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Smoothened receptor ligand and application thereof

A technology for smoothing receptors and ligands, which can be used in pharmaceutical formulations, medical preparations containing active ingredients, organic active ingredients, etc. It can solve problems such as not pointing out the role of substituent groups in improving the thermal stability of target proteins, and achieve enhanced interaction effect

Active Publication Date: 2017-06-13
SHANGHAI TECH UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the structure of smoothened receptor multi-domain integration has not been successful, which is also the basis for the design of small molecule drugs with high specificity to circumvent drug resistance
[0003] U.S. Patent US2010 / 324048 A1 did not introduce various functional groups including nitro groups into the compound, and did not point out the effect of the introduction of substituent groups on the thermal stability of the target protein

Method used

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  • Smoothened receptor ligand and application thereof
  • Smoothened receptor ligand and application thereof
  • Smoothened receptor ligand and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0026] Embodiment 1: Ligand and its synthesis

[0027] 1. Smoothened receptor ligands, the structural formulas of which are (I)-(XXIX).

[0028] 2. Except for ligands TC113, TC641, TC642, TC643, TC658 and TC659, other ligand synthesis methods are as follows:

[0029] Add 0.21g of 4-(N-Boc-methylamino)piperidine, 0.2g of 1,4-dichlorooxazine and 0.28g of potassium carbonate to 5mL of N-methylpyrrolidone (NMP), and heat to 80°C for 6h. Add 20mL saturated ammonium chloride solution after the reaction to quench, separate the organic phase, extract the water phase with dichloromethane three times, merge into the organic phase, wash with saturated ammonium chloride aqueous solution and saturated brine successively, and then wash with anhydrous sulfuric acid Dry over sodium, filter to remove sodium sulfate, and concentrate to obtain crude product. The crude product was separated by column chromatography (200-300 mesh silica gel, eluent: n-hexane:ethyl acetate=3:1) to obtain pure int...

Embodiment 2

[0100] Each ligand synthesized in Example 1 was subjected to thermostability test and cell activity test respectively:

[0101] 1. Thermal stability experiment:

[0102] SMO protein purification:

[0103] SMO protein was expressed in HEK293F cells (Life, Cat. No. K1663). Cells were cultured at 37°C until the cell density reached 1.0-1.3x10 6 cells / mL were collected, broken to obtain cell membranes, and suspended in 10 mM 4-(2-hydroxyethyl)piperazine-1-ethanesulfonic acid N-(2-hydroxyethyl)piperazine-N′-(2-ethane Sulfonic acid) (Sigma-Aldrich, product number H3375), 10mM magnesium chloride (Sigma-Aldrich, M4880), 20mM potassium chloride (Sigma-Aldrich, P9541) pH 7.5 buffer. Sodium chloride with a concentration of 1M was added to the above buffer solution to obtain a high-salt buffer solution, and sodium chloride with a concentration of 200mM was added to obtain a low-salt buffer solution. The cell membrane was washed with high-salt buffer (50 mL*3 times) and centrifuged, th...

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PUM

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Abstract

The invention provides a smoothened receptor ligand and application thereof. The smoothened receptor ligand is characterized in that the structural formula is as shown in thedescription, wherein Ar is a substituted or unsubstituted benzene ring or heteroaromatic ring; and m is equal to 0 or 1. A type of novel small-molecule ligands aiming at smoothened receptor (SMO) is developed in the invention. Nitro and similar functional groups are introduced to corresponding positions of the small molecules by combining with crystal structure data of the smoothened receptor, and the interaction between the ligand and the receptor is further enhanced. The small-molecule ligands can serve as tool molecules to be applied to function and structure research of the smoothened receptor and can also serve as pharmaceutical development candidates of smoothened receptor related diseases.

Description

technical field [0001] The present invention relates to smooth receptor ligands and applications thereof. Background technique [0002] Smoothened receptors belong to the F family of G protein-coupled receptors (GPCRs), and their dysfunction will lead to birth defects. In the 1950s in the western United States, it was found that many lambs were born with only one eye. Through the study of this kind of cyclopia, the first natural plant small molecule ligand cyclopamine (Cyclopamine) of the Smooth receptor was discovered. The functional regulation of smooth receptors is related to the occurrence and development of a series of cancers, so smooth receptors are important targets in drug development. In the past few decades, many lead compound ligands were discovered, and two small molecule drugs were launched to the market in 2015. However, drug resistance caused by smooth receptor mutants quickly emerged, and further modification of existing drugs is urgently needed. At the s...

Claims

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Application Information

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IPC IPC(8): C07D401/14C07D409/14C07F5/04A61K31/502A61K31/69A61P35/00
CPCC07D401/14C07D409/14C07F5/04
Inventor 陶厚朝瑞满德·史蒂文斯赵飞赵素文徐菲
Owner SHANGHAI TECH UNIV
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