Amidic Coupling in the Synthesis of Pyrroloquinoline 4‐ and 9‐Carboxamides as Potential STAT3 Inhibitors

Abstract

AbstractThe work describes the synthesis and characterization of a small series of pyrroloquinoline carboxamide derivatives considered on the STX‐0119 model, a known inhibitor of STAT3 (Signal transducers and activators of transcription 3) by interacting with SH2 domain. The scope was to learn SARs and possibly obtain active new compounds for cancer therapy. To this aim, the quinoline scaffold of the lead compound STX‐0119 was modified into the pyrroloquinoline tricycle to obtain two subsets of carboxamide derivatives showing different angular geometry 3H‐pyrrolo[3, 2‐f] and 7H‐pyrrolo[2, 3‐h]quinolines. Successful synthesis of thirty compounds was carried out, adopting methods using both convergent and linear pathways. Amidic coupling chemistry was applied to pyrroloquinoline carboxylic acids to generate the desired carboxamides of aromatic and aliphatic primary and secondary amines. Full physico‐chemical characterization including predicted LogP and LogD of all compounds was accomplished. The biological screening of antiproliferative activity against three human tumor cell lines by MTT test revealed low or no activity.