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3-(3,4,5-trimethoxybenzoyl)-benzofuran microtubulin inhibitor as well as preparation method and use thereof

A technology of trimethoxybenzoyl and trimethoxybenzoyl chloride, applied in the field of medicinal chemistry, can solve the problems of low bioavailability, limited wide application, easy dissimilation, etc., achieve strong proliferation inhibitory activity and inhibit tubulin Aggregation, effect of excellent tubulin inhibitory activity

Active Publication Date: 2017-09-15
SHANGHAI ECUST BIOMEDICINE CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although CA-4 has a broad-spectrum antitumor activity in vitro, it is limited by its poor water solubility, low bioavailability, and its cis-active configuration is easily dissimilated into an inactive trans-configuration during storage and in vivo metabolism. Its wide application in clinical

Method used

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  • 3-(3,4,5-trimethoxybenzoyl)-benzofuran microtubulin inhibitor as well as preparation method and use thereof
  • 3-(3,4,5-trimethoxybenzoyl)-benzofuran microtubulin inhibitor as well as preparation method and use thereof
  • 3-(3,4,5-trimethoxybenzoyl)-benzofuran microtubulin inhibitor as well as preparation method and use thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0032] Embodiment 1: the preparation of structural formula 1 compound

[0033] (1) In a 250mL round bottom flask wrapped with tinfoil, I 2 (5.1 g, 20.0 mmol) was dissolved in chloroform (150 mL) and stirred over 1.5 hours. In addition, compound formula 1 (R 1 =H) (20.0 mmol) was placed in a 250 mL round bottom flask wrapped with tinfoil, and silver trifluoroacetate AgOTFA (4.5 g, 20.0 mmol) was added. The chloroform solution was slowly (about 2-3 hours) added to the flask wrapped in tin foil, and the reaction was stirred at room temperature for 24 hours to end. Filter and wash the residue with chloroform. then saturate with Na 2 S 2 o 3 solution, saturated NaHCO 3 solution, extracted with saturated brine, and the resulting organic phase was washed with anhydrous Na 2 SO 4 dry. Filter, carry out column chromatography separation (with CH 2 Cl 2 as eluent, column chromatography protected from light). Obtain product, 2-iodo-5-methoxyphenol (formula 2, R 1 = H). Whit...

Embodiment 2

[0044] Embodiment 2: the preparation of structural formula 2 compound

[0045] (1) The phenolic raw material is formula 1 (R 1 =F), step is the same as step (1) in embodiment 1. Obtain product 2-iodo-4-fluoro-5-methoxyphenol (formula 2, R 1 =F).

[0046]

[0047] White solid, yield 39.92%. 1 H NMR (500MHz, CDCl 3 )δ=7.31(d,J=10Hz,1H),6.67(d,J=7.5Hz,1H),5.13-5.12(m,1H),3.85(s,3H). 19F NMR (470MHz, CDCl 3 )δ=-143.08. 13 C NMR (125MHz, CDCl 3 )δ=151.73(d, J=2.5Hz), 149.2, 146.82(d, J=240.6Hz), 123.70(d, J=22.5Hz), 100.30, 70.97(d, J=7.5Hz), 56.27.ESI -HRMS(m / z): calculated for C 7 h 6 FIO 2 (M+H) + ,268.94301,found:268.94769.

[0048] (2) The steps are the same as the steps (2) in Example 1. Obtain product 2-iodo-4-fluoro-5-methoxyphenyl acetate (formula 3, R 1 =F).

[0049]

[0050] White crystals, yield 81.28%. 1 H NMR (500MHz, CDCl 3 )δ=7.47(d,J=10Hz,1H),6.74(d,J=7.5Hz,1H),3.85(s,3H),2.35(s,3H). 19 F NMR (470MHz, CDCl 3 )δ=-135.80. 13 C NMR (125MHz, ...

Embodiment 3

[0060] Embodiment 3: anti-proliferation experiment

[0061] 1. Experimental method

[0062] Cells with a live cell ratio of more than 90% were used for experiments. Cell Proliferation Inhibition Assay Using EnoGeneCell TM Counting Kit-8 (CCK-8) Cell Viability Detection Kit. Cells were digested, counted, and made into a cell suspension with a concentration of 1×105 / mL, and 100 μL of cell suspension was added to each well of a 96-well plate (1×104 cells per well); the 96-well plate was placed at 37°C for 5 %CO 2 Cultivate in an incubator for 24 hours; add 100 μL of corresponding drug-containing medium to each well, and set up a negative control group, a vehicle control group, and a positive control group at the same time, with 5 replicate wells in each group; place the 96-well plate at 37°C, 5% CO 2 After culturing in the incubator for 72 hours; add 10 μL of CCK-8 solution to each well, incubate the culture plate in the incubator for 4 hours, measure the OD value at 450 nm w...

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Abstract

The invention discloses a 3-(3,4,5-trimethoxybenzoyl)-benzofuran microtubulin inhibitor as well as a preparation method and use thereof. A 3-(3,4,5-trimethoxybenzoyl)-benzofuran compound in the invention has an action mechanism similar to colchicine and is capable of inhibiting polymerization of microtubulins. The 3-(3,4,5-trimethoxybenzoyl)-benzofuran compound has very strong proliferation inhibition activity to human lung cancer cells A549, human gastric cancer cells MGC-803, human liver cancer cells HepG2, human colon cancer cells HCT-116, human cervical cancer cells HeLa and human breast cancer cells MCF-7.

Description

technical field [0001] The invention relates to the technical field of medicinal chemistry, in particular to a 3-(3,4,5-trimethoxybenzoyl)-benzofuran-based tubulin inhibitor, a preparation method and application thereof. The present invention also relates to intermediate compounds for the preparation of the target compounds. Background technique [0002] Tubulin is a protein family with multiple members, including α, β, γ, δ, ε, ζ, and η seven tubulins. Among them, α-tubulin and β-tubulin are the main components of microtubules. Microtubules are the main cytoskeletal components of eukaryotic cells and play key roles in the maintenance of cell shape, protein transport, signal transduction and mitosis, making them an effective target for cancer therapy. Microtubule-targeted drugs that act on tubulin have become effective anti-tumor drugs that have been studied more in recent years. Known microscopic protein inhibitors interact with tubulin through at least four binding site...

Claims

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Application Information

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IPC IPC(8): C07D307/80C07C69/14C07C69/63A61P35/00
Inventor 程利平全阳平庞婉
Owner SHANGHAI ECUST BIOMEDICINE CO LTD
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