92599-05-8

Usage

Uses

1-Amino-4-methoxynaphthalen HCl

Upstream product

• 2216-69-5 1-Methoxynaphthalene 
• 4900-63-4 1-methoxy-4-nitronaphthalene 

Relevant academic research and scientific papers

The relevance of Ki calculation for bi-substrate enzymes illustrated by kinetic evaluation of a novel lysine (K) acetyltransferase 8 inhibitor

Histone acetyltransferases (HATs) are important mediators of epigenetic post-translational modifications of histones that play important roles in health and disease. A disturbance of these modifications can result in disease states, such as cancer or inflammatory diseases. Inhibitors of HATs (HATi) such as lysine (K) acetyltransferase 8 (KAT8), could be used to study the epigenetic processes in diseases related to these enzymes or to investigate HATs as therapeutic targets. However, the development of HATi is challenged by the difficulties in kinetic characterization of HAT enzymes and their inhibitors to enable calculation of a reproducible inhibitory potency. In this study, a fragment screening approach was used, enabling identification of 4-amino-1-naphthol, which potently inhibited KAT8. The inhibitor was investigated for enzyme inhibition using kinetic and calorimetric binding studies. This allowed for calculation of the Ki values for both the free enzyme as well as the acetylated intermediate. Importantly, it revealed a striking difference in binding affinity between the acetylated enzyme and the free enzyme, which could not be revealed by the IC50 value. This shows that kinetic characterization of inhibitors and calculation of Ki values is crucial for determining the binding constants of HAT inhibitors. We anticipate that more comprehensive characterization of enzyme inhibition, as described here, is needed to advance the field of HAT inhibitors.

Photochemical generation and lifetimes in water of p-aryloxy- and p-alkoxyphenylnitrenium ions

This paper describes product and flash photolysis studies following irradiation in aqueous solution of 4X-C6H4N3 [X = MeO (12a), EtO (12b), PriO (12c), ButO (12d), C6H5O (12e), 4-MeOC6H4O (12f), F, Cl] and 4-methoxy-l naphthyl azide (15). p-Benzoquinone (or 1,4-naphthoquinone) is observed as a product, in yields of 70-90% with 12a-d, 15, 40% with 12e, 26% with 4-F and 15% with 4-Cl. The quinone arises by a pathway whereby the initially-formed singlet arylnitrene is quenched by protonation by a solvent water molecule to form a nitrenium ion. Hydration of this cation at the para position leads through a hemiacetal (or halohydrin) to the quinone imine, whose hydrolysis results in the final quinone product. Three kinetic processes are observed, the nitrenium hydration on the us time scale, the hemiacetal breakdown on the ms time scale, and the imine hydrolysis on the minutes time scale. The nitrenium ions have lifetimes in aqueous solution of 50 ns (4-PhO), 70 ns (4-MeOC6H4O), 370 ns (4-MeO), 550 ns (4-EtO), 1.25 μs (4-PriO), 1.56 μs (4-ButO) and 1.35 μs (4-methoxynaphthyl). A nitrenium transient is not observed with the 4-halophenyl azides, probably because the lifetime is too short for detection with ns laser flash photolysis (LFP). The alkoxyphenylnitrenium ions are argued to be better represented as oxocarbocations derived from O-alkylation of the quinone imine. The 4-ethoxyphenylnitrenium ion is not quenched by 0.01 mol dm-3 2′-deoxyguanosine, so that k2(dG) is less than 2 × 107 mol -1 dm3 s-1. This contrasts with the 4-biphenylylnitrenium ion, which has a similar solvent reactivity, but reacts with k2(dG) = 2 × 109 mol-1 dm3 s-1. The localization of the positive charge in the alkoxy system is a possible explanation behind this difference.

SUBSTITUTED GUANIDINES AND DERIVATIVES THEREOF AS MODULATORS OF NEUROTRANSMITTER RELEASE AND NOVEL METHODOLOGY FOR IDENTIFYING NEUROTRANSMITTER RELEASE BLOCKERS

Modulators of neurotransmitter release including substituted guanidines, N"-aminoguanidines, and N,N'N",N"'-tetrasubstituted hydrazinedicarboximidamides, and pharmaceutical compositions thereof are disclosed. Also disclosed are methods involving the use of such neurotransmitter release modulators for the treatment or prevention of pathophysiologic conditions characterized by the release of excessive or inappropriate levels of neurotransmitters. Also disclosed are screening assays for compounds which selectively inhibit glutamate release. Also disclosed are methods of blocking voltage sensitive sodium and calcium channels in mammalian nerve cells. "