Micromolecule selective depressant for STAT3 (Signal transducer and activator of transcription 3), as well as preparation method and applications thereof

A technology of molecular selectivity and inhibitors, applied in the direction of medical preparations containing active ingredients, pharmaceutical formulas, organic active ingredients, etc., can solve the problems of difficult medicinal use and poor bioavailability

Inactive Publication Date: 2011-10-19
NANJING UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, because phosphorylated polypeptides are easy to metabolize, have poor bioavailability, and are difficult to use i

Method used

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  • Micromolecule selective depressant for STAT3 (Signal transducer and activator of transcription 3), as well as preparation method and applications thereof
  • Micromolecule selective depressant for STAT3 (Signal transducer and activator of transcription 3), as well as preparation method and applications thereof
  • Micromolecule selective depressant for STAT3 (Signal transducer and activator of transcription 3), as well as preparation method and applications thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0057] Example 1 Virtual screening of small molecule selective inhibitors based on STAT3 protein structure.

[0058] The three-dimensional structure of STAT3β homodimer has been used in the screening of STAT3 small molecule selective inhibitors since it was determined in 1998. Its three-dimensional structure shows that STAT3β dimer occurs in the SH2 region of two STAT3 monomers. The two SH2 regions are connected together by their respective monomer fragments, and phosphoryl tyrosine Y705 is located in this region, which is an amino acid residue with important biological functions in STAT3β. Four adjacent amino acid residues are connected to The cavities on the SH2 domain of another monomer bind together.

[0059] In order to obtain organic small molecules that can inhibit or hinder the formation of STAT3β dimer, the protein crystal coded as 1BG1 was obtained from Protein Data Bank. The databases used in the virtual screening include Specs, Maybridge, these two databases inclu...

Embodiment 2

[0061] Example 2 Synthesis of N-bis(methylmercapto)methylene benzenesulfonamides.

[0062] 1 mmol R 1 Dissolve the base-substituted benzenesulfonamide in 2ml of DMF, add 80mg of NaOH, stir at room temperature to form a suspension, cool in an ice-water bath to 0°C, add 1mmol of carbon disulfide dropwise, complete the addition in about 3min, stir for 30min, and add 2mmol of dimethyl sulfate dropwise , about 30min after adding, react at room temperature for 2h, pour the reaction solution into a sufficient amount of water, precipitate a white solid, filter, wash with water, and dry to obtain the product N-bis(methylmercapto)methylene substituted benzenesulfonamide compound 2a~2l, Characterize the product. The reaction formula for this reaction is:

[0063] .

[0064] R 1 The base is different, the product is different, and the data of the characterization is also different. The detailed results Figure 7 .

Embodiment 3

[0065] Example 3 Synthesis of 2,2'-bis(benzenesulfonylamino)-6,6-bibenzoxazole.

[0066] The synthetic reaction formula of 2,2'-bis(benzenesulfonylamino)-6,6-bibenzoxazole is:

[0067] .

[0068] According to the above reaction formula, take 1mmol 3,3'-dihydroxybenzidinediamine and dissolve it in 8ml DMF, add 0.2ml of 5M sodium hydroxide solution, stir at room temperature for 30min, add dropwise 2mmol N-bis(methylmercapto)methylene The solution of benzenesulfonamide (2a) in 2ml of DMF was heated up to 150°C for 8h after the dropwise completion. After the reaction is complete, cool down to room temperature, add 2ml of acetic acid, pour into a sufficient amount of water, precipitate a solid, filter, wash with water, and dry to obtain the product 2,2'-bis(benzenesulfonylamino)-6,6-bibenzoxazole (DABB-1), yield 75%. Characterize the product, the result: 1 H NMR (300 MHz, DMSO): δ7.94 (m, 4H), 7.87 (s, 1H), 7.60 (m, 8H), 7.37 (d, J = 7.0 Hz, 2H); 13 C NMR (75 MHz, DMSO): δ...

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Abstract

The invention discloses a micromolecule selective depressant for STAT3 (Signal transducer and activator of transcription 3), as well as a preparation method and an applications thereof. The micromolecule selective depressant for the STAT3 comprises a structural formula I and a structural formula II; the preparation method comprises the steps of: taking alkaline as a catalyst in DMSO (Dimethyl sulfoxide) or DMF (Dimethylformamide) solvent, and carrying out cyclization on N-bis(methylthio) methylene-arylsulfonamide and 3.3'-dihydroxyl benzidine in the DMSO; and the applications are shown in aspects of preparing medicaments for treating cancers related to an abnormally activated STAT3 pathway and anti-tumor medicaments as an STAT3 signal pathway depressant. The STAT3 depressant is a micromolecule selective depressant, can be used for developing related cancer treating medicaments by determining action on cancer cells to evaluate the active result, thus having a wide range of application,as well as good curative effect of the medicaments. The varieties of the micromolecule selective depressants for the STAT3 are multiple, the preparation method is simple, the product purity is high, the yield is high and the practicability is strong.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry and relates to STAT3 inhibitors, in particular to a small molecule selective inhibitor of STAT3 and its preparation method and application. Background technique [0002] In recent years, due to the influence of various factors such as population aging, industrial development and environmental pollution, the incidence of cancer has also been increasing, and it has become the number one killer threatening human health and life, and its incidence is second only to cardiovascular diseases. And the cancer mortality rate is high. According to the report of the World Health Organization, 7.6 million people died of cancer in 2008 (accounting for about 13% of all deaths). And the number of cancer deaths worldwide is expected to continue to rise, surpassing 11 million by 2030. Traditional anticancer drugs have been unable to meet medical requirements. Although some new drugs have been launched in recent ...

Claims

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Application Information

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IPC IPC(8): C07D263/62C07D263/58A61K31/423A61P35/00A61P35/02
Inventor 李建新史志兵
Owner NANJING UNIV
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