Papers by Mohammad Alsanea
Molecules, 2015
A series of phenylbipyridinylpyrazoles was synthesized through the reaction of 2-(4-(2-chloropyri... more 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 GI50 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 ...
Plant Physiology and Biochemistry
Journal of Environmental Chemical Engineering
European Journal of Medicinal Chemistry, Jan 27, 2015
With the aim of discovering potent and selective kinase inhibitors targeting ROS1 kinase, we desi... more With the aim of discovering potent and selective kinase inhibitors targeting ROS1 kinase, we designed, synthesized and screened a series of new pyrazol-4-ylpyrimidine derivatives based on our previously discovered lead compound KIST301072. Compounds 6a-e and 7a-e showed good to excellent activities against ROS1 kinase, and seven out of tested compounds were more potent than KIST301072. Compound 7c was the most potent with IC50 of 24 nM. Moreover, compound 7c showed ROS1 inhibitory selectivity of about 170-fold, relative to that of ALK sharing about 49% amino acid sequence homology with ROS1 kinase in the kinase domain. In silico modeling of 7c at ROS1 active site revealed some essential features for ROS1 inhibitory activity. Based on this study as well as the previous studies, we could build a hypothetical model predicting the required essential features for ROS1 inhibitory activity. The model validity has been tested through a second set of compounds.
Bulletin of the Korean Chemical Society, 2015
A series of rationally designed ROS1 tyrosine kinase inhibitors 6a–9b with bipyridinyl pyrazole s... more 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, ALK and 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 pyrazole NH substituents. Careful selections of pyrazole NH substituent 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.
Journal of Enzyme Inhibition and Medicinal Chemistry
Development of 3-methyl/3-(morpholinomethyl)benzofuran derivatives as novel antitumor agents towa... more Development of 3-methyl/3-(morpholinomethyl)benzofuran derivatives as novel antitumor agents towards non-small cell lung cancer cells,
Drug Design, Development and Therapy
Introduction: Histone deacetylases (HDACs) represent one of the most validated cancer targets. Th... more Introduction: Histone deacetylases (HDACs) represent one of the most validated cancer targets. The inhibition of HDACs has been proven to be a successful strategy for the development of novel anticancer candidates. Methods: This work describes design and synthesis of a new set of HDAC inhibitors (7a-c and 8a, b) utilizing ligustrazine as a novel cap moiety, and achieving the pharmacophoric features required to induce the desired inhibition. Results: The newly synthesized derivatives were evaluated for their potential inhibitory activity toward two class I histone deacetylases, namely HDAC1 and HDAC2. The tested ligustrazine-based compounds were more potent toward HDAC2 (IC 50 range: 53.7-205.4 nM) than HDAC1 (IC 50 range: 114.3-2434.7 nM). Furthermore, the antiproliferative activities against two HDAC-expressing cancer cell lines; HT-29 and SH-SY5Y were examined by the MTT assay. Moreover, a molecular docking study of the designed HDAC inhibitors (7a-c and 8a,b) was carried out to investigate their binding pattern within their prospective targets; HDAC1 (PDB-ID: 4BKX) and HDAC2 (PDB-ID: 6G3O). Discussion: Compound 7a was found to be the most potent analog in this study toward HDAC1 and HDAC2 with IC 50 values equal 114.3 and 53.7 nM, respectively. Moreover, it was the most effective counterpart (IC 50 = 1.60 µM), with 4.7-fold enhanced efficiency than reference drug Gefitinib (IC 50 = 7.63 µM) against SH-SY5Y cells. Whereas, compound 8a (IC 50 = 1.96 µM) was the most active member toward HT-29 cells, being 2.5-times more potent than Gefitinib (IC 50 = 4.99 µM). Collectively, these results suggest that 7a merits further optimization and development as an effective new HDACI lead compound.
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Papers by Mohammad Alsanea