1. Academic Validation
  2. Novel 5-aminopyrazoles endowed with anti-angiogenetic properties: Design, synthesis and biological evaluation

Novel 5-aminopyrazoles endowed with anti-angiogenetic properties: Design, synthesis and biological evaluation

  • Eur J Med Chem. 2023 Nov 15;260:115727. doi: 10.1016/j.ejmech.2023.115727.
Matteo Lusardi 1 Bernhard Wehrle-Haller 2 Adama Sidibe 2 Marco Ponassi 3 Erika Iervasi 3 Camillo Rosano 3 Chiara Brullo 1 Andrea Spallarossa 4
Affiliations

Affiliations

  • 1 Department of Pharmacy, Section of Medicinal Chemistry, Università degli Studi di Genova, Viale Benedetto XV 3, I-16132, Genova, Italy.
  • 2 Department of Cell Physiology and Metabolism, University of Geneva, Rue Michel-Servet 1, 1211, Geneva, Switzerland.
  • 3 IRCCS Ospedale Policlinico San Martino, Proteomics and Mass Spectrometry Unit, L.go. R. Benzi, 10, 16132, Genova, Italy.
  • 4 Department of Pharmacy, Section of Medicinal Chemistry, Università degli Studi di Genova, Viale Benedetto XV 3, I-16132, Genova, Italy. Electronic address: [email protected].
Abstract

The promising anti-angiogenetic properties of previously synthesized pyrazolyl ureas provided the rationale for the synthesis of novel 5-aminopyrazoles 2-5, differently decorated on the pyrazole nucleus. All the derivatives were tested by MTT assays and proved to be non-cytotoxic against eight different tumor cell lines and normal fibroblasts. An EdU proliferation assay was carried out on human foreskin fibroblasts and VEGF stimulated human umbilical vein endothelial cells which confirmed the absence of cytotoxicity of the compounds on human cells up to 20 μM concentration. To evaluate the influence of the newly synthesized pyrazoles on MAPK and PI3K signaling pathways, the phosphorylation of ERK1/2 and Akt was analyzed by Western blots from HFF and HUVEC cell lysates stimulated with growth factors in the presence or absence of the compounds. Pyrazoles 3b and 3c showed a significant inhibition of Akt phosphorylation in both tested cell lines with lower phosphorylation levels than the reference compound GeGe-3 in HUVEC. Furthermore, derivatives 2 and 3 appeared to strongly affect the migration of HFF cells in a wound healing assay, confirming their potential ability to interfere with the angiogenesis process. The new pyrazole library extends the structure-activity relationships of the previously isolated compounds and highlights the attractiveness of this chemical class for pathological cell migration and angiogenesis.

Keywords

5-Aminopyrazoles; Akt phosphorylation; Angiogenesis; Cell migration; Cell proliferation; ERK1/2 phosphorylation.

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