Here, we describe the synthesis and biological characterization of 32 novel phenylalanine and leucine dipeptides modified on both the N and C termini by salicylic acid and aromatic or alicyclic amines, respectively. All compounds displayed antiproliferative activity in the tested cancer cell lines and eight of the compounds exhibited single digit micromolar GI50 values. Treated cells rapidly detached from surface of tissue culture dishes and we found that focal adhesion kinase (FAK), p130CAS and paxillin, which are important regulators of cell adhesion, were dephosphorylated at Y397, Y410 and Y118, respectively. The most potent compound reduced proliferation in the HCT-116 cell line in a dose-dependent manner, as shown by a decrease in 5-bromo-2'-deoxyuridine incorporation into DNA. Furthermore, this compound increased the levels of several apoptotic markers, including activated caspases, and increased site-specific poly-(ADP-ribose)polymerase (PARP) cleavage.

Department of Cell Biology Charles University Viničná 7 12800 Prague Czech Republic; Biotechnology and Biomedicine Centre of the Academy of Sciences and Charles University Průmyslová 595 25242 Vestec u Prahy Czech Republic

Institute of Organic Chemistry and Technology Faculty of Chemical Technology University of Pardubice Studentská 95 532 10 Pardubice Czech Republic

Laboratory of Growth Regulators Palacky University and Institute of Experimental Botany The Czech Academy of Sciences Šlechtitelů 27 78371 Olomouc Czech Republic

Laboratory of Growth Regulators Palacky University and Institute of Experimental Botany The Czech Academy of Sciences Šlechtitelů 27 78371 Olomouc Czech Republic; Institute of Molecular and Translational Medicine Faculty of Medicine and Dentistry Palacký University Hněvotínská 5 77900 Olomouc Czech Republic

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Study of Biological Activities and ADMET-Related Properties of Salicylanilide-Based Peptidomimetics