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

The TGF-β signaling cascade is a regulator of cellular processes such as growth, division, differentiation, migration, invasion and apoptosis. Due to the deep involvement of this signaling pathway in the processes of carcinogenesis, participants in the cascade are promising oncology targets. Based on literature data, we have proposed a new structural class of TGF-β receptor inhibitors based on 2-aminopyrimidines. Two universal approaches to their synthesis have been proposed; the key transformation is the three-component Biginelli condensation aimed at the formation of a pyrimidine fragment. Using the developed synthetic approaches, 16 new compounds were obtained, for which antiproliferative activity in vitro was established against a number of tumor cell lines.