Synthesis and Biological Evaluation of a New Family of STAT3 Inhibitors by a Diversity Oriented Approach Based on the Ugi-Multicomponent Reaction

Abstract STAT3 (Signal Transducer and Activator of Transcription 3) is a protein frequently hyperactivated in a wide range of tumors, and as such, it has emerged as a promising and relatively recent therapeutic target for the development of novel anticancer agents. In this framework, we have designed and synthesized a new family of STAT3 inhibitors using a diversity-oriented strategy centered on the Ugi multicomponent reaction, enabling rapid access to structurally varied molecular scaffolds. We subsequently evaluated their antiproliferative activity across eight different tumor cell lines, revealing that four of the 23 newly obtained compounds exhibit pharmacologically meaningful growth-inhibitory effects within the micromolar range of concentrations and displayed promising drug-like profiles. Taken together, these findings highlight the potential of our approach to generate effective STAT3-modulating chemotypes and underscore the value of multicomponent reactions in accelerating early-stage anticancer drug discovery.