1245157-85-0Relevant articles and documents
Design, Synthesis, and Evaluation of Dasatinib–Amino Acid and Dasatinib–Fatty Acid Conjugates as Protein Tyrosine Kinase Inhibitors
Tiwari, Rakesh K.,Brown, Alex,Sadeghiani, Neda,Shirazi, Amir Nasrolahi,Bolton, Jared,Tse, Amanda,Verkhivker, Gennady,Parang, Keykavous,Sun, Gongqin
, p. 86 - 99 (2017)
Derivatives of the tyrosine kinase inhibitor dasatinib were synthesized by esterification with 25 carboxylic acids, including amino acids and fatty acids, thereby extending the drug to interact with more diverse sites and to improve specificity. The dasatinib–l-arginine derivative (Das-R, 7) was found to be the most potent of the inhibitors tested, with IC50values of 4.4, 10) with an IC50value of 3.2 μm for Csk compared with 35 nm for Src. Furthermore, many compounds displayed increased selectivity toward Src over Abl. Compounds 15 (Das–glutamic acid) and 13 (Das–cysteine) demonstrated the largest gains (10.2 and 10.3 Abl/Src IC50ratios). Das-R (IC50=2.06 μm) was significantly more potent than the parent dasatinib (IC50=26.3 μm) against Panc-1 cells, whereas both compounds showed IC5051.2 pm against BV-173 and K562 cells. Molecular modeling and binding free energy simulations revealed good agreements with the experimental results and rationalized the differences in selectivity among the studied compounds. Integration of experimental and computational approaches in the design and biochemical screening of dasatinib derivatives facilitated rational engineering and diversification of the dasatinib scaffold, providing useful insight into mechanisms of kinase selectivity.
Preparation method of Dasatinib
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, (2019/02/10)
The invention provides a preparation method of Dasatinib. 2-Bromothiazole-5-formic acid and 2-methyl-4-amino-6-cloro pyridine are adopted as raw materials, a first-time substitution reaction is performed, the raw materials and 4-(2-acetyl oxyl) Ethylpiperazine are subjected to a second-time substitution reaction to prepare 2-[[6-[4-(2-acetyloxy ethyl)-1-piperazinyl]-2-methl-4-pyrimidyl]amino]-5-Febuxostat; then, the product and an acylating chlorination reagent are subjected to an acylating chlorination reaction and subjected to an amidation reaction with 2-cholo-6-methylaniline, and finally ahydrolysis reaction is performed to remove acetyl to prepare dasatinib. The raw materials are cheap and easy to obtain and low in cost; the technological process is simple, operation is safe and easy, technological wastewater generation amount is small, and the method is environmentally friendly; raw materials and intermediate products stability is suitable, the reaction activity and selectivityare high, reaction conditions are easy to obtain, side reactions are few, the manufactured dasatinib contains few impurities, the purity and yield are high, and industrial production of dasatinib is facilitated.
SYNTHESIS PROCESS OF DASATINIB AND INTERMEDIATE THEREOF
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, (2013/03/26)
Synthesis process of dasatinib is disclosed, which includes the step of reacting the compound of formula I with that of formula II to obtain the compound of formula III. Also disclosed is the compound of formula III which is used as an intermediate for synthesizing dasatinib. The substituents of R1, R2, R3 or R4 in formulae I, II or III are defined as in the description.
SYNTHESIS PROCESS OF DASATINIB AND INTERMEDIATE THEREOF
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, (2013/02/27)
Synthesis process of dasatinib is disclosed, which includes the step of reacting the compound of formula I with that of formula II to obtain the compound of formula III. Also disclosed is the compound of formula III which is used as an intermediate for synthesizing dasatinib. The substituents of R1, R2, R3 or R4 in formulae I, II or III are defined as in the description.
