2243-61-0

Basic information

• Product Name: 1,4-DIAMINONAPHTHALENE
• Synonyms: 1,4-NAPHTHALENEDIAMINE;1,4-DIAMINONAPHTHALENE;naphthalene-1,4-diamine;1,4-Naphthylenediamine;(4-amino-1-naphthyl)amine;(4-amino-1-naphthyl)amine(SALTDATA: 2HCl);(4-aMino-1-naphthyl)aMine dihydrochloride (SALTDATA: 2HCl);1,4-Diaminonaphthalene 97%
• CAS NO: 2243-61-0
• Molecular Formula: C₁₀H₁₀N₂
• Molecular Weight: 158.2
• EINECS: 218-816-2
• Mol File: 2243-61-0.mol

Chemical Properties

• Melting Point: 114-116 °C
• Boiling Point: 273.29°C (rough estimate)
• Flash Point: 211.5 °C
• Appearance: /
• Density: 1.1192 (rough estimate)
• Vapor Pressure: 1.17E-05mmHg at 25°C
• Refractive Index: 1.6441 (estimate)
• PKA: 5.72±0.10(Predicted)
• CAS DataBase Reference: 1,4-DIAMINONAPHTHALENE(CAS DataBase Reference)
• NIST Chemistry Reference: 1,4-DIAMINONAPHTHALENE(2243-61-0)
• EPA Substance Registry System: 1,4-DIAMINONAPHTHALENE(2243-61-0)

Safety Data

• Hazard Codes: Xn
• Statements: 22
• WGK Germany: 3
• RTECS: QJ3380000
• Hazardous Substances Data: 2243-61-0(Hazardous Substances Data)

Usage

General Description

Dark green to black crystalline solid.

Air & Water Reactions

1,4-DIAMINONAPHTHALENE may be sensitive to prolonged exposure to air. Insoluble in water.

Reactivity Profile

1,4-DIAMINONAPHTHALENE neutralizes acids in exothermic reactions to form salts plus water. May be incompatible with isocyanates, halogenated organics, peroxides, phenols (acidic), epoxides, anhydrides, and acid halides. Flammable gaseous hydrogen may be generated in combination with strong reducing agents, such as hydrides.

Fire Hazard

Flash point data for 1,4-DIAMINONAPHTHALENE are not available; however, 1,4-DIAMINONAPHTHALENE is probably combustible.

InChI:InChI=1/C10H10N2/c11-9-5-6-10(12)8-4-2-1-3-7(8)9/h1-6H,11-12H2

Upstream product

• 75358-95-1 pyridine-2-carboxylic acid naphthalen-1-ylamide 
• 86-57-7 1-Nitronaphthalene 
• 152873-78-4 naphthalene-1,4-diyl bis(trifluoromethanesulfonate) 
• 83-53-4 1,4-dibromonaphthalene 
• 83833-14-1 α-naphthyl red hydrochloride 
• 64-19-7 acetic acid 
• 7647-01-0 hydrogenchloride 
• 74217-45-1 4-(4-Amino-[1]naphthylazo)-phenol 
• 23939-67-5 [1,4]naphthoquinone-bis-chlorimin 
• 88246-92-8 5,8-diaminonaphthalene-1-sulfonic acid 
• 7782-99-2 sulphurous acid 
• 6357-89-7 1,4-diamino-naphthalene-2-sulfonic acid 
• 10034-85-2 hydrogen iodide 
• 3713-23-3 4-(4-amino-naphthalen-1-ylazo)-benzenesulfonic acid 

Downstream Products

• 130-15-4 [1,4]naphthoquinone 
• 1567836-16-1 diethyl 2,2′-(naphthalene-1,4-diylbis(((4-methoxyphenyl)sulfonyl)azanediyl))diacetate 
• 1567836-15-0 2,2′-(naphthalene-1,4-diylbis(((4-methoxyphenyl)sulfonyl)azanediyl))diacetic acid 
• 40484-55-7 N,N'-naphthalene-1,4-diyl-bis-benzamide 
• 46494-42-2 1,4-Naphthylendiisocyanat 

Relevant articles and documents

Unravelling the mechanism of cobalt-catalysed remote C-H nitration of 8-aminoquinolinamides and expansion of substrate scope towards 1-naphthylpicolinamide

Previously, an unexpected Co-catalysed remote C-H nitration of 8-aminoquinolinamide compounds was developed. This report provided a novel reactivity for Co which was assumed to proceed through the mechanistic pathway already known for analogous Cu-catalysed remote couplings of the same substrates. In order to shed light into this intriguing, and previously unobserved reactivity for Co, a thorough computational study has now been performed, which has allowed for a full understanding of the operative mechanism. This study demonstrates that the Co-catalysed remote coupling does not occur through the previously proposed Single Electron Transfer (SET) mechanism, but actually operates through a high-spin induced remote radical coupling mechanism, through a key intermediate with significant proportion of spin density at the 5- and 7-positions of the aminoquinoline ring. Additionally, new experimental data provides expansion of the synthetic utility of the original nitration procedure towards 1-naphthylpicolinamide which unexpectedly appears to operate via a subtly different mechanism despite having a similar chelate environment.

Polar Recognition Group Study of Keap1-Nrf2 Protein-Protein Interaction Inhibitors

Directly disrupting the Keap1-Nrf2 protein-protein interaction (PPI) has emerged as an attractive way to activate Nrf2, and Keap1-Nrf2 PPI inhibitors have been proposed as potential agents to relieve inflammatory and oxidative stress diseases. In this work, we investigated the diacetic moiety around the potent Keap1-Nrf2 PPI inhibitor DDO1018 (2), which was reported by our group previously. Exploration of bioisosteric replacements afforded the ditetrazole analog 7, which maintains the potent PPI inhibition activity (IC50 = 15.8 nM) in an in vitro fluorescence polarization assay. Physicochemical property determination demonstrated that ditetrazole replacement can improve the drug-like property, including elevation of pKa, log D, and transcellular permeability. Additionally, 7 is more efficacious than 2 on inducing the expression of Nrf2-dependent gene products in cells. This study provides an alternative way to replace the diacetic moiety and occupy the polar subpockets in Keap1, which can benefit the subsequent development of Keap1-Nrf2 PPI inhibitor.

Design, Synthesis, and Initial Evaluation of Affinity-Based Small-Molecule Probes for Fluorescent Visualization and Specific Detection of Keap1

Keap1 is a pluripotent protein which plays a predominant role in cellular homeostasis and stress responses. Given that the cellular environment is quite dynamic and versatile, further investigation of the function of Keap1 depends on tools for specific and real-time detection of Keap1. Herein, we report the development of functional affinity-based small-molecule probes which can overcome some shortcomings of current methods and be applied in further studying the function of Keap1.

Synthesis of Keap1-phosphorylated p62 and Keap1-Nrf2 protein-protein interaction inhibitors and their inhibitory activity

The Keap1-Nrf2 system is involved not only in biological defense but also in malignancy progression and chemoresistance. The ubiquitin-binding protein p62/Sqstm1 (p62), which is highly expressed in several cancers, competes with Nrf2 for Keap1 binding, leading to activation of Nrf2-mediated gene expression and survival of cancer cells. We had previously identified an inhibitor for the Keap1-phosphorylated-p62 (p-p62) protein-protein interaction (PPI), the acetonyl naphthalene derivative K67. In this study, we established facile synthetic routes for K67 and derivatives with various side chains on the C-2 position of naphthalene ring. K67 possessed high selectivity in the inhibition of Keap1-p-p62. Other derivatives showed potent Keap1-Nrf2 and Keap1-p-p62 PPI inhibitory activities, though the selectivity between the two activities was lower than K67.

Deconstructing Noncovalent Kelch-like ECH-Associated Protein 1 (Keap1) Inhibitors into Fragments to Reconstruct New Potent Compounds

Targeting the protein-protein interaction (PPI) between nuclear factor erythroid 2-related factor 2 (Nrf2) and Kelch-like ECH-associated protein 1 (Keap1) is a potential therapeutic strategy to control diseases involving oxidative stress. Here, six classes of known small-molecule Keap1-Nrf2 PPI inhibitors were dissected into 77 fragments in a fragment-based deconstruction reconstruction (FBDR) study and tested in four orthogonal assays. This gave 17 fragment hits of which six were shown by X-ray crystallography to bind in the Keap1 Kelch binding pocket. Two hits were merged into compound 8 with a 220-380-fold stronger affinity (Ki = 16 μM) relative to the parent fragments. Systematic optimization resulted in several novel analogues with Ki values of 0.04-0.5 μM, binding modes determined by X-ray crystallography, and enhanced microsomal stability. This demonstrates how FBDR can be used to find new fragment hits, elucidate important ligand-protein interactions, and identify new potent inhibitors of the Keap1-Nrf2 PPI.

Optimization of 1,4-bis(arylsulfonamido)naphthalene-N,N'-diacetic acids as inhibitors of Keap1-Nrf2 protein-protein interaction to suppress neuroinflammation

The protein–protein interaction (PPI) between kelch-like ECH-associated protein 1 (Keap1) and nuclear factor erythroid 2-related factor 2 (Nrf2) is recognized as a promising target for the prevention and treatment of oxidative stress-related inflammatory diseases. Herein, a series of novel 1,4-bis(arylsulfonamido)naphthalene-N,N'-diacetic acid analogs (7p-t and 8c) were designed to further explore the structure–activity relationships of the series. Their activities were measured first with a fluorescence polarization (FP) assay and more potent compounds were further evaluated using a more sensitive time-resolved fluorescence energy transfer (TR-FRET) assay, demonstrating IC50 values between 7.2 and 31.3 nM. In cytotoxicity studies, the naphthalene derivatives did not show noticeable toxicity to human HepG2-C8 and mouse brain BV-2 microglia cells. Among them, compound 7q bearing oxygen-containing fused rings was shown to significantly stimulate the cellular Nrf2 signaling pathway, including activation of antioxidant response element (ARE)-controlled expression of Nrf2 target genes and proteins. More importantly, 7q suppressed up-regulation of several pro-inflammatory cytokines in lipopolysaccharide (LPS)-challenged BV-2 microglial cells, representing a potential therapeutic application for controlling neuroinflammatory disorders.

Keap1-Nrf2 PPI inhibitor prodrug and preparation method and application

The invention discloses a Keap1-Nrf2 PPI inhibitor prodrug and a preparation method and application. According to the prodrug P-168 provided by the invention, a polar carboxylic acid group of an active compound 168 is blocked, so that the fat solubility is improved, and the membrane permeability and druggability are effectively improved; the prodrug P-168 is reduced under the condition of high ROS, a pharmacophore 168 and a fluorophore coumarin are released, expression of Nrf2 and downstream genes of Nrf2 is activated, anti-inflammatory activity is brought into play, and meanwhile fluorescenceis released to achieve visual monitoring.

SMALL MOLECULE DIRECT INHIBITORS OF KEAP1-NRF2 PROTEIN-PROTEIN INTERACTION

This patent document diclsoes novel compounds and methods of preventing or treating diseases or conditions related to Keapl-Nrf2 interaction activity by use of the novel compounds. As direct inhibitors of Keapl-Nrf2 interaction, the compounds disclosed herein are more specific and free of various undesirable effects than existing indirect inhibitors, and are potential dmg candidates of chemopreventive and therapeutic agents for treatment of various diseases or conditions involving oxidative stress and/or inflammation, including but not limited to cancers, diabetes, Alzheimer's, Parkinson's, and inflammatory bowel disease including ulcerative colitis.

Inhibitors of the protein–protein interaction between phosphorylated p62 and Keap1 attenuate chemoresistance in a human hepatocellular carcinoma cell line

Resistance to anticancer agents has been an obstacle to developing therapeutics and reducing medical costs. Whereas sorafenib is used for the treatment of human hepatocellular carcinoma (HCC), resistance limits its efficacy. p62, a multifunctional protein, is overexpressed in several HCC cell lines, such as Huh-1 cells. Phosphorylated p62 (p-p62) inhibits the protein–protein interaction (PPI) between Keap1 and Nrf2, resulting in the Nrf2 overactivation that causes drug resistance. We have found a unique Nrf2 inactivator, named K67, that inhibited the PPI between Keap1 and p-p62 and attenuated sorafenib resistance in Huh-1 cells. Herein, we designed and synthesised novel K67 derivatives by modification of the substituent at the 4-position of the two benzenesulfonyl groups of K67. Although these new derivatives inhibited the Keap1-p-p62 PPI to a level comparable to or weaker than that of K67, the isopropoxy derivative enhanced the sensitivity of Huh-1 cells to sorafenib to a greater extent than K67 without any influence on the viability of Huh-7 cells, which is a non-resistant HCC cell line. The isopropoxy derivative also increased the sensitivity of Huh-1 cells to regorafenib, which suggests that this derivative has the potential to be used as an agent to overcome chemoresistance based on Nrf2 inactivation.

Hydrogen peroxide-responsive Keap1-Nrf2 PPI inhibitor prodrug and preparation method and medical application thereof

The invention discloses a hydrogen peroxide-responsive Keap1-Nrf2 PPI inhibitor prodrug, and a preparation method and medical application thereof. The hydrogen peroxide-responsive Keap1-Nrf2 PPI inhibitor prodrug pro2 has a chemical structure as shown in the specification. According to the invention, a thiazolidinone part responsive to H2O2 is used for modifying a key carboxyl pharmacophore in a Keap1-Nrf2 inhibitor, and thus, the novel ROS responsive antioxidant prodrug pro2 is synthesized. The H2O2 activated prodrug pro2 can simultaneously realize the effects of targeted activation of Nrf2 and enhancement of in-vivo treatment efficacy, is based on the concept therapy of ROS activation-ROS removal, is also a first H2O2 responsive prodrug example suitable for oral administration, has the characteristics of druggability and high targeting, and is thus expected to be used clinically.