Novel 5-arylamino pyrazoles able to interfere with angiogenesis and Ca2+ homeostasis

In the last years, several pyrazole derivatives have been reported as antiangiogenetic agents. In particular, 5-phenylamino pyrazole I proved to inhibit Akt phosphorylation in human foreskin fibroblasts (HFF) and human umbilical vein endothelial cells (HUVEC) and to interfere with HFF migration in wound healing assays, being more active than our reference compound GeGe-3. In functional proteomics investigations on HUVEC, GeGe-3 proved to affect intracellular Ca2+ levels in a dose dependent fashion through the interaction with calreticulin (CALR). Docking simulations helped to elucidate the molecular basis of pyrazole I/CALR interaction. To further extend the SARs of derivatives I, novel 5-arylamino pyrazoles II and III were designed and synthesized. The new molecules share with I and GeGe-3 the N1- hydroxyalkyl or hydroxy phenyl chains and the free amino group at position five of the ring. Differently from their parents’ compounds, the novel derivatives presented variously substituted aryl-amino moieties at position three. All the isolated compounds were preliminary screened by MTT assays to prove the absence of cytotoxicity against normal human cells. Additionally, the effects on angiogenesis and calcium mobilization were evaluate in vitro on HUVEC. Selected derivatives showed improved antiangiogenic activities compared to GeGe-3 and I.