Design And Synthesis 2-(Substitutedpyridin-2-ylamino)-quinolin-8-ols

The urokinase plasminogen activator (uPA) system consists of the serine protease uPA, its glycolipid-anchoredreceptor, uPAR, and and iplasminogen activator inhibitor (PAI-Ⅰ, PAI-Ⅱ). It has been demonstrated as promising target for novel anticancer drug. An interaction between urokinase receptor (uPAR) on the surface of cancer cells andα5β1 integrin keeps a large proportion of theα5β1 integrin in a high-affinity and generates a signal transduction that activates ERK. In addition, the high-affinityα5β1 integrin mediates FN fibril formation which can suppress p38 activity. The combination of robust ERK activity and p38 inhibition generates a mitogenic signal that is potent enough to promote tumor growth. When the interaction between uPAR andα5β1 integrin was disrupted, ERK activity was inhibited and p38 increase. This low ERK/p38 activity can cause tumor cell dormacy.MS0012479,2-(pyridin-2-ylamino)-quinolin-8-ol, was found after vitual screenning which can bind to the specif site on uPAR that binds interginα5β1 integrin. In cell-based assy, MS0012479 can significantly inhibited ERK by disrupting the integrin/uPAR interaction and effectually disrupted FN-fibrils formation. A series of 2-(substituted pyridin-2-ylamino) quinolin-8-ols were designed and synthesized.15 of 17 compounds are new compounds which structures have been characterized by the application of 1H-NMR, MS and IR. The study of their ERK inhibition and FN-fibrils disruption are in progress.