboxylic acid as a raw material and carrying out decarboxylation coupling with disulfide under the action of a catalyst on the basis of researching a novel quinolone structure and a novel application thereof and the action of thioether bonds in drug molecule construction. HepG2 (human liver cancer cell) half-inhibition rate IC of common anticancer drug vincristine sulfate on the market₅₀The value was 48.53 uM. HepG2 (human liver cancer cell) half-inhibition rate IC of novel compound₅₀The value is 0.65uM, which is 2 orders of magnitude better than vincristine sulfate. The new compound guides the new direction of research of quinolone compounds and has important significance on the research of synthetic new antitumor drugs.

Disclosure of Invention

The invention aims to overcome the defect of low biological activity of the existing medicines and provides a new structure of a potential antitumor medicine compound.

The potential antitumor drug compound is 7-chloro-1-cyclopropyl-6-fluoro-3- (2,4, 6-trimethylbenzenesulfenyl) quinolin-4 (1H) -one, and the structural formula is as follows:

formula 57-chloro-1-cyclopropyl-6-fluoro-3- (2,4, 6-trimethylphenylthio) quinolin-4 (1H) -one

The preparation method of the novel compound can be prepared by the following steps:

7-chloro-1-cyclopropyl-6-fluoro-4-oxo-1, 4-dihydroquinoline-3-carboxylic acid and bis (2,4, 6-trimethylphenyl) disulfide in the solvent DMSO in Ag₂CO₃、Pd(OAc)₂And PPh₃The new compound 7-chloro-1-cyclopropyl-6-fluoro-3- (2,4, 6-trimethylbenzenesulfenyl) quinoline-4 (1H) -ketone is prepared by decarboxylation coupling one-step reaction under catalysis. The reaction formula is as follows:

has the advantages that: 1. the invention has simple and feasible synthetic route and easily obtained raw materials, and can be applied to the synthesis of similar compounds; 2. the results of preliminary biological activity tests show that the novel compound shows excellent tumor cell inhibitory activity, is a potential antitumor drug and has great significance for developing new antitumor drugs.

Detailed Description

The invention is further illustrated, but not limited, by the following examples.

Example 1:

7-chloro-1-cyclopropyl-6-fluoro-4-oxo-1, 4-dihydroquinoline-3-carboxylic acid (281.5mg, 1mmol), Ag₂CO₃(275mg,1mmol)，Pd(OAc)₂(22.4mg,0.1mmol), bis (2,4, 6-trimethylphenyl) disulfide (453mg,1.5mmol), PPh₃(52.4mg,0.2mmol), dissolved in DMSO (8mL), and then the reaction temperature was raised to 130 ℃ for 12 hours. After the reaction was completed, the temperature was lowered to room temperature, and then 25mL of CH was added to the reaction system₂Cl₂Adding 20mL of water, extracting by layers, and adding 20mL of CH₂Cl₂The aqueous phase was extracted twice, the organic phases were combined, dried over anhydrous sodium sulfate, the solvent was distilled off, and the residue was separated by means of a chromatography column (PE/EA,10:1to 2:1) to give the desired product 7-chloro-1-cyclopropyl-6-fluoro-3- (2,4, 6-trimethylbenzenethio) quinolin-4 (1H) -one in 88% yield.

¹H NMR(500MHz,CDCl₃)：8.13–8.06(m,1H),8.02(s,1H),7.98(d,J＝5.9 Hz,1H),6.71(s,5H),3.48–3.39(m,1H),2.21(s,9H),1.31–1.27(m,2H),1.08(q,J ＝6.7Hz,2H).¹³C NMR(126MHz,CDCl₃)174.38,156.07,154.08,148.64,143.18, 137.82,136.95,136.21,128.97,128.35,126.23,118.76,113.41,34.31,23.68,20.01, 8.32.HRMS(ESI+):Calculated for C₂₁H₁₉ClFNOS:[M+H]⁺388.0939,Found 388.0955.

Example 2 physiological Activity assay

Cell culture:

human hepatoma cell line: huh7, HepG2 was provided by shanghai institute of cell biology, china academy of sciences.

The cells were grown in RPMI-1640 medium + 10% fetal calf serum at 37 deg.C (5% CO)₂-95% air) growth in incubator.

Sample preparation: the compound 7-chloro-1-cyclopropyl-6-fluoro-3- (2,4, 6-trimethylbenzenethio) quinolin-4 (1H) -one obtained in example 1 was dissolved in DMSO to prepare a stock solution having a concentration of 5mM, and further diluted to a concentration of 1.0,10,100, and 500. mu.M, respectively, so that the DMSO concentration in the solution used in the experiment was less than 0.1% (v/v) in order to avoid the toxicity of DMSO.

Detecting cell proliferation by MTT method:

(1) taking a bottle of cell strains which are in good growth state and in logarithmic phase, and blowing and beating the cell strains into cell suspension by using a culture solution after conventional pancreatin digestion.

(2) After counting by the cell counting plate, the cell density was adjusted to 4-5X 104 cells/ml of cell suspension. The cell suspension (100. mu.l) and the culture medium (100. mu.l) were added to each well of the 96-well plate, and 200. mu.l of the culture medium was added to each well of the plate. Placing at 37 deg.C and saturated humidity with 5% CO₂Culturing in an incubator.

(3) After cell attachment, experimental groups were dosed with a range of concentrations of different compounds. The blank control group was added with the same amount of culture medium without drug and the zero setting wells were set. Each group is provided with 5 multiple holes.

(4) At 37 deg.C, saturated humidity, 5% CO₂After 72 hours of incubation in the incubator, 10. mu.l of freshly prepared MTT solution at a concentration of 5mg/ml was added to each well.

(5) After further culturing for 4 hours, the plate was taken out, the supernatant in the plate was carefully and slowly aspirated (without aspiration of the purple crystals at the bottom), 150. mu.l of DMSO was added, and after the purple crystals were completely dissolved, the absorbance (OD value) of each well was measured at 490nm with a microplate reader, and the cell inhibition was calculated according to the following formula: the cell inhibition ratio (%) × (control well OD value-administration well OD value)/(control well OD value-blank well OD value) × 100%.

Half-inhibitory IC of the Compound 7-chloro-1-cyclopropyl-6-fluoro-3- (2,4, 6-trimethylbenzenethio) quinolin-4 (1H) -one in the Huh7 cell Activity test group₅₀The value was 3.45 uM; in the HepG2 cell activity test group, the half-inhibition rate IC is higher than that of the HepG2 cell activity test group₅₀The value was 0.65uM, and excellent tumor cell inhibitory activity was exhibited.

Comparative example 1 physiological Activity test

Experimental procedure As in example 2, the compound was changed to 7-chloro-1-ethyl-6-fluoro-3- (4-methylphenylsulfanyl) quinolin-4 (1H) -one, whose half-inhibitory rate IC of Huh7 cells (human hepatoma cells)₅₀A value of 17.57 uM; HepG2 (human hepatoma cell) half-inhibition rate IC₅₀The value was 3.05 uM.

Comparative example 2 physiological Activity test

Experimental procedure As in example 2, the compound was changed to 7-chloro-1-cyclopropyl-6-fluoro-3-thiophenyl-quinolin-4 (1H) -one, and its half-inhibitory rate IC of Huh7 cells (human hepatoma cells)₅₀A value of 66.25 uM; HepG2 (human hepatoma cell) half-inhibition rate IC₅₀The value was 44.58 uM.

Claims

1. An antitumor drug compound, which is characterized in that the compound is 7-chloro-1-cyclopropyl-6-fluoro-3- (2,4, 6-trimethylbenzenesulfenyl) quinolin-4 (1H) -one, and the structural formula is as follows:

。