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Furan ring 2, 5-disubstituted-tetrahydroisoquinoline compound and preparation and application thereof

A tetrahydroisoquinoline and compound technology, which is applied in the fields of medicinal chemistry synthesis and pharmacotherapy, can solve the problems of affecting the pharmacokinetic properties of chemotherapeutic drugs, non-negligible toxicity of small molecules of inhibitors, increasing the toxic and side effects of drugs, and the like. Novel structure, good biological activity, and the effect of improving drug efficacy

Pending Publication Date: 2021-03-12
ZHEJIANG UNIV OF TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Among the first three generations of inhibitors, there are also drug molecules that have entered the clinical trial stage, but the main problems they face in clinical application are: 1. Poor selectivity of inhibitors to P-gp; 2. Insufficient inhibitory activity of inhibitors on P-gp; 3. The toxicity of small molecules of inhibitors cannot be ignored; 4. Inhibitors affect the pharmacokinetic properties of chemotherapy drugs, increasing the toxic and side effects of drugs, etc.
At present, there is no alternative strategy to deal with multidrug resistance in clinic, and it is urgent to develop new and efficient selective P-gp inhibitors for clinical use

Method used

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  • Furan ring 2, 5-disubstituted-tetrahydroisoquinoline compound and preparation and application thereof
  • Furan ring 2, 5-disubstituted-tetrahydroisoquinoline compound and preparation and application thereof
  • Furan ring 2, 5-disubstituted-tetrahydroisoquinoline compound and preparation and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0046] Example 1: 5-(2'-methoxyphenyl)-2-(2'-H-3,4-dihydro-6,7-methoxyisoquinoline)furan-2-carboxamide ( Ⅰ-2) Preparation

[0047]

[0048] (1) Add 5g (26.1mmol) of 5-bromo-2-furancarboxylic acid (II) and 10mL (156.2mmol) of dichloromethane into a 100mL three-necked flask equipped with a thermometer, stir and dissolve to form a clear solution. 7.5 g (63.0 mmol) of thionyl chloride was added with stirring. Raise the temperature to 60°C, react for 8 hours, and concentrate to dryness under reduced pressure with a rotary evaporator to remove excess solvent and unreacted thionyl chloride, and the obtained crude product 5.31g (25.6mmol) is 5-bromo-2-furyl chloride (Ⅲ), yield: 98%. for the next reaction.

[0049] (2) In a 50mL three-necked flask equipped with a thermometer, add 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride (7.5mmol) and 10mL (156.2mmol) dichloro methane, stirred and cooled to 0°C, and 15mL of 4mol / L sodium hydroxide aqueous solution was added drop...

Embodiment 2

[0056] Cytotoxicity of 2,5-disubstituted-tetrahydroisoquinoline compounds containing furan ring shown in the formula I to MCF-7 / ADR

[0057] Cell line: MCF-7 / ADR (human breast cancer cell line resistant to doxorubicin, purchased from Nanjing Kaiji Biotechnology Development Co., Ltd.).

[0058] Sample test concentration: 5 μM, dissolved in RPMI 1640 medium containing 1% DMSO+10% fetal bovine serum and added.

[0059] Test method: MTT (tetramethyl azolium salt) method was used to test the cell proliferation activity of the compound.

[0060] MCF-7 / ADR cells were incubated with RPMI 1640 medium (purchased from Gbico) containing 10% calf serum at 37°C, 5% CO 2 cultured under saturated humidity conditions. Cells in the logarithmic growth phase were taken at 1×10 5 / mL density in 96-well culture plate, 100 μL per well at 37 ° C, 5% CO 2 Cultured under the condition of saturated humidity, divided into blank control group and test compound group. Different test compounds prepared...

Embodiment 3

[0063] Example 3. Research on the multidrug resistance reversal activity of 2,5-disubstituted-tetrahydroisoquinolines containing furan rings represented by formula I on MCF-7 / ADR cells.

[0064] Cell line: MCF-7 / ADR (human breast cancer cell line resistant to doxorubicin).

[0065] Sample test concentration: 5 μM, dissolved in RPMI 1640 medium containing 1% DMSO+10% fetal bovine serum and added.

[0066] Positive control drug: verapamil, dissolved in RPMI 1640 medium containing 1% DMSO + 10% fetal bovine serum by volume and then added.

[0067] Test method: The MTT (tetramethyl azolium salt) method was used to conduct the cell proliferation activity test of the compound and doxorubicin in combination.

[0068] MCF-7 / ADR cells were incubated with RPMI 1640 medium (purchased from Gbico) containing 10% calf serum at 37°C, 5% CO 2 cultured under saturated humidity conditions. Cells in the logarithmic growth phase were taken at 1×10 5 / mL density in 96-well culture plate, 100 μL ...

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Abstract

The invention discloses a furan ring 2, 5-disubstituted-tetrahydroisoquinoline compound, a preparation method thereof and application of the furan ring 2, 5-disubstituted-tetrahydroisoquinoline compound serving as a tumor multidrug resistance reversal agent. Pharmacological experiment results show that the compound provided by the invention has excellent tumor multidrug resistance reversal activity, and can be clinically used as a tumor multidrug resistance reversal agent and a tumor metastasis inhibitor.

Description

[0001] (1) Technical field [0002] The invention belongs to the field of medicinal chemical synthesis and pharmacotherapeutics, and particularly relates to a furan ring 2,5-disubstituted-tetrahydroisoquinoline compound and its preparation method and its use as a tumor multidrug resistance reversal agent and tumor metastasis inhibition drug application. [0003] (2) Background technology [0004] Malignant tumor multidrug resistance (multidrug resistance, MDR) is an important reason leading to clinical tumor chemotherapy failure (Curr Med Chem.2012,19,1946-2025.). The overexpression of P-glycoprotein (P-glycoprotein, P-gp) in the ATP-binding (ABC) transporter family is the most widely studied mechanism of tumor MDR generation (Eur JMed Chem. 2016, 118, 219-229.). As a common transmembrane protein, P-gp will be overexpressed on the cell membrane of tumor cells with the progress of chemotherapy, which is the biggest obstacle to the continuous effectiveness of chemotherapy. Due ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D405/06A61P35/00A61P35/04
CPCA61P35/00A61P35/04C07D405/06
Inventor 王鸿李亚胜魏斌叶欣艺鲍晓泽孙漩嵘
Owner ZHEJIANG UNIV OF TECH
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