Novel SIRT6 small molecule agonist and applications thereof

An agonist, small molecule technology, applied in organic chemistry, antitumor drugs, drug combinations, etc., can solve problems such as tissue and organ damage

Inactive Publication Date: 2019-08-16
上海宇道生物技术有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In addition to killing cancer cells, traditional chemotherapy and radiotherapy can also kill normal cells and cause damage to tissues and organs

Method used

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  • Novel SIRT6 small molecule agonist and applications thereof
  • Novel SIRT6 small molecule agonist and applications thereof
  • Novel SIRT6 small molecule agonist and applications thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0050] Example 1. Fluor-de-Lys (FDL) assay to detect SIRT6 deacetylation activity and agonist EC 50

[0051] We developed a fluorescence-based quantitative method to detect SIRT6 deacetylation activity and agonist EC50. Fluorescein 4-amino-7-methylcoumarin (AMC) was labeled on the C-terminus of the acetylated polypeptide acetyl-Arg-His-Lys-Lys (ε-acetyl). SIRT6 can deacetylate this polypeptide, and then it is further cleaved by trypsin to generate free AMC, and then the reaction is quantified by fluorescence. A 50 μL reaction system contained 2.5 mM NAD+, 75 μM RHKK-Ac-AMC, 5 μM SIRT6, compound or DMSO, and reaction buffer (50 mM Tris-HCl, pH 8, 137 mM NaCl, 2.7 mM KCl, 1 mM MgCl2). Compounds were dissolved and diluted using DMSO. After the above reaction components were reacted at 37° C. for 2 hours, 40 mM nicotinamide was added to terminate the deacetylation reaction, and 6 mg / mL trypsin was added to carry out color reaction at 25° C. for 30 minutes. Finally, the reactio...

example 1

[0091] Example 1 (SOL)

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Abstract

The present invention provides a novel SIRT6 small molecule agonist and applications thereof, wherein the agonist is a tricyclic bisulfamide derivative represented by a formula (1) or a formula (2) ora pharmacologically acceptable salt thereof, in the formula (1), R1 and R2 are the same or different, and represent methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl, isopentyl(2-methylbutane) and hexyl, in the formula (2), R3 represents a nitrogen-containing tertiary amine aliphatic ring and a derivative thereof containing a substituent, and the nitrogen-containing tertiaryamine aliphatic ring comprises azacyclopropane, azacyclobutane, a pyrazole ring, a morpholine ring, a piperidine ring, a piperazine ring, azecycloheptane and azacyclooctane. According to the present invention, the efficient low-toxic SIRT6 small molecule agonist is designed and synthesized, can obviously activate the activity of SIRT6 in in-vitro experiments, is subjected to related research and activity evaluation on colon cancer cell lines in vivo, and has important significance in the development of drugs for diseases.

Description

technical field [0001] The present invention relates to the field of medicinal chemistry, in particular to a novel SIRT6 small molecule agonist and its application as a pharmaceutical compound to prevent or treat related diseases. Background technique [0002] In addition to encoding DNA genetic information, organisms also have many other genetic information, such as DNA methylation, histone modification, chromosomal reorganization, and non-coding RNA, which are called epigenetics. Epigenetic abnormalities can cause various diseases such as tumors, aging, immunity, and neurodegeneration. Since epigenetic drugs will not change the DNA sequence, the purposeful genetic state has less toxic side effects than traditional chemotherapy and radiotherapy. Altering epigenetic modifications through small molecule drugs is an attractive and promising research endeavor. Current drug research is mainly focused on DNA methylation, deacetylation in histone modification. At present, it ha...

Claims

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Application Information

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IPC IPC(8): C07D295/135C07D211/62C07D211/14C07D265/30C07C311/44C07D249/04C07D295/30C07D207/06C07D223/04C07D241/04C07D211/22C07D211/34C07D245/02C07D305/08C07D207/12C07D205/04A61P35/00
CPCC07C311/44C07D205/04C07D207/06C07D207/12C07D211/14C07D211/22C07D211/34C07D211/62C07D223/04C07D241/04C07D245/02C07D249/04C07D265/30C07D295/135C07D295/30C07D305/08
Inventor张健陈颖毅阮聪杨秀岩王承祥张秋芬商佳琳徐新愿
Owner上海宇道生物技术有限公司