75413-97-7Relevant academic research and scientific papers
Design and development of photoswitchable DFG-Out RET kinase inhibitors
Carrasco, Marta P.,Fleming, Cassandra,Gao, Chunxia,Xu, Yongjin,Andréasson, Joakim,Andreasson, M?ns,Gr?tli, Morten,H?versen, Liliana,Lundb?ck, Thomas
, (2022/03/23)
REarranged during Transfection (RET) is a transmembrane receptor tyrosine kinase that is required for development of multiple human tissues, but which is also an important contributor to human cancers. RET activation through rearrangement or point mutations occurs in thyroid and lung cancers. Furthermore, activation of wild type RET is an increasingly recognized mechanism promoting tumor growth and dissemination of a much broader group of cancers. RET is therefore an attractive therapeutic target for small-molecule kinase inhibitors. Non-invasive control of RET signaling with light offers the promise of unveiling its complex spatiotemporal dynamics in vivo. In this work, photoswitchable DFG-out RET kinase inhibitors based on heterocycle-derived azobenzenes were developed, enabling photonic control of RET activity. Based on the binding mode of DFG-out kinase inhibitors and using RET kinase as the test model, we developed a photoswitchable inhibitor with a quinoline “head” constituting the azoheteroarene. This azo compound was further modified by three different strategies to increase the difference in biological activity between the E-isomer and the light enriched Z-isomer. Stilbene-based derivatives were used as model compounds to guide in the selection of substituents that could eventually be introduced to the corresponding azo compounds. The most promising quinoline-based compound showed more than a 15-fold difference in bioactivity between the two isomers in a biochemical assay. However, the same compound showed a decreased Z/E (IC50) ratio in the cellular assay, tentatively assigned to stability issues. The corresponding stilbene compound gave a Z/E (IC50) ratio well above 100, consistent with that measured in the biochemical assay. Ultimately, a 7-azaindole based photoswitchable DFG-out kinase inhibitor was shown to display more than a 10-fold difference in bioactivity between the two isomers, in both a biochemical and a cell-based assay, as well as excellent stability even under reducing conditions.
COMPOSITION OF THE PRODUCTS AND KINETICS OF THE ISOPROPYLATION OF 1,2,3,4-TETRAHYDROQUINOLINE IN SULFURIC ACID
Okhrimenko, Z. A.,Chekhuta, V. G.,Kachurin, O. I.
, p. 409 - 412 (2007/10/02)
The kinetics of the alkylation of 1,2,3,4-tetrahydroquinoline with isopropyl alcohol in 90percent sulfuric acid at 60 deg C were studied.It was established that the rate of alkylation in the 5 position is higher than for corresponding position in the acyclic analog N,2-dimethylaniline; this was ascribed to the Mills-Nixon dynamic effect.
Selectivity in the Hydrogenation of 6- and 8-Substituted-quinolines
Hoenel, Michael,Vierhapper, Friedrich W.
, p. 1933 - 1939 (2007/10/02)
Quinoline (1) and the 6- or 8-substituted-quinolines (2)-(14) (R = Me, Pri, But, Ph, OMe, OH, CF3, or F) were hydrogenated catalytically on platinum under either weakly basic (solvent MeOH) or strongly acidic (solvent CF3CO2H) conditions.In methanol the only product was the corresponding 1,2,3,4-tetrahydro-compound.In trifluoroacetic acid, compounds hydrogenated in the benzene ring were isolated as major products; both electron-withdrawing and electron-donating substituents at C-6 or C-8 cause (sometimes drastic) reduction in yield.The products were characterized by their 1H and 13C n.m.r. spectra.
