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Gas Chromatographic Analysis
Published in Adorjan Aszalos, Modern Analysis of Antibiotics, 2020
Margosis [36] extracted with cyclohexane from 5% NaOH. Naphthalene was used as internal standard. The experimental conditions were injection port at 60°C, column (3% OV-17 on Gas Chrom Q 100/120) at 60°C, and FID at 150°C. The column had to be silylated by injection of a silyl reagent with the temperature at 275°C prior to the analysis. At the level of 1.7 ppm of N,N-dimethylaniline in antibiotic, the CV was 7.9. The limit of detection was about 0.5 ppm. Amounts found in commercial samples ranged up to 1500 ppm.
Organic Chemicals
Published in William J. Rea, Kalpana D. Patel, Reversibility of Chronic Disease and Hypersensitivity, Volume 4, 2017
William J. Rea, Kalpana D. Patel
Aromatic and heterocyclic amines are chemicals composed of single- and multiple-ring systems with an exocytic amino group. They do not occur in nature except for complex heterocyclines that are generated during pyrolysis. They are synthetics used in dye and drug manufacturing and as antioxidants.383 The typical monoarylamines and polyarylamines with carcinogenic potential include aniline and o-toluidine (sarcoma), o-anisidine and p-cresidine (bladder cancer), and phenacetin384 (Table 5.48). At high doses, anilines are carcinogenic, and through its metabolite phenylhydroxylamine, aniline is a powerful hematopoietic poison producing methemoglobinemia. o-Toluidine and 2,6-dimethylaniline are released from the local anesthetics prilocaine and lidocaine.385 High-level chronic abuse, but not ordinary intermittent drug use, of phenacetin has led to human bladder cancer.386 These aforementioned aromatic amines have been observed to trigger chemical sensitivity.
Substrates of Human CYP2D6
Published in Shufeng Zhou, Cytochrome P450 2D6, 2018
Lidocaine also undergoes hydrolytic conversion to result in 2,6-dimethylaniline (2,6-xylidine) (Figure 3.56) (Abdel-Rehim et al. 2000; Parker et al. 1996), a potential human carcinogen (Koujitani et al. 1999). Rat liver microsomal carboxylesterase ES-10, but not carboxylesterase ES-4, hydrolyzes lidocaine and monoethylglycinexylidide, but not glycinexylidide, to 2,6-xylidine (Alexson et al. 2002). 2,6-Dimethylaniline (2,6-Xylidine) can be further oxidized by CYP2A6 and 2E1 to 4-amino-3,5-dimethylphenol (i.e., 4-hydroxyxylidine) (Gan et al. 2001), but oxidation of the amino group to metabolites such as N-(2,6-dimethylphenyl) hydroxylamine is also noted in human and rats. 2,6-Xylidine can also be hydroxylated at the 3- or 4-position of the aromatic ring. In addition, 2,6-xylidine can be carboxylated to 2-amino-3-methylbenzoic acid in rabbits (Kammerer and Schmitz 1986). 4-Hydroxy-2,6-xylidine in glucuronide form is the major urinary metabolite found in man, accounting for 72.6% of an administered dose of lidocaine (Keenaghan and Boyes 1972; Tam et al. 1987). This metabolite is also the major metabolite in dogs (35.2%) but lesser in the urine of rats (12.4%) and guinea pigs (16.4%) (Keenaghan and Boyes 1972). Monoethylglycinexylidide is present in the urine in free and glucuronide- and sulfate-conjugated forms, while glycinexylidide is present mostly in the free form (Tam et al. 1990). Only 3% of lidocaine is excreted as unchanged drug. Phase II conjugation of N-(2,6-dimethylphenyl)hydroxylamine may result in reactive esters that decompose to a reactive nitrenium ion capable of reacting with protein and DNA. Reaction of the nitrenium ion with water is a second pathway for the formation of 4-amino-3,5-dimethylphenol (Gan et al. 2001). Further oxidation of 4-amino-3,5-dimethylphenol leads to the formation of the toxic iminoquinone species. Lidocaine can also be hydroxylated to 4-hydroxylidocaine to a minor extent in rats (Coutts et al. 1987) and rabbits (Kammerer and Schmitz 1986) and undergoes N-oxidation to its N-oxide seen in vitro only (Patterson et al. 1986).
New benzoxazole derivatives as potential VEGFR-2 inhibitors and apoptosis inducers: design, synthesis, anti-proliferative evaluation, flowcytometric analysis, and in silico studies
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2022
Hazem Elkady, Alaa Elwan, Hesham A. El-Mahdy, Ahmed S. Doghish, Ahmed Ismail, Mohammed S. Taghour, Eslam B. Elkaeed, Ibrahim H. Eissa, Mohammed A. Dahab, Hazem A. Mahdy, Mohamed M. Khalifa
The target benzoxazole derivatives 14a–o were synthesised following the general methodologies outlined in Schemes 1–3. The starting compounds, 2-mercapto-benzoxazoles 8a–c were synthesised by refluxing the appropriate 2-aminophenol derivatives 7a–c, carbon disulphide, and potassium hydroxide in methanol following the reported procedure33. Then, compounds 8a–c were treated with alcoholic KOH to afford the corresponding potassium salts, 9a–c (Scheme 1). On the other hand, 4-aminobenzoic acid 10 was reacted with chloroacetyl chloride in DMF to afford the chloroacetamide intermediate 11. Acylation of compound 11 was performed using thionyl chloride to yield 4–(2-chloroacetamido)benzoyl chloride 12 as described in the reported procedures14,34. Treating of 12 with commercially available amines namely, 2-methoxyaniline, 2,6-dimethoxyaniline, 2,6-dimethylaniline, 2,4-dichloroaniline, and 4-hydroxyaniline, in acetonitrile containing triethylamine (TEA), afforded the target key intermediates 13a–e (Scheme 2).
1,3-dimethyl-6-nitroacridine derivatives induce apoptosis in human breast cancer cells by targeting DNA
Published in Drug Development and Industrial Pharmacy, 2019
Qian Zhou, Hongshuai Wu, Chaoqun You, Zhiguo Gao, Kai Sun, Mingxin Wang, Fanghui Chen, Baiwang Sun
1,3-dimethyl-6-nitro-9–(3,5-dimethyl)phenylaminnoacridine(4). 4 was prepared from N,N-dimethylaniline and compound 8 according to the general procedure for 1. Yeild: 78.1%. 1 H NMR (400 MHz, DMSO) δ 10.82 (s, 1H), 8.05 (s, 1H), 7.38 (s, 2H), 6.88 (s, 1H), 6.79 (s, 1H), 6.60 (s, 1H), 6.27 (s, 2H), 2.60 (s, 3H), 2.33 (s, 3H), 2.17 (s, 6H). 13 C NMR (101 MHz, DMSO-d6) δ 152.28, 152.02, 148.26, 141.79, 141.74, 141.30, 140.79, 138.99, 138.50, 130.15, 126.90, 124.12, 115.94, 113.88, 112.59, 112.48, 111.55, 23.34, 21.52, 21.46. ESI-MS: [M-H]− 370.3. Elemental analysis calcd for C23H21N3O2(%): C 74.37, H 5.70, N 11.31; found: C 74.15, H 5.76, N 11.41.
Pyruvate kinase activators as a therapy target: a patent review 2011-2017
Published in Expert Opinion on Therapeutic Patents, 2018
Sevki Adem, Veysel Comakli, Naim Uzun
Wals and colleagues tested effects activation of molecules synthesized from 2-oxo-N-aryl-1,2,3,4-tetrahydroquinoline-6-sulfonamide scaffold utilizing the luminescent pyruvate kinase–luciferase coupled assay. Most of the compounds exhibited activator effects with AC50 values below 1 µM. A series of novel derivatives was developed altering the 3,4-dimethylaniline part with a variety of substituted anilines. It was reported that the hydrophobic groups (such as methyl, fluoro, and chloro) at the meta-position in interacting with the enzyme were more effective than at ortho and para position. It was also observed that the 3-methoxy analog decreased activation potency compared to the 3-methyl derivative. The combination analogs of methyl, fluoro, and chloro at the 3- and 4-positions showed good activation effect with AC50 values between 0.100 and 0.560 µM. Similarly, the analogs of methyl, fluoro, and chloro at the R1, R2, and R3 positions had high activation potency. Compound 10 (N-(3-chloro-4-fluorophenyl)-7-fluoro-2-oxo-1,2,3,4-tetrahydroquinoline-6-sulfonamide) from generated analogs selectivity exhibited the best activator effects against PKM2 with AC50 value 90 nM versus the other PK isoforms. This analog also tested for its ability to modulate PEP and ADP affinity for PKM2; researchers were observed that it exhibited a remarkable decrease in Km for PEP, but not ADP [26]. It is thought that fluorine and chlorinegroups at position R2 and R3 on the molecule may be effective in activation (Figure 2).