51411-04-2

Hazards Identification

Pictogram(s):

Signal:

Warning

GHS Hazard Statements:

H302 (100%): Harmful if swallowed [Warning Acute toxicity, oral]
H315 (100%): Causes skin irritation [Warning Skin corrosion/irritation]
H319 (100%): Causes serious eye irritation [Warning Serious eye damage/eye irritation]
H335 (100%): May cause respiratory irritation [Warning Specific target organ toxicity, single exposure; Respiratory tract irritation]

Precautionary Statement Codes:

P261, P264, P264+P265, P270, P271, P280, P301+P317, P302+P352, P304+P340, P305+P351+P338, P319, P321, P330, P332+P317, P337+P317, P362+P364, P403+P233, P405, and P501

Hazard Classes and Categories:

Acute Tox. 4 (100%)
Skin Irrit. 2 (100%)
Eye Irrit. 2A (100%)
STOT SE 3 (100%)

Usage

Uses

Used in Pharmaceutical Industry:
Alrestatin is used as an enzyme inhibitor for targeting aldose reductase, which plays a significant role in the development of diabetic complications, such as cataracts, neuropathy, and retinopathy. By inhibiting aldose reductase, Alrestatin can potentially reduce the severity of these complications and improve the quality of life for patients with diabetes.
Used in Research Applications:
In the field of scientific research, Alrestatin is utilized as a research tool to study the role of aldose reductase in various pathological conditions. It helps researchers understand the enzyme's function and its contribution to the development of diseases, which can lead to the discovery of new therapeutic strategies and treatments.
Used in Drug Development:
Alrestatin serves as a lead compound in the development of new drugs aimed at treating conditions related to aldose reductase overactivity. Its inhibitory properties make it a valuable starting point for designing and synthesizing novel compounds with improved efficacy and selectivity.

Originator

Alrestatin,BIOMOL

Manufacturing Process

1,3-Dioxo-1H-benz[de]isoquinoline-2(3H)-acetic acid: 1,8-Naphthalic acid anhydride (110 g, 0.556 mole), glycine (48 g, 0.64 mole) and dimethylformamide (750 ml) are heated and stirred at reflux for 2 hr. The homogeneous dark solution is cooled to about 100°C and 750 ml of hot water is added slowly to the stirred solution. The reaction mixture is cooled and allowed to stand in a refrigerator for 16 hr. The precipitate is collected and recrystallized from ethanol, using decolorizing charcoal, to give the title compound, MP: 271°-272°C. In practice it is usually used as sodium salt.

Biological Activity

Specific inhibitor of aldose reductase (IC 50 = 148 μ M). Attenuates glucose-induced angiotensin II production in rat vascular smooth muscle in vitro .

Enzyme inhibitor

This aldose reductase inhibitor and drug (FWfree-acid = 255.23 g/mol; CAS 51411-04-2), also known as 1,3-dioxo-1H-benz[de]isoquinoline-2(3H)- acetic acid) suppresses diabetes-associated, osmotic cell and tissue damage by inhibiting aldose reduction and thereby reducing the accumulation intracellular sorbitol. Primary Mode of Action of Aldose Reductase Inhibitors: A major cause of diabetic neuropathy is the intraneural osmotic pressure that builds up as a consequence of the over-accumulation of sorbitol, a polyol formed by aldose reductase (Reaction: Glucose + NADPH ? Sorbitol + NADP+ + H+). Similar considerations apply to cataract formation in the lens, another tissue rich in aldose reductase. In diabetes, aldose reductase activity increases as the concentration of glucose rises in the lens, peripheral nerves and glomerulus (tissues that are insulininsensitive); because sorbitol lacks a membrane carrier, its contributes to intracellular osmotic pressure, disrupting cell-cell interactions (especially synapses), eventually leading to retinopathy and neuropathy. The additive effects of aldose reductase (AR) and polyol dehydrogenase in producing sorbitol from glucose and fructose, acting in combination with agedependent decreased hexokinase is believed to account for diabetic cataract formation in human lenses under high glucose stress. AR’s Km for glucose of AR is roughly 200 mM, whereas its Km for NADPH is 0.06 mM. NADP inhibits human lens AR noncompetitively and has a K1 that is roughly equal to the Km for NADPH. Notably. The Km for fructose is 40 mM and that for NADH is 0.02 mM in the polyol dehydrogenase (PD) reaction. Therefore, although sorbitol formation is modest during normoglycemia, such is not the case for diabetic hyperglycemia. Moreover, the recent increased reliance on high-fructose corn syrup as a sweetener is problematic, in that glucose-sensing mechanisms in humans are largely unresponsive to fructose. Because sorbitol is not transported out of the lens, any increase in intracellular sortbitol must be compensated osmotically by the considerable uptake of water, a well-characterized cataractogenic event. By inhibiting sorbitol dehydrogenase, alrestatin lowers tha undesirable net accumulatrion of sorbitol during hyperglycemic episodes. At high enough concentrations, alrestatin also inhibits PD. Target(s): aldose reductase, or aldehyde reductase; 4-aminobutyrate aminotransferase; carbonyl reductase; succinate-semialdehyde dehydrogenase; polyol dehydrogenase, weakly inhibited, except at elevated concentrations; hexonate dehydrogenase, or glucuronate reductase.

InChI:InChI=1/C14H9NO4/c16-11(17)7-15-13(18)9-5-1-3-8-4-2-6-10(12(8)9)14(15)19/h1-6H,7H2,(H,16,17)

Upstream product

• 81-84-5 1,8-Naphthalic anhydride 
• 56-40-6 glycine 
• 78052-77-4 N-(carboethoxymethyl)-1,8-naphthalimide 
• 64-19-7 acetic acid 
• 135980-44-8 methyl (1,3-dioxo-1H,3H-benzo[de]isoquinolin-2-yl)acetate 
• 81-83-4 1,8-Naphthalimide 
• 5680-79-5 glycine ethyl ester hydrochloride 
• 476359-53-2 (1,3-dioxo-1H,3H-benzo[de]isoquinolin-2-yl)-acetic acid tert-butyl ester 
• 353262-66-5 N-(cyanomethyl)-1,8-naphthalimide 

Downstream Products

• 205536-87-4 2-Chloro-N-{4-[2-(1,3-dioxo-1H,3H-benzo[de]isoquinolin-2-yl)-acetylsulfamoyl]-phenyl}-acetamide 
• 150705-10-5 ethyl 4-(1,3-dioxo-2,3-dihydro-1H-benzo[d,e]isoquinolin-2-yl)butanoate 

Relevant academic research and scientific papers

Luminescent lanthanide-binding peptides: Sensitising the excited states of Eu(iii) and Tb(iii) with a 1,8-naphthalimide-based antenna

The investigation into the luminescence properties of a lanthanide-binding peptide, derived from the Ca-binding loop of the parvalbumin, and modified by incorporating a 1,8-naphthalimide (Naph) chromophore at the N-terminus is described. Here, the Naph is used as a sensitising antenna, which can be excited at lower energy than classical aromatic amino acids, such as tryptophan (the dodecapeptide of which was also synthesised and studied herein). The syntheses of the Naph antenna, its solid phase incorporation into the dodecapeptide, and the NMR investigation into the formation of the corresponding lanthanide complexes in solution is presented. We also show that this Naph antenna can be successfully employed to sensitize the excited states of both europium and terbium ions, the results of which was used to determined the stability constants of their formation complexes, and we demonstrated that our peptide 'loop' can selectively bind these lanthanide ions over Ca(ii).

DNA-Intercalative Platinum Anticancer Complexes Photoactivated by Visible Light

Photoactivatable agents offer the prospect of highly selective cancer therapy with low side effects and novel mechanisms of action that can combat current drug resistance. 1,8-Naphthalimides with their extended π system can behave as light-harvesting groups, fluorescent probes and DNA intercalators. We conjugated N-(carboxymethyl)-1,8-naphthalimide (gly-R-Nap) with an R substituent on the naphthyl group to photoactive diazido PtIV complexes to form t,t,t-[Pt(py)2(N3)2(OH)(gly-R-Nap)], R=H (1), 3-NO2 (2) or 4-NMe2 (3). They show enhanced photo-oxidation, cellular accumulation and promising photo-cytotoxicity in human A2780 ovarian, A549 lung and PC3 prostate cancer cells with visible light activation, and low dark cytotoxicity. Complexes 1 and 2 exhibit pre-intercalation into DNA, resulting in enhanced photo-induced DNA crosslinking. Complex 3 has a red-shifted absorption band at 450 nm, allowing photoactivation and photo-cytotoxicity with green light.

Exciton coupling in molecular salts of 2-(1,8-naphthalimido)ethanoic acid and cyclic amines: Modulation of the solid-state luminescence

In this study we have purposely altered the solid state luminescence properties of 2-(1,8-naphthalimido)ethanoic acid (NEaH) (0) via molecular salts formation with cyclic amines such as 1,4-diazabicyclo[2.2.2]octane (DABCO), quinuclidine (ABCO), 3-quinuclidinol (OH-ABCO), and piperazine (PIP). All crystalline materials have been characterized in the solid state via single-crystal and variable temperature powder X-ray diffraction and thermal methods; luminescence spectra in the solid state have been recorded. Exciton interactions have been determined with quantum-chemical calculations for all molecular organic salts, and tuning of their magnitude in response to changes in the crystal packing has been demonstrated. It is suggested that the variations in photoluminescence can be interpreted on the basis of the different excitonic interactions amongst the naphthalimide moieties.

Synthesis and antimicrobial/antimalarial activities of novel naphthalimido trans-β-lactam derivatives

This paper describes for the first time the synthesis and microbiological assessment of some new β-lactam derivatives containing a 1,8-naphthalimide functional group. These compounds were obtained through a [2 + 2] cyclocondensation (Staudinger reaction)

Variedly connected 1,8-naphthalimide-7-chloroquinoline conjugates: Synthesis, anti-mycobacterial and cytotoxic evaluation

Recent disclosures about anti-bacterial and anti-tubercular potential of naphthalimide and quinoline core respectively propelled us to synthesize a library of 1,8-naphthalimide-7-chloroquinoline hybrids. Different modes of linkage between two pharmacophoric units viz. simple alkyl chains and induction of amide bond were used and the substituents on the naphthalimide core were varied in order to determine Structure-Activity-Relationship (SAR). Our findings demonstrated that simple alkyl chain linked conjugates showed better activity profiles without any cytotoxicity, while the inclusion of amide bond enhanced the cytotoxic tendency. An interesting behaviour of conjugates in terms of activity and cytotoxicity was observed via switching over the nature of linker between two pharmacophores.

N-substituted glycine derivative as well as preparation method and application thereof

The invention discloses an N-substituted glycine derivative as well as a preparation method and application thereof, and belongs to the field of agricultural plant growth regulators. The structure of the N-substituted glycine derivative is shown as a general formula I, wherein R is one group selected from the following. The derivative can be used as a plant growth regulator.

Closing the Loop: Triazolylpyridine Coordination Drives the Self-Assembly of Metallomacrocycles with Tunable Topologies for Small-Molecule and Guanine-Quadruplex Recognition

The 2-(1,2,3-triazol-4-yl)pyridine motif, with its facile “click” synthesis and remarkable coordinative properties, is an attractive chelate for applications in the metal-directed self-assembly of intricate three-dimensional structures. Organic ligands th

WATER-SOLUBLE PEPTIDE FLUORESCENCE MATERIAL

A water-soluble peptide fluorescence material having a structure of formula (I): In formula (I), n is an integer greater than or equal to 1, R1 is independently selected from hydrogen or a nitrogen-containing functional group, R2 is independently selected from hydrogen or alkyl, and A1 is polymerized by at least one amino acid monomer and having a structure of formula (II): In formula (II), m is an integer greater than or equal to 1, and R3 in each, of the amino acid monomers of A1 is independently selected from hydrogen, alkyl, aralkyl, alkylthioaalkyl, hydroxyaralky, heteroaralkyl, carboxylalkyl, or guanidinylalkyl, A2 is —OR5 or —N(R4)2, and R4 is independently selected from hydrogen, alkyl, aralkyl, alkylthioaalkyl, hydroxyaralky, heteroaralkyl, carboxylalkyl, guanidinylalkyl, monoglycosyl, biglycosyl, or oligosaccharyl, and R5 is hydrogen, alkyl, aralkyl, alkylthioaalkyl, hydroxyaralky, heteroaralkyl, carboxylalkyl, or guanidinylalkyl.

A bis-naphthalimide functionalized pillar[5]arene-based supramolecular π-gel acts as a multi-stimuli-responsive material

In this work, a novel supramolecular π-gel has been constructed using a naphthalimide functionalized pillar[5]arene-based gelator (MP5). The gelator MP5 simultaneously contains a naphthalimide moiety as the π...π interaction site as well as a fluorophore. Interestingly, the MP5-based supramolecular π-gel (MP5-G) exhibits strong aggregation-induced emission (AIE). MP5-G exhibited good thermal-responsiveness, acid and base-responsiveness and cation and amino acid-responsiveness. Meanwhile, this supramolecular π-gel also shows selective fluorescence sensing for Fe3+via cation-π interactions with high selectivity and sensitivity, and the detection limit of MP5-G for Fe3+ is 6.06 × 10?8 M. Even more meaningfully, MP5-G could remove Fe3+ from water solution with excellent recyclability and ingestion capacity, and the Fe3+ removal rate can reach up to 99.8%. Furthermore, the Fe3+ coordinated supramolecular gel, MP5-FeG, shows selective fluorescence “turn-on” sensing for l-Cys. The detection limit of MP5-FeG for l-Cys is 1.0 × 10?8 M. Simultaneously, thin films based on these supramolecular gels were prepared, which were confirmed to be convenient test kits for detecting Fe3+ and l-Cys. In addition, these supramolecular π-gels could be used as sensitive ion sensors, sensitive logic gates and fluorescent display materials.

Imide bit or 4 - substituted 1, 8 - naphthalene imide derivatives as PARP inhibitors

The invention belongs to the field of medical chemistry, discloses use of imide site or 4-substituted 1, 8-naphthyl imide derivatives as PARP (poly adeno-sine diphosphate ribose polymerase) inhibitors, and in particular relates to the use of 1, 8-naphthyl imide derivative as shown in general formula (I), pharmacological or physiologically acceptable salts of the compound as shown in the general formula (I), and pharmaceutical compositions of the compound as shown in the general formula (I), as the PARP (poly adeno-sine diphosphate ribose polymerase) inhibitors. R1 and R2 have the meanings as defined.