- From Synthetic Simplified Marine Metabolite Analogues to New Selective Allosteric Inhibitor of Aurora B Kinase
-
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
-
p. 1197 - 1219
(2021/02/05)
-
- Synthesis method of ponatinib intermediate 3-acetenylimidazo [1, 2-b] pyridazine
-
The invention discloses a synthesis method of ponatinib intermediate 3-acetenylimidazo [1, 2-b] pyridazine. The synthesis method comprises the following steps: synthesizing a compound I from 3-pyridazinone and 2-chloroethylamine acid salt under an alkalin
- -
-
Paragraph 0034; 0035
(2020/04/22)
-
- HETEROARYL SUBSTITUTED AMINOPYRIDINE COMPOUNDS
-
Disclosed are compounds of Formula (I) Formula(I) or salts thereof, wherein HET is a heteroaryl selected from oxazolyl, pyrazolyl, imidazo[l,2-b]pyridazin-3-yl, and pyrazolo[l,5-a]pyrimidin-3-yl, wherein said heteroaryl is attached to the pyridinyl group in the compound of Formula (I) by a carbon ring atom in the heteroaryl and wherein said heteroaryl is substituted with zero to 2 Rb; and R1, R3, and Rb are define herein. Also disclosed are methods of using such compounds as modulators of IRAK4, and pharmaceutical compositions comprising such compounds. These compounds are useful in treating, preventing, or slowing inflammatory and autoimmune diseases, or in the treatment of cancer.
- -
-
Page/Page column 106; 107
(2017/01/09)
-
- Method for synthesizing 3-bromoimidazo[1,2-b]pyrazine
-
The invention relates to a method for synthesizing 3-bromoimidazo[1,2-b]pyrazine. 3-aminopyridazine, a chloroacetaldehyde aqueous solution and N-bromosuccinimide are used as raw materials. The ratio of the amount of substances of the 3-aminopyridazine to
- -
-
Paragraph 0024
(2016/12/01)
-
- Method for synthesizing 3-chloroimidazo[1,2-b]pyrazine
-
The invention relates to a method for synthesizing 3-chloroimidazo[1,2-b]pyrazine. 3-aminopyridazine, a chloroacetaldehyde aqueous solution and N-chlorosuccinimide are used as raw materials. The ratio of the amount of substances of the 3-aminopyridazine to chloroacetaldehyde is 1:0.75-3.0. The ratio of the amount of substances of the 3-aminopyridazine to the N-chlorosuccinimide is 1:0.9-2.3. In appropriate solvent, reacting is conducted at the temperature of 35-145 DEG C to generate a 3-chloroimidazo[1,2-b]pyrazine crude product, and a 3-chloroimidazo[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.
- -
-
Paragraph 0025
(2017/01/05)
-
- CAN-mediated oxidation of electron-deficient aryl and heteroaryl hydrazines and hydrazides
-
Aryl and heteroaryl hydrazines and hydrazides were successfully oxidised using CAN, deriving dehydrazinated products. The reaction pathway strongly depends on the nature of the substrate, resulting in the formation of hydrocarbons or alkoxy derivatives. When deuterated solvents such as methanol-d4 or acetonitrile-d3 were used, a regiospecific incorporation of deuterium was achieved. Georg Thieme Verlag Stuttgart.
- ?tefane, Bogdan,Polanc, Slovenko
-
scheme or table
p. 1279 - 1282
(2009/04/06)
-
- IMIDAZO[1,2-B]PYRIDAZINES FOR CORTICAL CHOLINERGIC DEFICIENCIES
-
The present invention relates to imidazo[1,2-b]-pyridazines having the formula: STR1 in which: R 1 represents hydrogen, a halogen atom, a C 1-C 4 alkoxy group or a C 1-C 4 alkyl group occupying one of the free positions of the benzene ring; R 2 represents
- -
-
-