Design, Synthesis, and Evaluation of Dasatinib-Amino Acid and Dasatinib-Fatty Acid Conjugates as Protein Tyrosine Kinase Inhibitors.

ABSTRACT: 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 IC₅₀ values of 4.4, <0.25, and <0.45 nm against Csk, Src, and Abl kinases, respectively. The highest selectivity ratio obtained in our study, 91.4 Csk/Src, belonged to compound 18 (Das-C₁₀ ) with an IC₅₀ value 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 l

SUBMITTER: Tiwari RK 

PROVIDER: S-EPMC5224969 | biostudies-literature | 2017 Jan

REPOSITORIES: biostudies-literature