Pyrazolo[3,4-<i>d</i>]pyrimidine Prodrugs: Strategic Optimization of the Aqueous Solubility of Dual Src/Abl Inhibitors

Vignaroli, Giulia; Zamperini, Claudio; Dreassi, Elena; Radi, Marco; Angelucci, Adriano; Sanità, Patrizia; Crespan, Emmanuele; Kiššová, Miroslava; Maga, Giovanni; Schenone, Silvia; Musumeci, Francesca; Botta, Maurizio

doi:10.1021/ml4000782

Cited by 17 publications

(24 citation statements)

References 32 publications

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“…aApparent permeability (Papp), representing the rate of passive penetration, was calculated as previously described [Vignaroli et al, ].…”

Section: Resultsmentioning

confidence: 99%

“…bMembrane retention (MR), expressed as the percentage of compound unable to reach the acceptor compartment, was calculated as previously reported [Vignaroli et al, ].…”

Section: Resultsmentioning

confidence: 99%

“…Three independent experiments were performed. Apparent permeability (Papp), representing the rate of passive penetration, and membrane retention (MR), expressed as the percentage of compound unable to reach the receiver compartment, were calculated as previously described [Vignaroli et al, ].…”

Section: Methodsmentioning

confidence: 99%

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SRC Family Kinase Inhibition Through a New Pyrazolo[3,4-d]Pyrimidine Derivative as a Feasible Approach for Glioblastoma Treatment

et al. 2015

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Glioblastoma (GB) is the most common and aggressive primary tumor of the central nervous system. The current standard of care for GB consists of surgical resection, followed by radiotherapy combined with temozolomide chemotherapy. However, despite this intensive treatment, the prognosis remains extremely poor. Therefore, more effective therapies are urgently required. Recent studies indicate that SRC family kinases (SFKs) could represent promising molecular targets for GB therapy. Here, we challenged four GB cell lines with a new selective pyrazolo[3,4-d]pyrimidine derivative SFK inhibitor, called SI221. This compound exerted a significant cytotoxic effect on GB cells, without significantly affecting non-tumor cells (primary human skin fibroblasts), as evaluated by MTS assay. We also observed that SI221 was more effective than the well-known SFK inhibitor PP2 in GB cells. Notably, despite the high intrinsic resistance to apoptosis of GB cells, SI221 was able to induce this cell death process in all the GB cell lines, as observed through cytofluorimetric analysis and caspase-3 assay. SI221 also exerted a long-term inhibition of GB cell growth and was able to reduce GB cell migration, as shown by clonogenic assay and scratch test, respectively. Moreover, through in vitro pharmacokinetic assays, SI221 proved to have a high metabolic stability and a good potential to cross the blood brain barrier, which is an essential requirement for a drug intended to treat brain tumors. Therefore, despite the need of developing strategies to improve SI221 solubility, our results suggest a potential application of this selective SFK inhibitor in GB therapy.

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“…aApparent permeability (Papp), representing the rate of passive penetration, was calculated as previously described [Vignaroli et al, ].…”

Section: Resultsmentioning

confidence: 99%

“…bMembrane retention (MR), expressed as the percentage of compound unable to reach the acceptor compartment, was calculated as previously reported [Vignaroli et al, ].…”

Section: Resultsmentioning

confidence: 99%

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SRC Family Kinase Inhibition Through a New Pyrazolo[3,4-d]Pyrimidine Derivative as a Feasible Approach for Glioblastoma Treatment

et al. 2015

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“…Due to the biologically importance of the pyrazolo[3,4-d]pyrimidine skeleton especially as antimicrobial agents (Burch 1968;Eweas et al 2012;Khobragade et al 2010), we focused on the synthesis of some novel 6-substituted 4-amino-pyrazolo[3,4-d]pyrimidines as potential prodrugs (Vignaroli et al 2013) using ethanolic sodium ethoxide solution. In vitro inhibitory effects of the synthesized compounds against seven gram-positive and -negative bacterial strains were evaluated via measuring inhibition zone diameter (IZD), and determining minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC).…”

Section: Introductionmentioning

confidence: 99%

Synthesis and in vitro antibacterial evaluation of 6-substituted 4-amino-pyrazolo[3,4-d]pyrimidines

et al. 2017

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Pyrazolo[3,pyrimidines are one of the most important classes of fused heterocyclic compounds which exhibit a broad range of biological and medicinal properties. They are known as anticancer, antifungal, antibacterial, antiviral and anti-inflammatory agents. In this study, some new 6-substituted 4-amino-pyrazolo[3,4-d]pyrimidine derivatives were prepared via reaction of 5-amino-3-methyl-1-phenyl-1H-pyrazole-4-carbonitrile with various nitriles in the presence of sodium ethoxide as catalyst. The inhibitory properties of synthesized compounds were studied according to CLSI guidelines against some pathogenic bacteria including four gram-positive strains (Streptococcus pyogenes, Staphylococcus aureus, Bacillus cereus and Bacillus subtilis subsp. spizizenii) and three gramnegative strains (Pseudomonas aeruginosa, Shigella flexneri and Salmonella enterica subsp. enterica). The antibacterial effects of all derivatives were compared with those of antibiotics belonging to different classes. The values were reported as inhibition zone diameter (IZD), minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC). The effect of substituents on the biological activity of derivatives was discussed as well. The inhibitory effect of compound 6a, was shown to be the most, with MIC values in the range of 32-4096 lg/mL. Since most of the synthesized compounds were effective against Streptococcus pyogenes and Pseudomonas aeruginosa, they can be considered as inhibitors of these two bacteria.

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“…Several strategies were applied to overcome this issue in recent years (i.e. introduction of hydrophilic moieties in solvent-exposed positions 42 , synthesis of prodrugs 43 and inclusion in cyclodextrins) 40 41 .…”

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confidence: 99%

Improvement of pyrazolo[3,4-d]pyrimidines pharmacokinetic properties: nanosystem approaches for drug delivery

Vignaroli

Calandro

Zamperini

et al. 2016

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Pyrazolo[3,4-d]pyrimidines are a class of compounds with a good activity against several cancer cell lines. Despite the promising anticancer activity, these molecules showed a poor aqueous solubility. This issue could threat the future development of pyrazolo[3,4-d]pyrimidines as clinical drug candidates. With the aim of improving their solubility profile and consequently their pharmacokinetic properties, we have chosen four compounds (1–4) on the base of their anti-neuroblastoma activity and we have developed albumin nanoparticles and liposomes for the selected candidates. Albumin nanoparticles and liposomes were prepared and characterized regarding size and ζ-potential distribution, polidispersity index, entrapment efficiency and activity against SH-SY5Y human neuroblastoma cell line. The most promising nanosystem, namely LP-2, was chosen to perform further studies: confocal microscopy, stability and drug release in physiological conditions, and biodistribution. Altogether, the obtained data strongly indicate that the encapsulation of pyrazolo[3,4-d]pyrimidines in liposomes represent an effective method to overcome the poor water solubility.

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Pyrazolo[3,4-d]pyrimidine Prodrugs: Strategic Optimization of the Aqueous Solubility of Dual Src/Abl Inhibitors

Cited by 17 publications

References 32 publications

SRC Family Kinase Inhibition Through a New Pyrazolo[3,4-d]Pyrimidine Derivative as a Feasible Approach for Glioblastoma Treatment

SRC Family Kinase Inhibition Through a New Pyrazolo[3,4-d]Pyrimidine Derivative as a Feasible Approach for Glioblastoma Treatment

Synthesis and in vitro antibacterial evaluation of 6-substituted 4-amino-pyrazolo[3,4-d]pyrimidines

Improvement of pyrazolo[3,4-d]pyrimidines pharmacokinetic properties: nanosystem approaches for drug delivery

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