Design, Synthesis, and In Vitro Antiproliferative Activity of 4,5,6-Trisubstituted 2-Aminopyrimidines as Potential TGF-β Inhibitors

Abstract

Signaling proteins involved in the TGF-β (transforming growth factor beta) pathway regulate cellular processes such as cell growth, division, differentiation, migration, invasion, and apoptosis. Due to the large contribution of the TGB-β signaling pathway to carcinogenesis, these proteins are promising oncotargets. Based on the literature data, we propose a new structural type of TGF-β receptor inhibitors that are 2-amino­pyrimidine derivatives. Two general approaches to their synthesis have been proposed, where the key step is the three-component Biginelli condensation producing the pyrimidine fragment. Sixteen new compounds have been synthesized, and their in vitro antiproliferative activity has been evaluated against a panel of tumor cell lines.