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The Isolated Hepatocyte and Isolated Perfused Liver as Models for Studying Drug- and Chemical-Induced Hepatotoxicity
Published in Robert G. Meeks, Steadman D. Harrison, Richard J. Bull, Hepatotoxicology, 2020
David J. Sweeny, Robert B. Diasio
While it is well recognized that cellular enzymes are unevenly distributed across the liver lobule (Jungermann and Katz, 1982), there also exists an oxygen gradient across the liver lobule of between 40 and 60 Torr (Lautt, 1976) which may contribute to the development of regional-specific hepa-totoxicities. Using microoxygen probes placed on either periportal or pericentral regions of the liver lobule, Thurman and co-workers have demonstrated that oxygen uptake by hepatocytes is dependent on the local oxygen tension (Matsumura et al., 1986). That is, when the oxygen concentration is greater in periportal regions, as is observed during anteriograde perfusion, hepatocytes in this region consume two to three times the amount of oxygen as do hepatocytes “downstream” in the pericentral region of the liver lobule. However, when the direction of perfusate flow was reversed, the pattern of oxygen consumption shifted so that pericentral hepatocytes consumed two to three times as much oxygen as periportal hepatocytes. By reversing the direction of flow through the liver (i.e., retrograde infusion) the toxicity produced by allyl alcohol could be shifted from hepatocytes primarily in the periportal region to hepatocytes primarily in the pericentral region of the liver lobule (Badr et al., 1986). These findings indicate that the oxygen gradient across the liver lobule is an important factor in determining the site of toxicity of allyl alcohol.
Manufacture of Glycerine from Petrochemical and Carbohydrate Raw Materials
Published in Eric Jungermann, Norman O.V. Sonntag, Glycerine, 2018
The distilled allyl alcohol is oxidized with a 2 M aqueous solution of H2O2 containing 0.2% tungstic oxide. The glycerol water mixture, which is generated within 2 hr reaction time at 60–70°C is distilled to afford high-purity glycerol. The filtered catalyst is recycled. Yield of glycerol (based on allyl alcohol) is 80–90%; the overall yield of glycerol based on propylene is about 50%. Isopropanol and hydrogen peroxide auxiliary raw materials can be produced from propylene; acetone is highly marketable.
Linkers in fragment-based drug design: an overview of the literature
Published in Expert Opinion on Drug Discovery, 2023
Dylan Grenier, Solène Audebert, Jordane Preto, Jean-François Guichou, Isabelle Krimm
The ether function is also widely used in medicinal chemistry due to its high stability. Two main reactions give access to ether derivatives, the Mitsunobu and the Williamson reactions. Szczepankiewicz et al. [19] linked two fragments with amide and ether functions, leading to the discovery of protein PTP1B inhibitors. One of the fragments carried a carboxylic acid function while the second, a naphthoic acid, had to be functionalized. A Mitsunobu reaction was used to obtain the ether linker containing a primary amine. Finally, the combination of the acid and amine fragments resulted in a 22 nM PTP1B inhibitor. For the same target, Liu et al. [20] combined two fragments with a more rigid linker (allyl ether) than usual. One fragment was modified by a Still coupling reaction to introduce an allyl alcohol function. The modified fragment was linked to the second fragment containing a phenolic function using a Mitsunobu reaction. A lead compound with an IC50 of 6.9 µM was obtained.
Further optimisation of a macromolecular ocular irritation test (OptiSafeTM)
Published in Cutaneous and Ocular Toxicology, 2023
Stewart Lebrun, Sara Chavez, Linda Nguyen, Roxanne Chan
In addition, the protocol was modified so that materials that buffer to an extreme pH with a criteria not met (CNM) result are then retested using the OS mid-range pH buffering PCHP. This resulted in additional substances being classified. Specifically, diethylaminopropionitrile (CASRN 5351–04-2) previously resulted in CNM for all replicates [10]; however, upon retesting with the updates, this substance met the criteria. Likewise, imidazole (CASRN 288–32-4) was CNM for [10]; however, the retest met the criteria. Sodium perborate tetrahydrate (CASRN 10486–00-7) was CNM for all OS replicates [10]. However, with retest, it met the criteria. The change in the PCHP pre-test solubility assessment resulted in the assignment of 2,5-dimethylhexanediol (CASRN 110–03-2) as insoluble for retesting. Additionally, butanedioic acid, sulfo-, 1,4-bis(2-ethylhexyl) ester, sodium salt (CASRN 577–11-7) was retested using the insoluble procedure. Both of these cases resulted in the correct GHS category 1 classification; but when previously tested, both chemicals were underpredicted. When the change in the buffering capacity PCHP pre-test was applied to 2,6-dichlorobenzoyl chloride (CASRN 4659–45-4), the predicted classification did not change. Similarly, the allyl alcohol (CASRN 107–18-6) and sodium chloroacetate (CASRN 3926–62-3) pre-tests indicated a mid-range PCHP but the predicted classifications did not change. Tables 3 and 4 show the resulting differences in the PCHPs.
Novel hydroxyl carboximates derived from β-elemene: design, synthesis and anti-tumour activities evaluation
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2022
Yuan Gao, Nian-Dong Mao, Hao Che, Li Xu, Renren Bai, Li-Wei Wang, Xiang-Yang Ye, Tian Xie
The interesting biological activities and the easy accessibility of novel compound 11a encouraged us to investigate more on N-alkyl-N-hydroxyl carboximate class analogs of β-elemene. In order to accomplish the work, we first needed to prepare 13-Br-β-elemene (4) in a workable amount (Scheme 1). Compound 4 was previously prepared from the corresponding allylic alcohol by Xu et al.19 using NBS/Ph3P condition. This route not only added one extra step of alcohol preparation but also required tedious separation of close related isomer in allylic alcohols. We worked out an alternative route of direct bromination at the 13-position (one of the allylic positions) of 1. By following the procedure in our patent application25, compound 4 was prepared in 30.1% yield with good purity, enough for the next step displacement reaction. The minor isomer 14-Br-β-elemene (6) did not interfere with the following step reaction.