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2-oxospiro[indoline-3, 4 '-pyran] ketone compound as well as synthesis method and application of 2-oxo spiro [indoline-3, 4'-pyran] ketone compound

A technology of ketone compounds and indoline, applied in organic chemistry, drug combination, antineoplastic drugs, etc., can solve the problems of difficulty in obtaining novel and diverse structures, fewer types of synthesis methods, insufficient catalyst activity, etc., and achieve excellent cytotoxicity , Novel product structure, mild condition effect

Active Publication Date: 2020-10-16
XUZHOU NORMAL UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, due to insufficient catalyst activity and fewer types of synthetic methods (only oxidative rearrangement and intramolecular Mannich reaction, etc.), only cyclic diketones with high activity and low steric hindrance can participate in spiroisatins and spirooxines. The synthesis of isatins makes the scope of substrates of these methods narrow, and it is difficult to obtain target products with novel and diverse structures.
So far, there is no report on the synthesis of spiroisatins and spiroisatins with low activity and large hindrance chain diketones

Method used

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  • 2-oxospiro[indoline-3, 4 '-pyran] ketone compound as well as synthesis method and application of 2-oxo spiro [indoline-3, 4'-pyran] ketone compound
  • 2-oxospiro[indoline-3, 4 '-pyran] ketone compound as well as synthesis method and application of 2-oxo spiro [indoline-3, 4'-pyran] ketone compound
  • 2-oxospiro[indoline-3, 4 '-pyran] ketone compound as well as synthesis method and application of 2-oxo spiro [indoline-3, 4'-pyran] ketone compound

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0023] Example 1 Synthesis of 2-oxospiro[indoline-3,4'-pyrone] derivative 5

[0024] 1-phenyl-1,3-butanedione 2 or dibenzoylmethane 2' (0.42mmol), substituted isatins 3 (0.4mmol), malononitrile 4 (0.8mmol), Add base derivative 1 (0.08mmol) and 10mL acetonitrile into a 50mL round bottom flask, reflux at 80°C for 16h, after the reaction (TLC monitoring), wash with saturated NaHCO 3 (aqueous solution) to adjust pH = 7, the mixture was washed with CH 2 Cl 2 Extraction (50mL×3), combined organic layers, anhydrous Na 2 SO 4 Drying, removal of solvent under vacuum, purification of column chromatography to obtain product 5 (V 二氯甲烷 :V 甲醇 =80:1).

[0025] Concrete reaction route is as follows:

[0026]

[0027]

[0028] The synthetic process of each following compound is described in detail below:

[0029]

[0030] 1. Preparation of Compound 5a

[0031] The structural formula of compound 5a is: (R=-CH 3 R'=5-CH 3 )

[0032]

[0033] 1-phenyl-1,3-butanedione 2 (...

Embodiment 2

[0256] Embodiment 2 The antitumor activity of each product of the present invention

[0257] In this example, the anti-tumor activity of compound 5 on human liver cancer cells (HepG2), non-small cell lung cancer cells (247), human non-small cell lung cancer cells (A549) and human liver epithelial cells were tested by the MTT method. (THLE), human bronchial epithelioid cells (HBE) toxicity (with cisplatin (DPP) and doxorubicin (DOX) as positive controls), the test results are shown in Table 2.

[0258] Table 2 IC50 (μM) of compound 5 on three kinds of cell lines a

[0259]

[0260] a IC 50 Greater than or equal to 50μg / mL marked as "-"

[0261] The results in Table 2 show that: 8 compounds (5b, 5e, 5g, 5i, 5j, 5k, 5m, 5o) have good inhibitory effects on one or more of the above three cancer cell lines.

[0262] Compounds (5b, 5e, 5k, 5o) have good toxicity to human triple-positive breast cancer cells (MCF-7), and their IC 50 The values ​​are all less than 100.00 μM. F...

Embodiment 3

[0265] The antibacterial activity of embodiment 3 each product of the present invention

[0266] Escherichia coli (18H5) carrying the NDM-1 gene recombinant plasmid and Staphylococcus aureus (18H8) carrying different drug-resistant genes isolated from the clinic, two drug-resistant bacteria and three common bacteria (Escherichia coli, gold Staphylococcus aureus (Staphylococcus aureus) and Klebsiella pneumoniae (Klebsiella pneumoniae), and Meropenem (Meropenem) was used as a positive control to test the antibacterial activity of the series of two types of 17 spirocyclic isatin compounds.

[0267] Use methanol to prepare the product to 10 μM, suck 6 μL into a new centrifuge tube, wait for the methanol to evaporate to leave a quantitative solid product, add 6 μL DMSO and 294 μL Luria-Bertani (LB) solution (to ensure that the DMSO solution in the final 96-well plate is less than 2%), thus the product is made into a 200 μM sample and then diluted to 20 μM and 2 μM with LB solution ...

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Abstract

The invention discloses a 2-oxospiro[indoline-3, 4 '-pyran] ketone compound. The structural general formula of the 2-oxospiro[indoline-3, 4 '-pyran] ketone compound is shown as one of the following formulas, and the preparation method comprises the following steps: selecting 1-phenyl-1, 3-butanedione or benzil, substituted isatin and malononitrile as raw materials and a heterocyclic Base derivative as a catalyst, and carrying out a one-step reaction to obtain the 2-oxospiro[indoline-3, 4'-pyran] ketone compound. The 2-oxospiro[indoline-3, 4 '-pyran] ketone compound partially has different degrees of inhibition effects on human tri-positive breast cancer cells, human tri-negative breast cancer cells and human non-small cell lung cancer cells. Part of the compounds have different degrees ofbacteriostatic activity on two drug-resistant bacteria, staphylococcus aureus carrying different drug-resistant genes and three common bacteria.

Description

technical field [0001] The invention relates to the technical field of chemical synthesis, in particular to a class of novel 2-oxospiro[indoline-3,4'-pyrone] derivatives and their synthesis method and application. Background technique [0002] Isatin, also known as indolindione, is an important class of nitrogen-containing heterocyclic compounds, which widely exist in natural products and drug molecular structures. Isatin and its derivatives can easily cross the blood-brain barrier, so they have broad-spectrum biological properties, such as antifungal, antimalarial, antituberculosis, antiviral and anticancer, etc. [0003] At present, some compounds containing isatin skeleton have been applied clinically (Formula A), such as: Indiyubin, a bisindole compound isolated from the traditional Chinese medicine Indigofera tinctoria L, can target a variety of Sunitinib for body tyrosine kinases, small molecule tyrosine kinase inhibitors-nintedanib, potent VEGFR (Flk-1 / KDR) autophosp...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D491/107A61P35/00A61P31/04A61P31/10
CPCC07D491/107A61P35/00A61P31/04A61P31/10Y02A50/30
Inventor 刘润芯任璇璇苑睿张鹏周生亮宛瑜吴翚
Owner XUZHOU NORMAL UNIVERSITY