87124-01-4Relevant academic research and scientific papers
Design and synthesis of benzodiazepines as brain penetrating PARP-1 inhibitors
Cui, Yating,Gou, Wenfeng,Hou, Wenbin,Li, Yiliang,Luo, Lingling,Shang, Haihua,Sun, Tiemin,Sun, Xiao,Yu, Jiang
, p. 952 - 972 (2022/03/31)
The poly (ADP-ribose) polymerase (PARP) inhibitors play a crucial role in cancer therapy. However, most approved PARP inhibitors cannot cross the blood-brain barrier, thus limiting their application in the central nervous system. Here, 55 benzodiazepines were designed and synthesised to screen brain penetrating PARP-1 inhibitors. All target compounds were evaluated for their PARP-1 inhibition activity, and compounds with better activity were selected for further assays in?vitro. Among them, compounds H34, H42, H48, and H52 displayed acceptable inhibition effects on breast cancer cells. Also, computational prediction together with the permeability assays in?vitro and in?vivo proved that the benzodiazepine PARP-1 inhibitors we synthesised were brain permeable. Compound H52 exhibited a B/P ratio of 40 times higher than that of Rucaparib and would be selected to develop its potential use in neurodegenerative diseases. Our study provided potential lead compounds and design strategies for the development of brain penetrating PARP-1 inhibitors.HIGHLIGHTS Structural fusion was used to screen brain penetrating PARP-1 inhibitors. 55 benzodiazepines were evaluated for their PARP-1 inhibition activity. Four compounds displayed acceptable inhibition effects on breast cancer cells. The benzodiazepine PARP-1 inhibitors were proved to be brain permeable.
Structural spectroscopic study of enantiomerically pure synthetic cathinones and their major metabolites
Spálovská, Dita,Pa?kan, Martin,Jurásek, Bronislav,Kucha?, Martin,Kohout, Michal,Setni?ka, Vladimír
supporting information, p. 850 - 860 (2021/01/25)
New psychoactive substances (NPSs) have become a popular alternative to illicit drugs of abuse. However, to determine their metabolic pathways in the human organism, a detailed knowledge of their structure is crucial. Here, we present a comprehensive spectroscopic structural study of synthetic cathinones (clephedrone, flephedrone, and brephedrone) and their major human metabolites, desmethyl derivatives. Chiral high-performance liquid chromatography was utilized to obtain the individual enantiomers of the parent synthetic cathinones and their assumed major metabolites synthesized de novo. The developed chromatographic method made it possible to obtain the target optically pure substances on a multimilligram scale. Electronic and vibrational circular dichroism, combined with infrared and ultraviolet spectroscopy and supported by DFT calculations, were used to determine their absolute configuration and the chiroptical methods to elucidate their molecular structure in detail. Two stable conformers of each substance were found in aqueous solution. Their relative abundances were estimated based on the Boltzmann distribution and the population weighted spectra were obtained. Very good agreement was achieved between the experimental and simulated spectra, enabling the 3D structures of the studied substances to be determined in aqueous solution. This journal is
