- From Synthetic Simplified Marine Metabolite Analogues to New Selective Allosteric Inhibitor of Aurora B Kinase
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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.
- 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
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p. 1197 - 1219
(2021/02/05)
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- Sonogashira Couplings Catalyzed by Fe Nanoparticles Containing ppm Levels of Reusable Pd, under Mild Aqueous Micellar Conditions
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Nanoparticles derived from FeCl3 containing the ligand XPhos and only 500 ppm Pd effect Sonogashira couplings in water between rt and 45 °C. The entire aqueous reaction medium can be easily recycled using an "in-flask" extraction. Several tande
- Handa, Sachin,Jin, Bo,Bora, Pranjal P.,Wang, Ye,Zhang, Xiaohua,Gallou, Fabrice,Reilly, John,Lipshutz, Bruce H.
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p. 2423 - 2431
(2019/03/08)
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- Ppm Pd-catalyzed, Cu-free Sonogashira couplings in water using commercially available catalyst precursors
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A new catalyst that derives from commercially available precursors for copper-free, Pd-catalyzed Sonogashira reactions at the sustainable ppm level of precious metal palladium under mild aqueous micellar conditions has been developed. Both the palladium pre-catalyst and ligand are commercially available, bench stable, and highly cost-effective. The catalyst is applicable to both aryl- and heteroaryl-bromides as educts. A wide range of functional groups are tolerated and the aqueous reaction medium can be recycled. An application to a key intermediate associated with an active pharmaceutical ingredient (ponatinib) is discussed.
- Jin, Bo,Gallou, Fabrice,Reilly, John,Lipshutz, Bruce H.
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p. 3481 - 3485
(2019/03/28)
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- Novel imidazo[1,2-b]diazine amide type Bcr-Abl kinase inhibitors and preparing method and applications thereof
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Novel imidazo[1,2-b]diazine amide type Bcr-Abl kinase inhibitors and a preparing method and applications thereof are disclosed. The general structure formula of the inhibitors is shown as a formula I. The invention also provides pharmaceutically acceptable salts and compositions including compounds of the formula I, and methods of utilizing the salts and the compositions to prepare medicines preventing and/or treating protein kinase abnormity related diseases, particularly medicines for diseases related to Bcr-Abl protein kinase activity abnormity.
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Paragraph 0050; 0051
(2017/12/09)
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- Method for synthesizing 3-iodoimidazo[1,2-b]pyrazine
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The invention relates to a method for synthesizing 3-iodoimidazo[1,2-b]pyrazine. 3-aminopyridazine, a chloroacetaldehyde aqueous solution and N-iodosuccinimide are used as raw materials. The ratio of the amount of substances of the 3-aminopyridazine to chloroacetaldehyde is 1:0.8-3.5. The ratio of the amount of substances of the 3-aminopyridazine to the N-iodosuccinimide is 1:0.65-2.1. In appropriate solvent, reacting is conducted at the temperature of 40-150 DEG C to generate a 3-iodoimidazo[1,2-b]pyrazine crude product, and a 3-iodoimidazo[1,2-b]pyrazine pure product is obtained after purification. According to the method, the raw materials can be obtained easily, the price is reasonable, and meanwhile no heavy metal and corrosive gases are used in the preparation reaction; reacting is moderate, no special requirement for reaction equipment exists, and production can be conducted through common corrosion resistance equipment. Besides, the reaction condition is moderate.
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Paragraph 0021
(2016/10/27)
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