Novel pyrazolo[3,4-d]pyrimidines as dual Src/Bcr-Abl kinase inhibitors: Synthesis and biological evaluation for chronic myeloid leukemia treatment

Maria, Salvatore Di; Picarazzi, Francesca; Mori, Mattia; Cianciusi, Annarita; Carbone, Anna; Crespan, Emmanuele; Perini, Cecilia; Sabetta, Samantha; Deplano, Serenella; Poggialini, Federica; Molinari, Alessio; Aronne, Rossella; Maccioni, Elias; Maga, Giovanni; Angelucci, Adriano; Schenone, Silvia; Musumeci, Francesca; Dreassi, Elena

doi:10.1016/j.bioorg.2022.106071

Cited by 8 publications

(8 citation statements)

References 41 publications

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“…Furthermore, data reported in Table 1 show that introducing a fluorine atom in the ortho or ortho/para positions of the anilino ring (compounds 2f and 2g ) led to inactive compounds. We already reported that a 2-fluoro-3-hydroxy anilino derivative was less active than the corresponding chloro analog compound [ 12 ]; in the study, we also demonstrated that moving the fluorine to the para position or the presence of two fluorine atoms did not lead to positive effects on the activity.…”

Section: Resultssupporting

confidence: 57%

“…Furthermore, we investigated the effect of the presence of an unsubstituted ( 2c, h, j, k, n, p-s ) or a substituted ( 2d-g, i, l, m, o ) anilino ring at the C4 position. In particular, we decorated the aromatic ring in C4 with different halogen atoms and, in a few cases, with a hydroxyl group since this polar group was recently shown to increase the enzymatic activity of our in-house 4-amino pyrazolo[3,4-d]pyrimidines [ 12 , 13 ]. Finally, we functionalized unsubstituted anilino derivatives 2p-s with a halogen atom on the para position of the N1 2-chloro-2-phenylethyl side chain, affording structural analogs of compound 1c .…”

Section: Resultsmentioning

confidence: 99%

“…A careful comparison of previous and current data allowed us to shed light on this behavior and expand our SAR knowledge. Many of the best in-house thioethylmorpholinyl derivatives that are active as Src inhibitors bear a 2-chloro-5-hydroxy anilino group at C4 [ 12 ]. Modeling studies highlighted that the OH was able to form a hydrogen bond with a residue of glutamate of the catalytic pocket of Src, enhancing the affinity between the kinase and the inhibitor [ 7 ].…”

Section: Resultsmentioning

confidence: 99%

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Identification and Biological Characterization of the Pyrazolo[3,4-d]pyrimidine Derivative SI388 Active as Src Inhibitor

et al. 2023

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Src is a non-receptor tyrosine kinase (TK) whose involvement in cancer, including glioblastoma (GBM), has been extensively demonstrated. In this context, we started from our in-house library of pyrazolo[3,4-d]pyrimidines that are active as Src and/or Bcr-Abl TK inhibitors and performed a lead optimization study to discover a new generation derivative that is suitable for Src kinase targeting. We synthesized a library of 19 compounds, 2a-s. Among these, compound 2a (SI388) was identified as the most potent Src inhibitor. Based on the cell-free results, we investigated the effect of SI388 in 2D and 3D GBM cellular models. Interestingly, SI388 significantly inhibits Src kinase, and therefore affects cell viability, tumorigenicity and enhances cancer cell sensitivity to ionizing radiation.

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Section: Resultssupporting

confidence: 57%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

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Identification and Biological Characterization of the Pyrazolo[3,4-d]pyrimidine Derivative SI388 Active as Src Inhibitor

et al. 2023

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“…Dasatinib is used to treat Imatinib resistant patients with BCR::ABL1 point mutations, except in the presence of T315I mutation. 7 We suspect these changes might result from somatic mutation of blast cells during TKI therapy. It is unknown whether the complex karyotype and the presentation of basophilic precursors in this CML blast crisis were related to the Imatinib therapy, or if these changes accelerated this patient into blast crisis.…”

Section: Discussionmentioning

confidence: 99%

Acute Basophilic Leukemia Arising from Chronic Myeloid Leukemia with +8, I(17q)(q10) and der(22)t(9;22) After Imatinib Therapy

Shan,

Dong,

2023

JBM

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Acute basophilic leukemia (ABL) arising from chronic myeloid leukemia (CML) with abundant mast cells (MCs), coexisting with a complex karyotype is rare. Here, we report an 81-year-old man admitted to our hospital with a history of ABL. He was diagnosed with CML in the chronic phase in January 2018, and Imatinib was used at a daily dose of 400mg. Then, transformation to ABL with abundant MCs in the bone marrow and complex karyotypes including 48,XY, trisomy 8 (+8), isochromosome 17(q10) [i(17)(q10)], and derivative chromosome 22 t(9;22) [der(22)t(9;22)] were discovered simultaneously in January 2022. In conclusion, the increased number of MCs in our case is a reminder that they might play an important role in the prognosis of CML and trigger the development of complex karyotypes. Moreover, this is the first case report of ABL arising from CML with abundant MCs, coexisting with 48,XY, +8, i(17)(q10), and der(22)t(9;22), during Imatinib treatment. Further studies are needed to better characterize this rare condition.

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“…We also investigated the permeationenhancing effect of cherry extract with selected in-house pyrazolo [3,4-d]pyrimidines. These derivatives, known to be potent tyrosine kinase inhibitors active against both solid and liquid tumors (e.g., glioblastoma, neuroblastoma, and leukaemia), were selected on the basis of previously published in vitro ADME data [8][9][10]. Since our work would concern the possible alterations of permeability in the presence of the cherry extract, pyrazolopyrimidine derivatives were heterogeneously selected according to this property.…”

Section: Introductionmentioning

confidence: 99%

Sweet Cherry Extract as Permeation Enhancer of Tyrosine Kinase Inhibitors: A Promising Prospective for Future Oral Anticancer Therapies

Poggialini,

Vagaggini,

Brai

et al. 2023

Pharmaceuticals

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Although patients would rather oral therapies to injections, the gastrointestinal tract’s low permeability makes this method limiting for most compounds, including anticancer drugs. Due to their low bioavailability, oral antitumor therapies suffer from significant variability in pharmacokinetics and efficacy. The improvement of their pharmacokinetic profiles can be achieved by a new approach: the use of natural extracts enriched with polyphenolic compounds that act as intestinal permeability enhancers. Here, we propose a safe sweet cherry extract capable of enhancing oral absorption. The extract was characterized by the HPLC-UV/MS method, evaluated for in vitro antioxidant activity, safety on the Caco-2 cell line, and as a potential permeation enhancer. The sweet cherry extract showed a high antioxidant capacity (ABTS and DPPH assays were 211.74 and 48.65 µmol of Trolox equivalent/g dried extract, respectively), high content of polyphenols (8.44 mg of gallic acid per gram of dry extract), and anthocyanins (1.80 mg of cyanidin-3-glucoside equivalent per g of dry extract), reassuring safety profile (cell viability never lower than 98%), and a significant and fully reversible ability to alter the integrity of the Caco-2 monolayer (+81.5% of Lucifer yellow permeability after 2 h). Furthermore, the ability of the sweet cherry extract to improve the permeability (Papp) and modify the efflux ratio (ER) of reference compounds (atenolol, propranolol, and dasatinib) and selected pyrazolo[3,4-d]pyrimidine derivatives was investigated. The obtained results show a significant increase in apparent permeability across the Caco-2 monolayer (tripled and quadrupled in most cases), and an interesting decrease in efflux ratio when compounds were co-incubated with sweet cherry extract.

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Novel pyrazolo[3,4-d]pyrimidines as dual Src/Bcr-Abl kinase inhibitors: Synthesis and biological evaluation for chronic myeloid leukemia treatment

Cited by 8 publications

References 41 publications

Identification and Biological Characterization of the Pyrazolo[3,4-d]pyrimidine Derivative SI388 Active as Src Inhibitor

Identification and Biological Characterization of the Pyrazolo[3,4-d]pyrimidine Derivative SI388 Active as Src Inhibitor

Acute Basophilic Leukemia Arising from Chronic Myeloid Leukemia with +8, I(17q)(q10) and der(22)t(9;22) After Imatinib Therapy

Sweet Cherry Extract as Permeation Enhancer of Tyrosine Kinase Inhibitors: A Promising Prospective for Future Oral Anticancer Therapies

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