2199-45-3Relevant articles and documents
From Synthetic Simplified Marine Metabolite Analogues to New Selective Allosteric Inhibitor of Aurora B Kinase
Juillet, Charlotte,Ermolenko, Ludmila,Boyarskaya, Dina,Baratte, Blandine,Josselin, Béatrice,Nedev, Hristo,Bach, Stéphane,Iorga, Bogdan I.,Bignon, Jér?me,Ruchaud, Sandrine,Al-Mourabit, Ali
, p. 1197 - 1219 (2021/02/05)
Significant inhibition of Aurora B was achieved by the synthesis of simplified fragments of benzosceptrins and oroidin belonging to the marine pyrrole-2-aminoimidazoles metabolites isolated from sponges. Evaluation of kinase inhibition enabled the discovery of a synthetically accessible rigid acetylenic structural analogue EL-228 (1), whose structure could be optimized into the potent CJ2-150 (37). Here we present the synthesis of new inhibitors of Aurora B kinase, which is an important target for cancer therapy through mitosis regulation. The biologically oriented synthesis yielded several nanomolar inhibitors. The optimized compound CJ2-150 (37) showed a non-ATP competitive allosteric mode of action in a mixed-type inhibition for Aurora B kinase. Molecular docking identified a probable binding mode in the allosteric site "F"and highlighted the key interactions with the protein. We describe the improvement of the inhibitory potency and specificity of the novel scaffold as well as the characterization of the mechanism of action.
PREPARATION OF 4,5-DIALKYL-3-ACYL-PYRROLE-2-CARBOXYLIC ACID DERIVATIVES BY FISCHER-FINK TYPE SYNTHESIS AND SUBSEQUENT ACYLATION
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Page/Page column 19-21, (2008/06/13)
The present invention relates to an improved synthesis of pyrrole capping group precursors of formula I-a: comprising: combining an aqueous solution of the compound of formula IV-a: wherein R3 is C1-12 aliphatic, C3-12 alkyl-cycloaliphatic, C3-12 alkyl-aryl, C3-12 alkyl-heteroaryl, or C3-12 alkyl-cycloaliphatic; with a compound of formula V-a, wherein R1 and R2 are each independently C1-6 aliphatic; in the presence of zinc, water, and optionally an additional suitable solvent to form a compound of formula VI.
Thermolysis of Alkyl 2-Azidopenta-2,4-dienoates
Moody, Christopher J.,Rees, Charles W.,Rodrigues, J. Augusto R.,Tsoi, Siu Chung
, p. 2801 - 2817 (2007/10/02)
Treatment of the α,β-unsaturated aldehydes (1), (3), (5), and (7) with ethyl azidoacetate gives the 2-azidopentadienoate esters (2), (4), (6) and (8) which are decomposed in boiling toluene and similar solvents.The dienyl nitrenes so generated undergo competitive electrocyclisation onto the diene to give 2H-pyrroles and insertion into methyl or methylene groups to give dihydropyridines, isolated as the pyridines.Thus azide (2) gives the 2H-pyrrole (9) and the pyridine (10), and azide (4) gives the 2H-pyrrole (13) and the tetrahydroquinoline (12).Thermolyses of the chlorine-containing azides are more complex, however, giving several products in low yields.Thus five products, (11), (15), (16), (17), and (18), were isolated from the azide (6) and a mechanistic pathway (Scheme 4) is proposed for their formation.Decomposition of azide (8) is even more complex, the dihydroindole (25) being the only isolable pure product.This extra complexity results from the varied reaction pathways available to the chloro-2H-pyrrole intermediates.On stronger heating (200 deg C) the 2H-pyrroles (9) and (13) aromatise by shifts to the 1H-pyrroles (11) and (14) respectively.
