1207435-87-7Relevant academic research and scientific papers
Discovery and development of extreme selective inhibitors of the ITD and D835Y mutant FLT3 kinases
Baska, Ferenc,Sipos, Anna,?rfi, Zoltán,Nemes, Zoltán,Dobos, Judit,Szántai-Kis, Csaba,Szabó, Eszter,Szénási, Gábor,Dézsi, László,Hamar, Péter,Cserepes, Mihály T.,Tóvári, József,Garamv?lgyi, Rita,Krekó, Marcell,?rfi, László
, (2019)
Aberrant activation of FMS-like tyrosine receptor kinase 3 (FLT3) is implicated in the pathogenesis of acute myeloid leukemia (AML) in 20–30% of patients. In this study we identified a highly selective (phenylethenyl)quinazoline compound family as novel potent inhibitors of the FLT3-ITD and FLT3-D835Y kinases. Their prominent effects were confirmed by biochemical and cellular proliferation assays followed by mice xenograft studies. Our modelling experiments and the chemical structures of the compounds predict the possibility of covalent inhibition. The most effective compounds triggered apoptosis in FLT3-ITD AML cells but had either weak or no effect in FLT3-independent leukemic and non-leukemic cell lines. Our results strongly suggest that our compounds may become therapeutics in relapsing and refractory AML disease harboring various ITD and tyrosine kinase domain mutations, by their ability to overcome drug resistance.
Design, synthesis and molecular modeling studies of 2-styrylquinazoline derivatives as EGFR inhibitors and apoptosis inducers
Amin, Noha H.,Elsaadi, Mohammed T.,Zaki, Shimaa S.,Abdel-Rahman, Hamdy M.
, (2020/10/21)
Herein, we report the synthesis of novel 2-substituted styrylquinazolines conjugated with aniline or sulfonamide moieties, anticipated to act as potent anticancer therapeutic agents through preferential EGFR inhibition. In doing so, all the synthesized compounds were screened for their in vitro anticancer activities (nine subpanels) at the National Cancer Institute (NCI), USA. The resulting two most active anticancer compounds (7b and 8c) were then chemically manipulated to investigate feasible derivatives (12a-e and 15a-d). MTT cytotoxicity, in vitro cell free EGFR and anti-proliferative activity against EGFR/ A549 cell line evaluation for the most active broadly spectrum candidates (7a/b, 8c/e, 12b and 15d) was conducted. Promising results were obtained for the styrylquinazoline-benzenesulfonamide derivative 8c (IC50 = 8.62 μM, 0.190 μM and = 79.25%), if compared to lapatanib (IC50 = 11.98 μM, 0.190 μM, and 79.25%), respectively. Moreover, its apoptotic induction potential was studied through cell cycle analysis, Annexin-V and caspase-3 activation assays. Results showed a clear cell arrest at G2/M phase, a late apoptotic increase (76 folds) and a fruitful caspase-3 expression change (8 folds), compared to the control. Finally, molecular docking studies of compounds 7a/b, 8c/e, 12b and 15d revealed proper fitting into the active site of EGFR with a low binding energy score for compound 8c (?13.19 Kcal/mole), compared to lapatanib (?14.54 Kcal/mole).
Investigating the anti-proliferative activity of styrylazanaphthalenes and azanaphthalenediones
Mrozek-Wilczkiewicz, Anna,Kalinowski, Danuta S.,Musiol, Robert,Finster, Jacek,Szurko, Agnieszka,Serafin, Katarzyna,Knas, Magdalena,Kamalapuram, Sishir K.,Kovacevic, Zaklina,Jampilek, Josef,Ratuszna, Alicja,Rzeszowska-Wolny, Joanna,Richardson, Des R.,Polanski, Jaroslaw
experimental part, p. 2664 - 2671 (2010/06/14)
A group of styrylazanaphthalenes and azanaphthalenediones were synthesized and tested for their anti-proliferative activity. Most of the compounds were obtained with the use of microwave-assisted synthesis. The lipophilicity of the compounds was measured by RP-HPLC and their anti-proliferative activity was assayed against the human SK-N-MC neuroepithelioma and HCT116 human colon carcinoma cell lines. Active compounds were also tested in clonogenity and comet assays. Several quinazolinone and styrylquinazoline analogues were found to have markedly greater anti-proliferative activity than desferoxamine and cis-platin.
Investigating biological activity spectrum for novel styrylquinazoline analogues
Jampilek, Josef,Musiol, Robert,Finster, Jacek,Pesko, Matus,Carroll, James,Kralova, Katarina,Vejsova, Marcela,O'Mahony, Jim,Coffey, Aidan,Dohnal, Jiri,Polanski, Jaroslaw
experimental part, p. 4246 - 4265 (2010/03/01)
In this study, series of ring-substituted 2-styrylquinazolin-4(3H)-one and 4-chloro-2-styrylquinazoline derivatives were prepared. The syntheses of the discussed compounds are presented. The compounds were analyzed by RP-HPLC to determine lipophilicity. They were tested for their inhibitory activity on photosynthetic electron transport (PET) in spinach (Spinacia oleracea L.) chloroplasts. Primary in vitro screening of the synthesized compounds was also performed against four mycobacterial strains and against eight fungal strains. Several compounds showed biological activity comparable with or higher than that of the standard isoniazid. It was found that the electronic properties of the R substituent, and not the total lipophilicity of the compound, were decisive for the photosynthesis-inhibiting activity of tested compounds.
