13023-74-0Relevant articles and documents
Targeting receptor tyrosine kinase VEGFR-2 in hepatocellular cancer: Rational design, synthesis and biological evaluation of 1,2-disubstituted benzimidazoles
Abdel-Mohsen, Heba T.,Abdullaziz, Mona A.,Ali, Mamdouh M.,El Diwani, Hoda I.,El Kerdawy, Ahmed M.,Flanagan, Keith J.,Mahmoud, Abeer E. E.,Ragab, Fatma A. F.,Senge, Mathias O.
, (2020)
In this study, a novel series of 1,2-disubstituted benzo[d]imidazoles was rationally designed as VEGFR-2 inhibitors targeting hepatocellular carcinoma. Our design strategy is twofold; it aimed first at studying the effect of replacing the 5-methylfuryl moiety of the well-known antiangiogenic 2-furylbenzimidazoles with an isopropyl moiety on the VEGFR-2 inhibitory activity and the cytotoxic activity. Our second objective was to further optimize the structures of the benzimidazole derivatives through elongation of the side chains at their one-position for the design of more potent type II-like VEGFR-2 inhibitors. The designed 1,2-disubstituted benzimidazoles demonstrated potent cytotoxic activity against the HepG2 cell line, reaching IC50 = 1.98 μM in comparison to sorafenib (IC50 = 10.99 μM). In addition, the synthesized compounds revealed promising VEGFR-2 inhibitory activity in the HepG2 cell line, e.g., compounds 17a and 6 showed 82% and 80% inhibition, respectively, in comparison to sorafenib (% inhibition = 92%). Studying the effect of 17a on the HepG2 cell cycle demonstrated that 17a arrested the cell cycle at the G2/M phase and induced a dose-dependent apoptotic effect. Molecular docking studies of the synthesized 1,2-disubstituted benzimidazoles in the VEGFR-2 active site displayed their ability to accomplish the essential hydrogen bonding and hydrophobic interactions for optimum inhibitory activity.
Beyond organic solvents: synthesis of a 5-HT4receptor agonist in water
Bailey, J. Daniel,Helbling, Edward,Mankar, Amey,Stirling, Matthew,Hicks, Fred,Leahy, David K.
supporting information, p. 788 - 795 (2021/02/09)
Reducing or eliminating organic solvent use in pharmaceutical manufacturing is perhaps the most effective way to reduce the environmental, health, and safety impacts of drug substance manufacturing. With this in mind, we have developed a process to manufacture an investigational 5-HT4receptor agonist that is conducted almost entirely in water, including multiple controlled isolations. Key transformations carried out in aqueous media include a benzimidazole cyclization, amide bond formation, reductive amination, and a selective oxidation of an aliphatic alcohol. Compared to the first-generation manufacturing process using organic solvents, the aqueous process described here uses 77% less material inputs, 94% less organic solvent, and, surprisingly, 48% less water, while improving overall yield from 35% to 56%.
