Biological evaluation of pyrazolyl-urea and dihydro-imidazo-pyrazolyl-urea derivatives as potential anti-angiogenetic agents in the treatment of neuroblastoma

Abstract

Pyrazolyl-urea and dihydro-imidazo-pyrazolyl-urea compounds (STIRUR 13, STIRUR 41 and BUR 12) have been demonstrated to exert a strong inhibitory effect on interleukin 8 or N-formyl-methionyl-leucyl-phenylalanine-induced chemotaxis of human neutrophils. Since the migration of cancer cells is comparable to that of neutrophils, the purpose of this study is to evaluate the biological effect of STIRUR 13, STIRUR 41 and BUR 12 on ACN and HTLA-230, two neuroblastoma (NB) cell lines with different degree of malignancy. HTLA-230 cells, stage-IV NB cells, have high plasticity and can serve as progenitors of endothelial cells. The results herein reported show that the three tested compounds were not cytotoxic for both NB cells and did not alter their clonogenic potential. However, all compounds were able to inhibit the ability of HTLA-230 to form vascular-like structures. On the basis of these findings, pyrazolyl-urea and dihydro-imidazo-pyrazolyl-urea derivatives could be proposed as agents potentially effective in counteracting NB malignancy by inhibiting cell migration and tumor angiogenesis which represent important hallmarks responsible for cancer survival and progression.

New Series of Pyrazoles and Imidazo-Pyrazoles Targeting Different Cancer and Inflammation Pathways

“…In addition, we tested, as lead compound, previously synthetized BUR 12 ( 3a , Figure 2 ) [ 21 ], endowed with the same imidazo-pyrazole scaffold of compounds 7–9 and similar fluoro-urea moiety of derivative 6 . BUR 12 recently emerged as a new interesting compound able to counteract the ability of cancer cell lines (HTLA-230) to form capillary-like structures [ 22 ]. Our aim is to confirm if this nucleus could be as interesting as antiangiogenic compound, as previously reported.…”

“…Compounds 9c – g , more strictly related to the previous 2 and 3 and endowed with an amide function at position 6 of the imidazo-pyrazole scaffold, showed less activity (IC 50 values between 80 and 300 μM), but as expected, they are able to interfere with p38MAPK pathways in platelet and also in VEGF-stimulated HUVEC cells. Particularly compound 9e emerged as the most interesting of the series, resulting in being more active than BUR 12 , previously reported as a promising antiangiogenic derivative [ 22 ].…”

“…In the past, we synthesized different pyrazole and imidazo-pyrazole compounds able to inhibit neutrophil chemotaxis by interfering with ERK1/2, AKT and p38MAPK phosphorylation [ 19 , 20 ], and to block the angiogenesis process, acting on p38MAPK and PI3K signaling in VEGF-stimulated Human Umbilical Vein Endothelial cells (HUVEC) and in neuroblastoma cell lines [ 21 , 22 ] ( Figure 1 , compounds 1–3 ).…”

Amino-Pyrazoles in Medicinal Chemistry: A Review

“…Pyrazole-containing molecules display a broad range of biological activities, including anti-inflammatory [5,6], anticonvulsant [7], anticancer [8,9], antiviral [10], antidepressant [11], analgesic [12], antibacterial [13][14][15], antifungal [16], and selective enzyme inhibition [16,17]. Moreover, several pyrazole compounds are currently used in clinics as antiinflammatory and analgesic (Celecoxib, Tepoxalin, and Betazole), anticancer (Crizotimib), antiobesity (Surinabant and Difenamizole), antidepressant, and tranquilliser (Fezolamine and Mepiprazole) drugs, thus confirming the pharmacological value of this heterocycle.…”

Investigating the Therapeutic Effects of Small Molecule Imipridones In Pediatric Neuroblastoma. (c2020)

“…Consequently, it is suggested that NB is highly susceptible to anti-angiogenic treatment (Weinstein et al, 2003). An example of anti-angiogenic agent is the Pyrazolyl-urea compound STIRUR 13 which demonstrated strong inhibition of IL-8 induced neutrophil migration (Marengo et al, 2020). It is important to note that IL-8 is a chemokine that stimulates the movement of neutrophils and is found highly expressed in a range of tumor types where it plays a crucial role in angiogenesis and vascular simulation (Angara et al, 2018).…”