Back to Search
Start Over
Novel tetrasubstituted 5-Arylamino pyrazoles able to interfere with angiogenesis and Ca2+ mobilization.
- Source :
-
European Journal of Medicinal Chemistry . Oct2024, Vol. 276, pN.PAG-N.PAG. 1p. - Publication Year :
- 2024
-
Abstract
- In the last years, 5-pyrazolyl ureas and 5-aminopyrazoles have been investigated for their antiangiogenetic properties and their potential interaction with the ubiquitous Ca2+ binding protein Calreticulin. Based on the structure of the active compounds I and GeGe-3 , novel 5-arylamino pyrazoles 2 and 3 were synthesized through a stepwise procedure. In MTT assays, all the new derivatives proved to be non-cytotoxic against eight different tumor cell lines, normal fibroblasts, and endothelial cells. Furthermore, selected derivatives showed relevant antiangiogenetic properties, resulting more effective than reference molecules I and GeGe-3 in inhibiting HUVEC endothelial tube formation. 5-Arylamino pyrazoles 2a and 2d were identified as the most interesting compounds and significantly prevented tube formation of tumor secretome-stimulated HUVEC. Furthermore, the two compounds inhibited HUVEC migration in wound healing assay and altered cell invasion capability. Additionally, 2a and 2d strongly affected Ca2+ mobilization and cytoskeletal organization of HUVEC cells, being as active as the reference compound GeGe-3. Differently from previous studies, molecular docking simulations suggested a poor affinity of 2a towards Calreticulin, one of the interacting partners of the lead compound GeGe-3. Collectively, this new amino-pyrazole library further extends the structure-activity relationships of the previously prepared derivatives and confirmed the biological attractiveness of this chemical scaffold as antiangiogenetic agents. [Display omitted] • To extend SARs of antiangiogenic compounds I and GeGe- 3, aminopyrazole derivatives 2 and 3 were designed and synthesized. • Selected compounds inhibited the endothelial cells tube formation without showing any cytotoxicity. • Pyrazoles 2a and 2d showed antiangiogenetic properties on unstimulated and tumor secretome-stimulated HUVEC cells. • 2a and 2d interfered with Calcium mobilization and F-actin organization in HUVEC. [ABSTRACT FROM AUTHOR]
Details
- Language :
- English
- ISSN :
- 02235234
- Volume :
- 276
- Database :
- Academic Search Index
- Journal :
- European Journal of Medicinal Chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 178886162
- Full Text :
- https://doi.org/10.1016/j.ejmech.2024.116715