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

ABSTRACT: 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.

SUBMITTER: Vignaroli G

PROVIDER: S-EPMC4761914 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Synthesis and Antibacterial Evaluation of New Pyrazolo[3,4-d]pyrimidines Kinase Inhibitors.

Project description:Pyrazolo[3,4-d]pyrimidines represent an important class of heterocyclic compounds well-known for their anticancer activity exerted by the inhibition of eukaryotic protein kinases. Recently, pyrazolo[3,4-d]pyrimidines have become increasingly attractive for their potential antimicrobial properties. Here, we explored the activity of a library of in-house pyrazolo[3,4-d]pyrimidines, targeting human protein kinases, against Staphylococcus aureus and Escherichia coli and their interaction with ampicillin and kanamycin, representing important classes of clinically used antibiotics. Our results represent a first step towards the potential application of dual active pyrazolo[3,4-d]pyrimidine kinase inhibitors in the prevention and treatment of bacterial infections in cancer patients.

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AuNP Pyrazolo[3,4-d]pyrimidine Nanosystem in Combination with Radiotherapy against Glioblastoma.

Project description:Gold-nanoparticle (AuNP)-conjugated drugs represent a promising and innovative antitumor therapeutic approach. In our study, we describe the design, the synthesis, the preparation, and the characterization of AuNPs conjugated with the pyrazolo[3,4-d]pyrimidine derivative SI306, a c-Src inhibitor. AuNPs-SI306 showed a good loading efficacy (65%), optimal stability in polar media and in human plasma, and a suitable morphological profile: a ζ-potential of -43.9 mV, a nanoparticle diameter of 48.6 nm, and a 0.441 PDI value. The antitumoral activity of AuNPs-SI306 was evaluated in vitro in the glioblastoma model, by the low-density growth assay, and also in combination with radiotherapy (RT). Results demonstrated that AuNPs had a basal radiosensitization ability and that AuNPs-SI306, when used in combination with RT, were more effective in inhibiting tumor cell growth with respect to AuNPs and free SI306.

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One-Flask Synthesis of Pyrazolo[3,4-d]pyrimidines from 5-Aminopyrazoles and Mechanistic Study.

Project description:A novel one-flask synthetic method was developed in which 5-aminopyrazoles were reacted with N,N-substituted amides in the presence of PBr₃. Hexamethyldisilazane was then added to perform heterocyclization to produce the corresponding pyrazolo[3,4-d]pyrimidines in suitable yields. These one-flask reactions thus involved Vilsmeier amidination, imination reactions, and the sequential intermolecular heterocyclization. To study the reaction mechanism, a series of 4-formyl-1,3-diphenyl-1H-pyrazol-5-yl-N,N-disubstituted formamidines, which were conceived as the chemical equivalent of 4-(iminomethyl)-1,3-diphenyl-1H-pyrazol-5-yl-formamidine, were prepared and successfully converted into pyrazolo[3,4-d]pyrimidines. The experiments demonstrated that the reaction intermediates were the chemical equivalents of 4-(iminomethyl)-1,3-diphenyl-1H-pyrazol-5-yl)formamidines. The rate of the reaction could be described as being proportional to the reactivity of amine reactants during intermolecular heterocyclization, especially when hexamethyldisilazane was used.

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A convenient four-component one-pot strategy toward the synthesis of pyrazolo[3,4-d]pyrimidines.

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Plasmin-Binding Tripeptide-Decorated Liposomes Loading Pyrazolo[3,4-d]pyrimidines for Targeting Hepatocellular Carcinoma.

Project description:Hepatocellular carcinoma (HCC) is one of the most fatal cancer types worldwide. HCC cells were proved to overexpress c-Src and Sgk1, a tyrosine and a serine-threonine kinase, respectively, whose role is crucial for the development and progression of the tumor. Pyrazolo[3,4-d]pyrimidine derivatives are a class of tyrosine kinase inhibitors that have shown good activity against HepG2. HCC cells were also proved to overexpress plasmin, which is localized on the cell surface bound to its receptors. In this study, a tripeptide with sequence d-Ala-Phe-Lys, which binds a specific reactive site of plasmin, was synthesized and characterized. This tripeptide was used to decorate liposomes encapsulating three selected pyrazolo[3,4-d]pyrimidines. Liposomes bearing tripeptide have been characterized, not showing remarkable differences with respect to the corresponding tripeptide-free liposomes. In vitro HepG2 cell uptake profiles and cytotoxicities showed that the presence of the tripeptide on the liposomal membrane surface improves the cell-penetrating ability of liposomes and increases the activity of two of the three tested compounds.

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One-pot synthesis of novel 1H-pyrimido[4,5-c][1,2]diazepines and pyrazolo[3,4-d]pyrimidines.

Project description:Novel 1H-pyrimido [4,5-c][1,2]diazepines 3 & 4 and pyrazolo [3,4-d]pyrimidines 6 were regioselectively synthesised by the reaction of 1,3-dimethyl-6-hydrazinouracils 1 with various alpha,beta-unsaturated compounds 2 and alpha-ketoalkynes 8 in excellent yields.

| S-EPMC1470455 | biostudies-literature

Four-component bicyclization approaches to skeletally diverse pyrazolo[3,4-b]pyridine derivatives.

Project description:A novel four-component bicyclization strategy has been established, allowing a flexible and practical approach to 37 examples of multicyclic pyrazolo[3,4-b]pyridines from low-cost and readily accessible arylglyoxals, pyrazol-5-amines, aromatic amines, 4-hydroxy-6-methyl-2H-pyran-2-one, and cyclohexane-1,3-diones. The polysubstituted cyclopenta[d]pyrazolo[3,4-b]pyridines were stereoselectively synthesized through a microwave-assisted special [3+2+1]/[3+2] bicyclization with good control of the spatial configuration of exocyclic double bonds. The novel [3+2+1]/[2+2+1] bicyclization resulted in 17 examples of unreported pyrazolo[3,4-b]pyrrolo[4,3,2-de]quinolones. Reasonable mechanisms for forming two new types of multicyclic pyrazolo[3,4-b]pyridines are also proposed.

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New Three-Component Bicyclization Leading to Densely Functionalized Pyrazolo[3,4-d]thiazolo[3,2-a]pyrimidines.

Project description:A novel three-component bicyclization for the efficient synthesis of densely functionalized pyrazolo[3,4-d]thiazolo[3,2-a]pyrimidines has been established from readily accessible aryl aldehydes, α-thiocyanate ketones and pyrazol-5-amines. The reaction pathway involves nucleophilic addition/5-exo-trig /6-endo-trig bicyclization sequence, resulting in continuous multiple bond-forming events including C-N and C-C bonds to rapidly a molecular complexity.

| S-EPMC5489242 | biostudies-literature

Biological Evaluation and Molecular Docking with In Silico Physicochemical, Pharmacokinetic and Toxicity Prediction of Pyrazolo[1,5-a]pyrimidines.

Project description:Pyrazolo[1,5-a]pyrimidines 5a-c, 9a-c and 13a-i were synthesized for evaluation of their in vitro antimicrobial properties against some microorganisms and their immunomodulatory activity. The biological activities of pyrazolo[1,5-a]pyrimidines showed that the pyrazolo[1,5-a]pyrimidines (5c, 9a, 9c, 13a, 13c, 13d, 13e and 13h) displayed promising antimicrobial and immunomodulatory activities. Studying the in silico predicted physicochemical, pharmacokinetic, ADMET and drug-likeness properties for the pyrazolo[1,5-a]pyrimidines 5a-c, 9a-c and 13a-i confirmed that most of the compounds (i) were within the range set by Lipinski's rule of five, (ii) show higher gastrointestinal absorption and inhibition of some CYP isoforms, and (iii) have a carcinogenicity test that was predicted as negative and hERG test that presented medium risk. Moreover, the molecular docking study demonstrated that the compounds 5c, 9a, 9c, 13a, 13c, 13d, 13e and 13h are potent inhibitors of 14-alpha demethylase, transpeptidase and alkaline phosphatase enzymes. This study could be valuable in the discovery of a new series of drugs.

| S-EPMC7144935 | biostudies-literature

Pyrazolo[3,4-d]pyrimidines as sigma-1 receptor ligands for the treatment of pain. Part 1: 4-acylamino derivatives.

Project description:The synthesis of a new series of 4-acylaminopyrazolo[3,4-d]pyrimidines active on the sigma-1 receptor (?1R) is reported. Compounds were efficiently prepared using a two to three step process starting from commercially available 1H-pyrazolo[3,4-d]pyrimidin-4-amine. A SAR study shows that the ?1R requires the presence of relatively highly lipophilic substituents at opposite sides of the central scaffold, while selectivity versus the ?2R can be improved by shortening the distance of the basic nitrogen to it. Compound 9a was among the most active and selective in vitro derivatives and exhibited potent antinociceptive properties in several pain models in mice, indicating its antagonistic behaviour.

| S-EPMC6072305 | biostudies-other

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