1192885-45-2Relevant academic research and scientific papers
Optimization of bipyridinyl pyrazole scaffolds via design, synthesis and screening of a new series of ROS1 kinase-modulating compounds
Al-Sanea, Mohammad M.,Park, K Byung Sun,Abdelazem, K Ahmed Z.,Selim, Khalid B.,Yoo, Kyung Ho,Sim, Taebo,Tae, Jin Sung,Lee, So Ha
, p. 305 - 311 (2015)
A series of rationally designed ROS1 tyrosine kinase inhibitors 6a-9b with bipyridinyl pyrazole scaffold was synthesized and screened. The scaffold itself has showed an exclusive selectivity profile over ROS1 closely related kinases,ALKand c-Met. The aim of this study was to further explore the structure-activity relationships (SAR) of the bipyridinyl pyrazole core structure, and to improve its ROS1 inhibitory potency. The rational of this study was to explore the nature of the proposed binding site for the pyrazoleNHsubstituents. Careful selections of pyrazoleNHsubstituent groups along with their regioisomers were considered. The compounds exhibited high degree of potency, IC50 values of 21-159 nM. A detailed SAR of bipyridinyl pyrazole scaffold has been finally well established and the virtual screening strategy, through molecular docking, has been performed for this type of ROS1 kinase inhibitors and the docked poses along with the activity data have gone in consistent with SAR specifications.
Synthesis and in vitro screening of phenylbipyridinylpyrazole derivatives as potential antiproliferative agents
Al -Sanea, Mohammad M.,Elkamhawy, Ahmed,Zakaria, Ahmed,Park, Byung Sun,Kwon, Youngjoo,Lee, So Ha,Lee, Sang Woo,Kim, In Tae
, p. 1031 - 1045 (2015/01/30)
A series of phenylbipyridinylpyrazoles was synthesized through the reaction of 2-(4-(2-chloropyridin-4-yl)-3-(3-methoxy-5-methylphenyl)-1H-pyrazol-1-yl)acetonitrile (4) with different 6-substituted pyridine-3-ylboronic acids. The final compounds 5a-j were screened at 10 μM against over 60 tumor cell lines at the U.S. National Cancer Institute (NCI). In light of the NCI results, compounds 5c and 5h showed a broad spectrum of activity against NCI cell lines with mean growth of 53% and 58%, respectively. Compound 5e behaved differently as it showed high degree of selectivity and potency by inhibiting 96% of growth of leukemia SR cell line at 10 μM. Standard COMPARE analyses were performed at the GI 50 level and the results exhibit high correlation in the form of pairwise correlation coefficient (PCC) of more than 0.6 between three of the current compounds and three standard known anticancer agents. Compound 5e demonstrated high correlation levels with merbarone (NSC S336628) with a PCC value of 0.631. Compound 5h showed a considerably high PCC value of 0.626 with dichloroallyl lawsone, while compound 5i, showed PCC values of 0.601 and 0.604 with both dichloroallyl lawsone and N,N-dibenzyldaunomycin (NSC S268242), respectively. These three standard agents have anticancer activity via two major mechanism of actions, inhibition of topoisomerase II and inhibition of biosynthesis of pyrimidine nucleotides, therefore, compounds 5a-j are promising therapeutic agents for targeting different human malignancies. Prediction of drug-likeness and toxicity of these newly synthesized derivatives were also considered.
PYRAZOLE COMPOUNDS WITH INHIBITORY ACTIVITY AGAINST ROS KINASE
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, (2011/02/18)
Disclosed herein are novel pyrazole compounds, pharmaceutically acceptable salts thereof, a method for preparing the same, and uses thereof as anticancer agents.
Design, synthesis, screening, and molecular modeling study of a new series of ROS1 receptor tyrosine kinase inhibitors
El-Deeb, Ibrahim M.,Park, Byung Sun,Jung, Su Jin,Yoo, Kyung Ho,Oh, Chang-Hyun,Cho, Seung Joo,Han, Dong Keun,Lee, Jae Yeol,Lee, So Ha
scheme or table, p. 5622 - 5626 (2010/04/30)
A series of rationally designed ROS1 tyrosine kinase inhibitors was synthesized and screened. Compound 12b has showed good potency with IC50 value of 209 nM, which is comparable with that of the reference lead compound 1. Molecular modeling studies have been performed, that is, a homology model for ROS1 was built, and the screened inhibitors were docked into its major identified binding site. The docked poses along with the activity data have revealed a group of the essential features for activity. Overall, simplification of the lead compound 1 into compound 12b has maintained the activity, while facilitated the synthetic advantages. A molecular interaction model for ROS1 kinase and inhibitors has been proposed.
