Abstract
A series of Phe-Gly dipeptide-derived piperazinones containing an aromatic urea moiety and a basic amino acid has been synthesized and evaluated as inhibitors of human platelet aggregation induced by the PAR1 agonist SFLLRN and as cytotoxic agents in human cancer cells. The synthetic strategy involves coupling of a protected basic amino acid benzyl amide to 1,2- and 1,2,4-substituted-piperazinone derivatives, through a carbonylmethyl group at the N1-position, followed by formation of an aromatic urea at the exocyclic moiety linked at the C2 position of the piperazine ring and removal of protecting groups. None of the compounds showed activity in the biological evaluation.
Highlights
Most cellular effects of thrombin are mediated by activation of the protease-activated receptor 1(PAR1) [1,2]
Activation of PAR1 by thrombin involves the proteolytic cleavage of the N-terminal exodomain between Arg41 and Ser42
We focused our attention on the piperazine ring, since this system is recognized as a privileged scaffold, due to its recurrent presence in biological active compounds [20,21]
Summary
Most cellular effects of thrombin are mediated by activation of the protease-activated receptor 1(PAR1) [1,2]. Numerous studies have shown that PAR1 is overexpressed in invasive and Molecules 2014, 19 metastatic tumors and that its expression levels directly correlate with the degree of invasiveness of the cancer [8,9,10,11,12,13] Based on these facts, this receptor is starting to be considered a promising target for cancer therapy, in the search of angiogenesis inhibitors [2]. Activation of PAR1 by thrombin involves the proteolytic cleavage of the N-terminal exodomain between Arg and Ser42 This cleavage unveils the recognition sequence SFLLRN that acts as a tethered ligand, auto-activating the receptor [14].
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