Combining X-ray Crystallography and Molecular Modeling toward the Optimization of Pyrazolo[3,4-<i>d</i>]pyrimidines as Potent c-Src Inhibitors Active in Vivo against Neuroblastoma

Tintori, Cristina; Fallacara, Anna Lucia; Radi, Marco; Zamperini, Claudio; Dreassi, Elena; Crespan, Emmanuele; Maga, Giovanni; Schenone, Silvia; Musumeci, Francesca; Brullo, Chiara; Richters, André; Gasparrini, Francesca; Angelucci, Adriano; Festuccia, Claudio; Monache, Simona Delle; Rauh, Daniel; Botta, Maurizio

doi:10.1021/jm5013159

Cited by 58 publications

(76 citation statements)

References 57 publications

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“…1A) thanks to its favorable and previously characterized set of ADME and activity properties (13). The compound exhibited the ability to inhibit c-SRC tyrosine kinase in cell-free assays at micromolar concentration.…”

Section: Introductionmentioning

confidence: 99%

Suppression of SRC Signaling Is Effective in Reducing Synergy between Glioblastoma and Stromal Cells

Calgani

Vignaroli

Zamperini

et al. 2016

Molecular Cancer Therapeutics

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Glioblastoma cells efficiently interact with and infiltrate the surrounding normal tissue, rendering surgical resection and adjuvant chemo/radiotherapy ineffective. New therapeutic targets, able to interfere with glioblastoma's capacity to synergize with normal brain tissue, are currently under investigation. The compound Si306, a pyrazolo[3,4-d]pyrimidine derivative, selected for its favorable activity against SRC, was tested in vitro and in vivo on glioblastoma cell lines. In vivo, combination treatment with Si306 and radiotherapy was strongly active in reducing U-87 xenograft growth with respect to control and single treatments. The histology revealed a significant difference in the stromal compartment of tumoral tissue derived from control or radiotherapy-treated samples with respect to Si306-treated samples, showing in the latter a reduced presence of collagen and a-SMA-positive cells. This effect was paralleled in vitro by the capacity of Si306 to interfere with myofibroblastic differentiation of normal fibroblasts induced by U-87 cells. In the presence of Si306, TGF-b released by U-87 cells, mainly in hypoxia, was ineffective in upregulating a-SMA and b-PDGFR in fibroblasts. Si306 efficiently reached the brain and significantly prolonged the survival of mice orthotopically injected with U-87 cells. Drugs that target SRC could represent an effective therapeutic strategy in glioblastoma, able to block positive paracrine loop with stromal cells based on the b-PDGFR axis and the formation of a tumor-promoting microenvironment. This approach could be important in combination with conventional treatments in the effort to reduce tumor resistance to therapy. Mol Cancer Ther; 15(7); 1535-44. Ó2016 AACR.

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Section: Introductionmentioning

confidence: 99%

Suppression of SRC Signaling Is Effective in Reducing Synergy between Glioblastoma and Stromal Cells

Calgani

Vignaroli

Zamperini

et al. 2016

Molecular Cancer Therapeutics

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“…Pyrazolo [3,4-d] pyrimidine derivatives display a broad spectrum of biological properties, such as antiviral (Bektemirov et al, 1981), antibacterial (Rostamizadeh et al, 2013) and antitumor (Tintori et al, 2015). The present work is a continuation of our studies of pyrazolo [3,4-d]pyrimidine derivatives (El Hafi et al, 2017).…”

Section: Structure Descriptionmentioning

confidence: 70%

1-Methyl-4-phenyl-3-[4-(trifluoromethyl)phenyl]-1H-pyrazolo[3,4-d]pyrimidine

Hafi¹,

Boulhaoua²,

Lahmidi³

et al. 2018

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In the title molecule, C 19 H 13 F 3 N 4 , the pyrazolopyrimidine unit is slightly nonplanar [dihedral angle between the five-and six-membered rings = 3.03 (15) ]. In the crystal, offset head-to-tail -stacking interactions between pyrazolopyrimidine units [centroid-centroid separation = 3.665 (2) Å ] together with weak C-HÁ Á ÁN hydrogen bonds form stepped chains propagating along the caxis direction. The structure was refined as a two-component twin. Structure descriptionPyrazolo [3,4-d] pyrimidine derivatives display a broad spectrum of biological properties, such as antiviral (Bektemirov et al., 1981), antibacterial (Rostamizadeh et al., 2013 and antitumor (Tintori et al., 2015). The present work is a continuation of our studies of pyrazolo [3,4-d]pyrimidine derivatives (El Hafi et al., 2017).In the title molecule (Fig. 1), the pyrazolopyrimidine unit is slightly non-planar as indicated by the dihedral angle of 3. 03 (15) between the mean planes of the five-and sixmembered rings. The plane of the C7-C12 benzene ring bearing the CF 3 substituent is inclined to the pyrazole moiety by 31.98 (16) while the plane of the C14-C19 benzene ring is inclined by 50.69 (14) to that of the pyrimidine ring. In the crystal, offset, head-to-tail -stacking interactions between adjacent pyrazolopyrimidine units reinforced by weak, complementary C6-H6BÁ Á ÁN1 hydrogen bonds form centrosymmetric dimers, which are connected into stepped chains along the c axis direction by weak, complementary C4-H4Á Á ÁN2 hydrogen bonds (Table 1 and Figs. 2 and 3). The centroid-centroid distance for the -stacking interaction is 3.665 (2) Å .

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“…Schenone et al have reported a wide library of potent KIs endowed with a pyrazolo[3,4-d] pyrimidine scaffold [17,18]. Many of these compounds are active on different cancer cell lines, and some also showed activity in in vivo mouse models [19,20]. Among the members of this library, compound SI214 ( Figure 1a) is a potent Src inhibitor (K i = 90 nM) and possesses a considerable antiproliferative effect on the SH-SY5Y Neuroblastoma cell line (IC 50 = 80 nM).…”

Section: Introductionmentioning

confidence: 99%

Starch/Poly(glycerol-adipate) Nanocomposites: A Novel Oral Drug Delivery Device

et al. 2020

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Biocompatible and bio-based materials are an appealing resource for the pharmaceutical industry. Poly(glycerol-adipate) (PGA) is a biocompatible and biodegradable polymer that can be used to produce self-assembled nanoparticles (NPs) able to encapsulate active ingredients, with encouraging perspectives for drug delivery purposes. Starch is a versatile, inexpensive, and abundant polysaccharide that can be effectively applied as a bio-scaffold for other molecules in order to enrich it with new appealing properties. In this work, the combination of PGA NPs and starch films proved to be a suitable biopolymeric matrix carrier for the controlled release preparation of hydrophobic drugs. Dynamic Light Scattering (DLS) was used to determine the size of drug-loaded PGA NPs, while the improvement of the apparent drug water solubility was assessed by UV-vis spectroscopy. In vitro biological assays were performed against cancer cell lines and bacteria strains to confirm that drug-loaded PGA NPs maintained the effective activity of the therapeutic agents. Dye-conjugated PGA was then exploited to track the NP release profile during the starch/PGA nanocomposite film digestion, which was assessed using digestion models mimicking physiological conditions. The collected data provide a clear indication of the suitability of our biodegradable carrier system for oral drug delivery.

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Combining X-ray Crystallography and Molecular Modeling toward the Optimization of Pyrazolo[3,4-d]pyrimidines as Potent c-Src Inhibitors Active in Vivo against Neuroblastoma

Cited by 58 publications

References 57 publications

Suppression of SRC Signaling Is Effective in Reducing Synergy between Glioblastoma and Stromal Cells

Suppression of SRC Signaling Is Effective in Reducing Synergy between Glioblastoma and Stromal Cells

1-Methyl-4-phenyl-3-[4-(trifluoromethyl)phenyl]-1H-pyrazolo[3,4-d]pyrimidine

Starch/Poly(glycerol-adipate) Nanocomposites: A Novel Oral Drug Delivery Device

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