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Hepatotoxic and Hepatocarcinogenic Effects of Chlorinated Ethylenes*
Published in Robert G. Meeks, Steadman D. Harrison, Richard J. Bull, Hepatotoxicology, 2020
Jeffrey L. Larson, Richard J. Bull
It is known that the initial oxidation is followed by a preferential chlorine migration and subsequent formation of an aldehyde or an acid chloride, which can be further metabolized to an acid or an alcohol (Bonse and Henschler, 1976). The formation of an unstable reactive acid chloride is one reactive intermediate which binds cellular macromolecules. Dekant et al. (1987) identified the majority of alkylated macromolecules arising from PCE metabolism as N-trichloroacetylated phospholipids. Phospholipid adducts have also been identified following administration of TCE or VCD (Reichert et al., 1979; Dekant et al., 1984). Conjugation of reactive intermediates with glutathione is also known to occur for the chlorinated ethylenes and plays the major role in VDC toxicity, as will be discussed later (Allemand et al., 1978; Liebler et al., 1985).
Chemistries of Chemical Warfare Agents
Published in Brian J. Lukey, James A. Romano, Salem Harry, Chemical Warfare Agents, 2019
Terry J. Henderson, Ilona Petrikovics, Petr Kikilo, Andrew L. Ternay Jr., Harry Salem
With less reactive aromatic compounds, a stronger Lewis acid may be required, but the monosubstituted acyl chloride can be isolated. Under appropriate conditions, a symmetric, substituted ketone is formed. Thus, benzophenone can be isolated by the reaction with excess benzene as shown (Wilson and Fuller, 1922):
Uro-Angiographic Contrast Agents—The Holy Grail
Published in Christoph de Haën, X-Ray Contrast Agent Technology, 2019
In analogy to the esterification of the carboxyl group in known ionic triiodinated contrast agents, amidation of the kind that was to become the basis for breakthrough nonionic compounds was contemplated. The industrially practical preparation of the acid chloride intermediates bearing acylated aniline functions posed an unexpected obstacle. These difficulties constituted a hurdle significant enough to impede for a while continued exploration in that direction. It is noteworthy that the value of nonionic molecules as uro-angiographic contrast agents was not fully recognized until much later and thus at this time the motivation for overcoming the synthetic difficulties was low. Since the economic circumstances at the time were not favorable for the industrial development of uro-angiographic novelties (see Section “Perfecting Ionic Uro-Angiographic Contrast Agents”), pursuit of nonionicity did not acquire importance for many more years.
Discovery of 3,6-disubstituted pyridazines as a novel class of anticancer agents targeting cyclin-dependent kinase 2: synthesis, biological evaluation and in silico insights
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2020
Ahmed Sabt, Wagdy M. Eldehna, Tarfah Al-Warhi, Ohoud J. Alotaibi, Mahmoud M. Elaasser, Howayda Suliman, Hatem A. Abdel-Aziz
Ethyl 6-chloro-5-(trifluoromethyl)pyridazine-3-carboxylate 6 (0.04 g, 0.16 mmol) was added to a mixture of THF/H2O (4:1) and LiOH hydrate (0.80 mmol) at 0 °C, then the reaction mixture was stirred for 1 h at room temperature. The reaction mixture was then evaporated to dryness and the residue was dissolved in H2O, neutralised carefully with a 1 N HCl, and extracted with ethyl acetate. Organic layers were collected, dried over anhydrous sodium sulphate, filtered and the solvent was removed under reduced pressure to yield the corresponding carboxylic acid. The later acid derivative was dissolved in dry 1,2-dichloroethane (5 ml), then thionyl chloride (0.9 mmol) and DMF (2–3 drops) were added to the solution. The mixture was refluxed for 3 h then evaporated to dryness to produce the crude product of acyl chloride 7. This compound was used immediately for the next step to prepare key amide intermediates 9a–evia stirring with primary amines 8a–e (0.32 mmol) in methylene chloride (4 ml) and in the presence of TEA (0.80 mmol) for 4 h at room temperature. The obtained precipitate was filtered off and washed with petroleum ether, then used in the next step without further purification.
Design, synthesis and biological activity of selective hCAs inhibitors based on 2-(benzylsulfinyl)benzoic acid scaffold
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2019
Giulia Rotondi, Paolo Guglielmi, Simone Carradori, Daniela Secci, Celeste De Monte, Barbara De Filippis, Cristina Maccallini, Rosa Amoroso, Roberto Cirilli, Atilla Akdemir, Andrea Angeli, Claudiu T. Supuran
The reaction of the ester 45 with hydroxylamine hydrochloride in methanol at room temperature for 48 h gave the N-hydroxy benzamide 5126. Compounds 47–49 were obtained converting the carboxylic acids 39–41 to the corresponding acyl chlorides by means of oxalyl chloride in the presence of a catalytic amount of dry DMF. Acyl chlorides were subsequently treated with ammonium hydroxide (NH4OH), to afford the desired amides (Scheme 4)27. The amide 50 was obtained by a different route (Scheme 5). At first, it was synthesised the amide from the anthranilic acid activated by SOCl2 in DMF at room temperature as previously reported. The addiction of NaH and phenylacetyl chloride in dry THF at room temperature let to the final amide 50.
Folate receptor-targeted mixed polysialic acid micelles for combating rheumatoid arthritis: in vitro and in vivo evaluation
Published in Drug Delivery, 2018
Nan Zhang, Chunyu Xu, Na Li, Shasha Zhang, Lingling Fu, Xiao Chu, Haiying Hua, Xianghui Zeng, Yongxing Zhao
FTIR spectrums indicated hydroxyl and amide functional group and of PSA around 3400 and 1650 cm−1, respectively. CC showed featured acyl chloride peak at 1790 cm−1, carbon–hydrogen bond at 2950 cm−1, and double peaks for C(CH3)2 at 1400 cm−1. Successful conjugation of CC to PSA destroyed acyl chloride group and resulted in the peak disappearance at 1790 cm−1. (Figure 1(A)) NMR result of PSA-CC also confirmed the appearance of hydrogens that belonged to CC at 0.5–1.5 ppm. (Supplementary Figure S1) CMC results indicated that PSA-CC and FA-PSA-CC started to form micelles at the concentration of 46.2 ± 3.9 and 32.1 ± 5.2 μg/mL, respectively (Supplementary Figure S2(A,B)). TEM showed a round shape of PSA-CC and FA-PSA-CC micelles with the size 80–100 nm (Figure 1(B,C)). TEM results were consistent with dynamic light scattering results. The size of PSA-CC and FA-PSA-CC micelles was 93.8 ± 13.4 and 83.8 ± 13.4 nm respectively using zeta-sizer. Both of PSA-CC and FA-PSA-CC micelles showed a sufficient negative charge and small PDI, indicating a high stability in solution (Supplementary Figure S2(C)). With Dex loading, the size of PSA-CC and FA-PSA-CC micelles increased slightly (Supplementary Figure S3).