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Naphthalene sulfonamide compound and preparation methods and applications thereof

A technology of naphthalene sulfonamide and compound, applied in the field of medicinal chemistry, can solve the problems of high molecular polarity, reduced molecular polar surface area, unfavorable membrane penetration, etc.

Active Publication Date: 2019-09-20
CHINA PHARM UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] As a small molecule inhibitor of Keap1-Nrf2 PPI, the compound DDO-1002 (chemical structure is as follows) obtained by our research group in the previous research is the most active compound, which has a high affinity for Keap1, but the presence of dicarboxylic groups leads to greater polarity of the molecule. Not conducive to membrane penetration, resulting in poor cell viability
The research group designed and synthesized a series of naphthalenesulfonamide Keap1-Nrf2PPI small molecule inhibitors with β amino acid structure by breaking its symmetric structure and removing the sulfonamide structure on one side to reduce the polar surface area of ​​the molecule. Among them, DDO- 1146 (chemical structure as follows) has better activity, but there is still a big gap between it and DDO-1002. At the same time, due to the existence of dicarboxylic groups, the molecular polarity is still relatively large

Method used

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  • Naphthalene sulfonamide compound and preparation methods and applications thereof
  • Naphthalene sulfonamide compound and preparation methods and applications thereof
  • Naphthalene sulfonamide compound and preparation methods and applications thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0047] Example 1: Synthesis and structure confirmation of compounds

[0048] 1. General rules of experiment

[0049] All the chemical reagents used in this paper were commercially pure or analytically pure. Melting points were determined using a M.P. 50 MeltingPoint System (thermometer uncalibrated). 1 H-NMR, 13 C-NMR nuclear magnetic resonance spectrum is measured by Bruker AV300 type (300MHz) nuclear magnetic resonance instrument (TMS is an internal standard substance, mass spectrum is measured by Agilent 1946A-MSD type mass spectrometer (ESI-MS), Water Q-Tof type mass spectrometer (HRMS) , the purity was determined by HPLC, the chromatographic column was an Agilent C18 (4.6×150 mm, 3.5 μM) type reversed-phase column, and the mobile phase was methanol:water:trifluoroacetic acid=85:15:0.1.

[0050] The concentration of the solvent used was the N-1100 rotary evaporator produced by EYELA Instrument Co., Ltd. (carrying out at 40 ° C), the silica gel used for column chromatogr...

Embodiment 2

[0453] Embodiment 2: the active test of compound

[0454] 1. Keap1-Nrf2PPI competitive inhibition test based on fluorescence polarization (FP experiment)

[0455] For the FP experiment, a 384-well black plate produced by Corning (model 3676) was used, and the total reaction volume was 40 μL. 20 μL of compound, 10 μL of 4 nM FITC-labeled Nrf2 9 peptide, and 10 μL of 12 nM Keap1 Kelch domain protein were added to the wells in the order. For positive control, use 20 μL 200 nM DDO-1002, 10 μL 4 nM FITC-labeled Nrf2 9 peptide, 10 μL 12 nM Keap1 Kelch domain protein, for negative control, use 20 μL HEPES buffer, 10 μL 4 nM FITC-labeled Nrf2 9 peptide, 10 μL 12 nM For the Keap1 Kelch domain protein blank control, 10 μL of 4 nM FITC-labeled Nrf2 9 peptide and 30 μL of HEPES buffer were used. After addition, incubate at room temperature for 30 min. The detection instrument is SpectraMax Multi-Mode Microplate Reader (Molecular Devices), the excitation light wavelength is 485nm, the e...

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Abstract

The invention discloses a naphthalene sulfonamide compound and preparation methods and applications thereof. The naphthalene sulfonamide compound provided by the invention can interfere with Keap1-Nrf2 binding and activate Nrf2 so as to alleviate inflammatory damage and improve inflammatory microenvironment, has potential anti-inflammatory activity, and can be used for preparing anti-inflammatory medicine for the inflammatory damage of many inflammation-related diseases. The diseases include chronic obstructive pulmonary disease (COPD), Alzheimer's disease, Parkinson's disease, atherosclerosis, chronic kidney disease (CKD), diabetes, intestinal inflammation, rheumatoid arthritis and the like.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and in particular relates to a naphthalenesulfonamide compound, a preparation method and an application. Background technique [0002] Oxygen (O 2 ) are essential for cellular energy metabolism and living systems, but reactive oxygen species (ROS) are generated during these metabolic processes, and ROS play a major role in the initiation and progression of cancer, inflammatory diseases, and neurodegenerative diseases. The antioxidant defense system consisting of detoxifying and antioxidant enzymes can attenuate the damaging effects of ROS, such as superoxide dismutase (SOD), glutathione catalase (GPx), thioredoxin, HO-1 , ferritin, glutathione reductase, NAD(P)H dehydrogenase (NQO1) and glutathione S-transferase (GST). Antioxidant enzymes are regulated by antioxidant response elements (AREs), and nuclear factor E2-related factor 2 (Nrf2) is one of the major ARE-binding transcription factors. ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C311/29C07C303/40C07D307/82A61P25/28A61P25/16A61P29/00A61P39/06A61P11/00A61P9/10A61P3/10A61P13/12A61P1/00A61P19/02
CPCC07C311/29C07D307/82A61P25/28A61P25/16A61P29/00A61P39/06A61P11/00A61P9/10A61P3/10A61P13/12A61P1/00A61P19/02C07C311/21C07C311/46C07D307/79Y02P20/55A61K31/63A61K31/343
Inventor 尤启冬姜正羽刘雨亭陆朦辰邵红丽赵静徐晓莉郭小可王磊
Owner CHINA PHARM UNIV
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