N-acetylanthranilic Acid Research Articles

Isolation and crystal structure of the first Pr(IV) coordination polymer and the complex anti-proliferative activity evaluation against seven cancer cell lines

This paper presents isolation procedures of single crystals of a polymeric quadrivalent praseodymium complex [(L)PrIV(L)4(OH0.94Cl0.06)2PrIV(L)] (HL = N-acetylanthranilic acid). This novel product, that astonishingly formed via in situ air oxidation of hydrated praseodymium (III) chloride is one of a few Pr(IV) complexes ever known and the first coordination polymer of Pr(IV), was mainly characterized based on X-ray single crystal diffraction studies and other data {elemental analysis, solution molar conductivity, TGA/DTA and spectroscopy (FT-IR, UV-Vis. and 1H and 13CNMR)}. The dimeric Pr(IV) complex crystallized in the monoclinic space group P21/n where each Pr(IV) center is eight-coordinate via two oxygen atoms from one terminal carboxylate moiety, four oxygen atoms from four bridging carboxylates, one hydroxyl group (OH) substituted by 6 % of chlorine and an anilide oxygen atom from L ligand anion that its carboxylate moiety binds another Pr(IV) ion resulting in the assembly of the complex as 1D coordination polymer. The anti-proliferative activity of the complex was evaluated using MTT assay against seven cancer cell lines and the results indicated more cytotoxic effect on A-375 (melanoma cells) and HepG-2 (liver cancer) with IC50 respectively of 723 and 982 µg/ml in comparison to the effects against the other cell lines (MDA-MB-231, T-24, MCF-7, A549 and PC-3). However, this complex generally showed lower anti-proliferative activities against the studied cell lines in comparison to classical anticancer agents.

Binuclear Cu(II) complex based on N-acetylanthranilic acid induces significant cytotoxic effect on three cancer cell lines

This paper presents the isolation of single crystals of an anionic Cu(II) complex (NH4)(NHEt3)[Cu2(L)4Cl2]{HL = N-acetylanthranilic acid and NEt3= triethylamine}. The analyses revealed the complex packing in the triclinic "P-1" space group in addition to its dimeric structure and the octahedral geometry around the Cu(II)ions. In the complex, all the four carboxylate ligands are bridging the two Cu(II) centers and the charge on the anionic complex is compensated by an ammonium and protonated triethylamine ions. This Cu(II) complex is interestingly exerting highly significant cytotoxic effect on MDA-MB-231 breast cancer cells with IC50of 131.2 µg/ml and moderate anti-proliferative activity against both PC-3 prostatic cancer and T-24 transitional cell carcinoma cells with IC50 of 200.7 and 300.3 µg/ml, respectively.

UPLC-Triple TOF-MS/MS based metabolomics approach to reveal the influence of nitrogen levels on Isatis indigotica seedling leaf

Isatis indigotica Fortune represents a significant economic resource in China, which the leaves (Daqingye) remain until now important and popular herbal drug in traditional Chinese medicine (TCM). Nitrogen nutrition is in great demand during plant growth stage, and nitrogen levels are usually related with plants biosynthesis of primary and secondary metabolites. To investigate the influence of nitrogen nutrition levels on various metabolites of Isatis leaf, untargeted metabolomics analysis based on LC–MS (UPLC-Triple-TOF system) was used to obtain the response of Isatis leaf under different nitrogen levels: 0 mmol·L−1(deficient), 7.5 mmol·L−1 (low) and 15 mmol·L−1 (high). Based on the results, dihydroxyindole, anthranilic acid, N-acetylanthranilic acid significantly discriminated the three treatments. Low nitrogen generally led to the decrease of most amino acids, while the increase of phenylalanine, indole-3-pyruvate acid, and some specialized metabolites including quercetin, indigo and indirubin were observed. The change in content of indole-3-acetic acid (IAA) was speculated to be the potential low nitrogen tolerance mechanism of I. indigotica. Our findings suggest that nitrogen levels significant affect metabolic capacity of Isatis leaf; low nitrogen treatments induce the accumulation of active ingredients. This result will provide leads into understanding the physiological adaption to nitrogen levels of Isatis leaf and quality improvement research of Daqingye.

Utility of anthranilic acid and diethylacetylenedicarboxylate for the synthesis of nitrogenous organo/organometallic compounds as urease inhibitors.

Fumarate diester 3 was synthesized upon reacting anthranilic acid with diethylacetylenedicarboxylate. Compound 3 was reacted with different nucleophiles in mild reaction conditions. Selected reaction routes that afforded products 6, 9, 10, 11, and 12 were explained. The estimated mechanism for the reaction of 3 with ethylenediamine to afford 9 was proved by X-ray single-crystal and retro-synthetic reaction. Acetyl anthranilic acid was utilized with zinc and copper to afford the organometallic compounds 14a and 14b, respectively. Three single crystals were afforded for 3, 9 and the organocopper complex 14b. Target compounds were screened for their inhibitory potential against urease enzyme. Most compounds were more potent than thiourea as standard inhibitor, considering that oxopiperazine 9 exhibited double the activity: IC50 = 8.16 ± 0.65 µM (thiourea IC50 = 20.04 ± 0.33 µM). Docking studies were in agreement with the in vitro enzyme assay.

LC–MS based urinary metabolomics study of the intervention effect of aloe-emodin on hyperlipidemia rats

Hyperlipidemia has been highlighted to be one of the most prominent and global chronic condition nowadays. Daming capsule (DMC), a traditional Chinese medicine (TCM) preparation, has treated hyperlipidemia on clinic in China for decades. Our recent study showed that aloe-emodin (AE) is one of the main bioactive components in DMC. Therefore, the present study aims to further investigate the lipid-lowering effect by serum biochemistry and histopathological examination, and reveal the underlying mechanisms by urinary metabolomics approach. After oral administration of AE for 6 weeks, the total cholesterol (TC) and low-density lipoprotein-cholesterol (LDL-c) levels in 50 and 100 mg/kg AE groups were both decreased significantly (P < 0.05 and P < 0.001). An ultra-performance liquid chromatography/electrospray ionization quadruple time-of-flight mass spectrometry (UPLC-ESI-QTOF-MS) followed by principal components analysis (PCA), partial least squares- discriminant analysis (PLS-DA), orthogonal partial least squares-discriminant analysis (OPLS-DA), correlation analysis, heat map, and KEGG pathways was employed to identify 26 potential biomarkers. Twenty three among them were restored by AE including L-citrulline, 6-methylaminopurine, imidazoleacetic acid riboside, N-acetylhistamine, 3-methyladenine, 1-methyladenosine, dopamine, N1-methyl-4-pyridone-3-carboxamide, formylanthranilic acid, 4-pyridoxate, cAMP, salsolinol, isethionate, d-ribonic acid, 3-sulfolactic acid, vitamin C, mesaconic acid, sulfosalicylic acid, salicyluric acid, N-acetylanthranilic acid, 4,6- Dihydroxyquinoline, sebacic acid and hyocholic Acid. The related metabolic pathways include TCA cycle, the metabolism of amino acids, taurine, B vitamins, purines and pyrimidines. The results indicate that AE has a favorable therapeutic effect on HFD-induced hyperlipidemia by adjusting the metabolic disorders. Notably, urinary metabolomics combined with pattern recognition analysis provides a powerful and reliable approach into the research and development of TCM and phytochemicals.

N-Acetylborrelidin B: a new bioactive metabolite from Streptomyces mutabilis sp. MII.

In the course of our screening program for new bioactive compounds, a naturally new 18-membered macrolide antibiotic, N-acetylborrelidin B (1) along with borrelidin (2) were obtained from the marine Streptomyces mutabilis sp. MII. The strain was isolated from a sediment sample collected in the Red Sea at the Hurghada Coast and characterized taxonomically. Additional nine diverse bioactive compounds were reported: 6-prenyl-indole-3-acetonitrile (3), sitosteryl-3β-d-glucoside, campesterol, ferulic acid, linoleic acid methyl ester, linoleic acid, N-acetylanthranilic acid, indole 3-acetic acid methyl ester, indole 3-carboxylic acid, and adenosine. Structure 1 was confirmed by in-depth NMR studies and by mass spectra, and comparison with related literature data. The antimicrobial activity of the strain extract and compounds 1 and 2 were studied using a panel of pathogenic microorganisms. The in vitro cytotoxicity of compounds 1 and 2 as well as the crude extract were tested against the human cervix carcinoma cell line (KB-3-1).

Structural diversity in phenyl bismuth(III) bis(carboxylate) complexes

In order to probe the effect of solvent and substituents on the formation of bismuth carboxylates, triphenylbismuth (BiPh3) was treated with salicylic acid, 5-bromosalicylic acid, 3-methoxysalicylic acid, 5-nitrosalicylic acid, 3-methylanthranilic acid, 5-chloroanthranilic acid, and N-acetylanthranilic acid in a 1:2 ratio in a variety of solvents. The following compounds were isolated and structurally characterized: [PhBi(5-Br-2-OH-C6H3CO2)2(Me2CO)], 1; [PhBi(5-Br-2-OH-C6H3CO2)2(EtOH)]·(EtOH) (H2O), 2; [PhBi(5-O2N-2-OH-C6H3CO2)2(4,4′-bipy)]·EtOH (4,4′-bipy = 4,4’-bipyridine), 3; [PhBi(5-Cl-2-NH2-C6H3CO2)2], 4; [Ph2Bi2(3-MeO-2-OH-C6H3CO2)4(EtOH)], 5; [Ph2Bi2(3-MeO-2-OH-C6H3CO2)4(i-PrOH)], 6; [PhBi(2-MeC(O)NH–C6H3CO2)2]·EtOH, 7; [PhBi(3-MeO-2-OH-C6H3CO2)2]∞·PhCH3, 8; [PhBi(3-Me-2-NH2-C6H3CO2)2(2,2′-bipy)]·0.42MeCN; (2,2′-bipy = 2,2′-bipyridine), 9; cis-[PhBi(5-Br-2-OH-C6H3CO2)2]2, 10; trans-[PhBi(5-Br-2-OH-C6H3CO2))2]2·2MeCN, 11; [PhBi(5-Br-2-OH-C6H3CO2))2]2·2MeOH, 12, trans- [PhBi(2-OH-C6H4CO2)2]2, 13. Compounds 1 and 2 are monomeric possessing a coordinated solvent molecule in an equatorial coordination site of a pentagonal pyramidal bismuth(III) center. The same coordination geometry is found in 3 where two such units are tethered together via the 4,4’-bipyridine ligand. Compounds 5 and 6 form dimers in which one Bi atom attains a pentagonal pyramidal geometry via coordination of the solvent and the other via binding to the phenol group of a 3-methoxysalicylate ligand attached to the other Bi atom. Compounds 7 and 8 are polymeric. In 7, a coordination polymer is created by the donation of the acetyl oxygen atom of the [PhBi(2-MeC(O)NHC6H3CO2)2] unit to an adjacent [PhBi(2-MeC(O)NHC6H3CO2)2] center, while in 8 a similar situation arises but through the phenolic and methoxy oxygen atoms of a 3-methoxysalicylate ligand, giving rise to the first observed hexagonal pyramidal coordination complex of a bismuth carboxylate. In 9, one of the carboxylate ligands is bidentate while the other remains monodentate, displaying the same structural geometry as previously reported for [PhBi(2-MeO-C6H4CO2)2(2,2′-bipy)]·0.5EtOH and [PhBi(4-Me-2-OH-C6H3CO2)2(2,2′-bipy)]. Compounds 10–13 are dimeric structures arising from shared carboxylate oxygen atoms that bridge the two bismuth atoms.

DFT Cancer Energy Barrier and Spectral Studies of Aspirin, Paracetamol and Some Analogues

Comparative DFT computations were studied between Paracetamol (PA) and its analogues such as p-nitroace- tanilide (PA-NO2), p-bromoacetanilide (PA-Br) and N-acetylanthranilic acid (NAA) which can be considered also as analogue of Aspirin (ASP). As well, Thio-Aspirin, Acetyl-Thio-Salicylic acid, (TASP) is another analogue of ASP. From DFT studies, it has been concluded that PA and its analogues have the predominant trans-conformers with respect to directions of the carbonyl group in the acetyl moiety and the amino-hydrogen atom but the predominant conformer of NAA molecule is the cis-form. Phenacetin (PH) molecule which has ethoxy group in the Para-position instead of the hydroxyl group in the Para-position in PA molecule is another analogue of PA. The electron transfer energy between the drugs and the nucleic acid bases can be illustrated as cancer energy barrier. The cancer energy barriers were calculated from the DFT parameters for all the studied molecules showing the carcinogenic effect. The metabolized product N-acetylimidoquinone, m-PA, is produced in the liver from PA and PH. m-PA has higher electron affinity more than those of the nucleic acid bases indicating to the strong electronic withdrawing power from the nucleus in the human being liver cell, hence m-PA is responsible for the carcinogenic behavior of the liver cell since it has low energy barrier with guanine, 0.3 eV. Therefore the electron transfer between m-PA and guanine takes place spontaneously in the liver. From CI calculations it has been concluded that the singlet transition energies for the trans and cis conformers of PA are the same. The comparative spectral studies have been scanned for some analogues in the visible and UV regions using solvents of different polarities. The complex between PA and Zn2+ was studied by DFT method.

2-(3-ETHYL-2,2-DIMETHYLCYCLOBUTYLMETHYL)-4(3H)-QUINAZOLINONES

Anthranilic acid and its 5-bromo and 4-chloro derivatives react with pinanoic and pinonoic acid chlorides to give the corresponding N-acyl derivatives. The pinanoyl derivatives give the corresponding 2-(3-ethyl-2,2-dimethyl-cyclobutylmethyl)-4-(3H)-quinazolinones when refluxed in formamide. Pinanoylanthranilic acid reacts with dicyclohexylcarbodiimide to give 2-(3-ethyl-2,2-dimethyl-cyclobutylmethyl)benz-3,1-oxazin-4(H)-one and subsequently with hydrazine hydrate to give 3-amino-2-(3-ethyl-2,2-dimethylcyclobutylmethyl)-4(3H)-quinazolinone. Refluxing of the pinanoyl- and pinonoylanthranilic acids with acetic anhydride gives acetylanthranilic acid, and pinonoylanthranilic acid gives 4(3H)-quinazolinone with formamide. Authors: F. M. Avotin'sh, M. V. Petrova, P. V. Pastors, and A. Ya. Strakov. English Translation in Chemistry of Heterocyclic Compounds , 1999, 35 (6), pp 722-728 http://link.springer.com/article/10.1007/BF02251633

2-(3-ACETYLAMINO-2,2-DIMETHYLCYCLOBUTYL)METHYL-4(3H)-QUINAZOLINONES

Beckmann rearrangement of N-[3-(1-hydroxyimino)ethyl-2,2-dimethylcyclobutyl]acetylanthranilic acid, and its 5-bromo and 4-chloro derivatives gives the corresponding N-(3-acetylamino-2,2-dimethylcyclobutyl)acetylanthranilic acids. Treatment of these acylanthranilic acids with formamide gives 2-(3-acetylamino-2,2-dimethylcyclobutyl)methyl-4(3H)-quinazoline and its 6-bromo and 7-chloro derivatives. Authors: F. M. Avotin'sh, M. V. Petrova, N. N. Tonkikh, and A. Strakov. English Translation in Chemistry of Heterocyclic Compounds , 2000, 36 (11), pp 1326-1328 http://link.springer.com/article/10.1023/A%3A1017579719809

CIDNP and EPR Study of Phototransformation of Lappaconitine Derivatives in Solution

Chemically induced dynamic nuclear polarization (CIDNP) and electron paramagnetic resonance (EPR) techniques have been used to study the paramagnetic species formed during the photolysis of the alkaloid lappaconitine and its synthetic analogues in solution. Lappaconitine is a photosensitive antiarrhythmic and hypertension drug, whose major photoproduct (N-acetyl anthranilic acid) is also a potent photosensitizer. Both these compounds are lipophilic and might bind efficiently to cell membranes thereby causing phototoxic damage. Photolysis of natural lappaconitine (I) as well as its N(20) des-ethyl derivatives (N-Bz (II), N-Me (III), N-H (IV), and N(O)-Et (V)) results in cleavage of the ester bond with the formation of N-acetyl anthranilic acid (VIII) and corresponding enamine. The lappaconitine derivative V shows maximum photostability which correlates with reference data about its low toxicity. It was shown that the primary reaction step is electron transfer from the amino group to the anthranilic fragment of lappaconitine resulting in an intermediate biradical. The final products are formed via fragmentation of the neutral lappaconitine radicals.

Anti-inflammatory Activity and PGE2 Inhibitory Properties of Novel Phenylcarbamoylmethyl Ester-Containing Compounds

A variety of 4-(un)substituted phenylcarbamoyl methyl ester-containing compounds 3a-d, 5a-d and 7a-d were synthesized via reaction in N,N-dimethylformamide of (un)substituted chloroacetanilides 2a-d with the potassium salts of ibuprofen (1), naproxen (4) and N-acetylanthranilic acid (6). Moreover, other 4-(un)substituted phenylcarbamoylmethyl ester-containing compounds 10a-d were synthesized via the attack of (un)substituted chloroacetanilides 2a-d on one of the carboxylic acid groups of the potassium salt of 4-(2-carboxyethylcarboxamido)benzoic acid (8) in N,N-dimethylformamide, with subsequent cyclization of the other one giving finally a pyrrolidinone structure. Anti-inflammatory properties of the synthesized compounds were evaluated in vivo utilizing a standard acute carrageenan-induced paw oedema method in rats and the most promising prepared anti-inflammatory active agents were evaluated for ulcerogenic liability in rats using ibuprofen and naproxen as reference standards in both screenings. PGE2 inhibitory properties of the highly promising anti-inflammatory agents synthesized and low gastric ulcerogenic liabilities were tested with a PGE2 assay kit technique.

Phototransformation products of the alkaloid lappaconitine: Multinuclear NMR study

The NMR technique has been applied to characterize the phototransformation products of the natural alkaloid lappaconitine. It was demonstrated that the photolysis of lappaconitine 1 results in cleavage of the ester bond with elimination of N-acetylanthranilic acid. The final reaction product was found to be an immonium salt 4 of N-acetylanthranilic acid and enamine 3. An equilibrium between the imine cation and the enamine 3 was detected.

Mechanisms of photoinduced electron transfer reactions of lappaconitine with aromatic amino acids. Time-resolved CIDNP study

CIDNP techniques were applied to the investigation of the elementary mechanism of photoinduced interaction between anti-arrhythmic drug lappaconitine and amino acids tyrosine and tryptophan. It has been shown that the reactions involve the formation of lappaconitine radical anion. Lappaconitine radical anion is unstable and rapidly eliminates N-acetyl anthranilic acid via protonation and ether bond cleavage. The rate constant of ether bond cleavage was estimated to be equal to 4 x 10(5) s(-1). The role of single electron transfer is discussed in the light of the model of drug-receptor interactions.

Triboluminescent Crystals from the Microwave Oven. In California, N-Acetylanthranilic Acid and Anthranilic Acid Are Controlled Substances—Have You Been Using Them Illegally?

California classifies N-acetylanthranilic acid as a controlled substance that also appears on the DEA List 1. According to the California Bureau of Narcotics Enforcement Precursor Program unauthorized and unregulated possession or storage of this compound is considered a felony.

Contribution of hydrogen bonding to protein stability estimated from isotope effects.

An unresolved issue in structural biology concerns the relative contribution of H bonds to protein stability. We use the small molecules 4-acetamidobenzoic acid and N-acetylanthranilic acid as model compounds to relate the energetic contribution from hydrogen bonds (H bonds) to the deuterium/hydrogen amide isotope effect. N-Acetylanthranilic acid models carbonyl-amide H bonds formed during protein folding; 4-acetamidobenzoic acid models the unfolded state in which the amide H bonds to water. NMR is used to measure shifts in the pK(a) of the ionizable carboxyl group when the amides of the compounds are either protonated or deuterated. From the pK(a) shift, we obtain a quantitative scale factor: SF = partial partial differential(DeltaG(HB))/partial partial differential(RT ln Phi), where DeltaG(HB) is the change in free energy of an H bond upon isotope substitution and Phi is the fractionation factor. Isotope effect data also are reported for a small globular protein, lambda repressor, using the "C(m) experiment". The protein's isotope effect, which reports on the shape of the energy well, is converted to H-bonding free energy by applying the scale factor. We estimate that amide-related H bonds (amide-carbonyl and amide-water) contribute favorably to protein stability by approximately 30-50 kcal/mol in lambda repressor, GCN4 coiled coil, and cytochrome c but unfavorably by approximately 6 kcal/mol in ubiquitin. The results indicate that H-bond strength varies from one protein to another and presumably at different sites within the same protein.

2-(3-Acetylamino-2,2-dimethylcyclobutyl)-methyl-4(3H)-quinazolinones

Beckmann rearrangement of N-[3-(1-hydroxyimino)ethyl-2,2-dimethylcyclobutyl]acetylanthranilic acid, and its 5-bromo and 4-chloro derivatives gives the corresponding N-(3-acetylamino-2,2-dimethylcyclobutyl)acetylanthranilic acids. Treatment of these acylanthranilic acids with formamide gives 2-(3-acetylamino-2,2-dimethylcyclobutyl)methyl-4(3H)-quinazoline and its 6-bromo and 7-chloro derivatives.

2-(3-ethyl-2,2-dimethylcyclobutyl-methyl)-4(3H)-quinazolinones

Anthranilic acid and its 5-bromo and 4-chloro derivatives react with pinanoic and pinonoic acid chlorides to give the corresponding N-acyl derivatives. The pinanoyl derivatives give the corresponding 2-(3-ethyl-2,2-dimethyl-cyclobutylmethyl)-4-(3H)-quinazolinones when refluxed in formamide. Pinanoylanthranilic acid reacts with dicyclohexylcarbodiimide to give 2-(3-ethyl-2,2-dimethylcyclobutylmethyl)benz-3,1-oxazin-4(H)-one and subsequently with hydrazine hydrate to give 3-amino-2-(3-ethyl-2,2-dimethylcyclobutylmethyl)-4(3H)-quinazolinone. Refluxing of the pinanoyl- and pinonoylanthranilic acids with acetic anhydride gives acetylanthranilic acid, and pinonoylanthranilic acid gives 4(3H)-quinazolinone with formamide.

Synthesis and Resolution of Quinazolinone Atropisomeric Phosphine Ligands(,).

The syntheses of 2-methyl-3-[2'-(diphenylphosphino)phenyl]-4(3H)-quinazolinone (MPQ, 1a) and methyl-substituted analogues were achieved in good yield by coupling N-acetylanthranilic acid with the corresponding phosphinoanilines. Resolution of ligand 1bwas achieved using (-)-di-&mgr;-chlorobis[(S)-dimethyl-(1-phenylethyl)aminato-C(2),N]dipalladium(II) (5). The resulting crystalline complex (S,R)-6 served to unambiguously assign the absolute configuration of antipode (R)-(-)-1b. A practical resolution of this series of ligands 1a-c was accomplished using the (benzenesulfonyl)hydrazone derivative of camphorsulfonic acid (7) as a resolving agent.

Cyclization of N-acylanthranilic acids with Vilsmeier reagents. Chemical and structural studies

Vilsmeier reagents, generated from e.g. N, N-dimethylformamide and oxalyl chloride, react with N-acetylanthranilic acid to produce the 2-(2′-dimethylamino)ethenyl-4H-3,1-benzoxazin-4-one 13a.. N-phenylacetylanthranilic acid similarly gave 2-(2′-dimethylamino-1′-phenyl)ethenyl-4 H-3,1-benzoxazin-4-one 6a, whose structure has been determined by X-ray crystallography. The benzoxazinone 6a could readily be converted to fused heterocyclic systems, thus e.g. 13a and hydrazine hydrate gave pyrazolo[5,1-b]-4 H-quinazoline 20a. Reaction of N-acetylated anthranilic acids and oxalyl chloride alone gave the fused oxazolidine-4,5-diones 24. The structure of one representative, 24a, was established by X-ray crystallography. Thermolysis of 24a gave, after elimination of CO+CO 2, 2-benzyl-4H-3,1-benzoxazin-4-one 7 in quantitative yield.