Dasatinib is an orally active non-selective tyrosine kinase inhibitor that is used for treatment of adult chronic myeloid leukemia and Philadelphia positive acute lymphoblastic leukemia. Herein, dasatinib-amino acid conjugates were synthesized and evaluated for comparative tyrosine kinase inhibition and anticancer activities. Dasatinib was reacted with Boc-protected N-terminal amino acids, followed by Boc deprotection to afford 15 dasatinib-amino acid conjugates. Compounds were screened against Abl, Csk, and Src. IC50 values of selected derivatives illustrated the capacity to modulate dasatinib by at least ten-fold. Src IC50 values ranged from 0.25�6.6 nM. Dasatinib-arginine derivatives showed higher selectivity towards Abl compared to Csk and Src, and exhibited slightly higher inhibition activity than dasatinib. On the other hand, introducing glutamic acid and cysteine residues reduced the inhibition activity significantly for all three kinases. All compounds inhibited the cell proliferation of SK-OV-3 and CCRF-CEM cells similar to dasatinib at a concentration of 1 �M.

Synthesis and evaluation of dasatinib amino acid derivatives for their anticancer and protein tyrosine kinase activity

244th National Meeting (2012)

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