Design, Synthesis, Biological Activity, and ADME Properties of Pyrazolo[3,4-<i>d</i>]pyrimidines Active in Hypoxic Human Leukemia Cells: A Lead Optimization Study

Radi, Marco; Dreassi, Elena; Brullo, Chiara; Crespan, Emmanuele; Tintori, Cristina; Bernardo, Vincenzo; Valoti, Massimo; Zamperini, Claudio; Daigl, Henry; Musumeci, Francesca; Carraro, Fabio; Naldini, Antonella; Filippi, Irene; Maga, Giovanni; Schenone, Silvia; Botta, Maurizio

doi:10.1021/jm1012819

Cited by 77 publications

(66 citation statements)

References 67 publications

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“…We recently screened a family of dual Src/Abl inhibitors characterized by a substituted pyrazolo[3,4-d]pyrimidine scaffold [28,29] for their ability to inhibit Sgk1 and Akt kinase activity, competing with ATP for its binding domain. One of these molecules, compound 3 (henceforth SI113), was particularly effective in inhibiting Sgk1 kinase activity, being much less effective on Akt1 activity, probably because it fits better with the lipophilic area of the ATP binding domain that in Sgk1 is larger than in Akt1 [30].…”

Section: Introductionmentioning

confidence: 99%

SI113, a Specific Inhibitor of the Sgk1 Kinase Activity that Counteracts Cancer Cell Proliferation

D’Antona

Amato

Talarico

et al. 2015

Cell Physiol Biochem

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Background/Aims:Published observations on serum and glucocorticoid regulated kinase 1 (Sgk1) knockout murine models and Sgk1-specific RNA silencing in the RKO human colon carcinoma cell line point to this kinase as a central player in colon carcinogenesis and in resistance to taxanes. Methods:By in vitro kinase activity inhibition assays, cell cycle and viability analysis in human cancer model systems, we describe the biologic effects of a recently identified kinase inhibitor, SI113, characterized by a substituted pyrazolo[3,4-d]pyrimidine scaffold, that shows specificity for Sgk1. Results: SI113 was able to inhibit in vitro cell growth in cancer cells derived from tumors with different origins. In RKO cells, this kinase inhibitor blocked insulin-dependent phosphorylation of the Sgk1 substrate Mdm2, the main regulator of p53 protein stability, and induced necrosis and apoptosis when used as a single agent. Finally, SI113 potentiated the effects of paclitaxel on cell viability. Conclusion:Since SI113 appears to be effective in inducing cell death in RKO cells, potentiating paclitaxel sensitivity, we believe that this new molecule could be efficiently employed, alone or in combination with paclitaxel, in colon cancer chemotherapy.

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Section: Introductionmentioning

confidence: 99%

SI113, a Specific Inhibitor of the Sgk1 Kinase Activity that Counteracts Cancer Cell Proliferation

D’Antona

Amato

Talarico

et al. 2015

Cell Physiol Biochem

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“…Obviously, several pyrazolopyrimidine models as compounds 1-3 ( Fig.1) were reported to possess anticancer and cytotoxic activity. [5][6][7] Compound 2 was reported to be an effective anti-tumour agent and a scaffold to adenosine (ATP) binding receptor in several kinases. 6 Moreover, various (3,4-dimethoxyphenyl)-5-fluorobenzothiazole (PMX610) [12][13][14][15] are famous with their potency that enable them to be effective anti-cancer agents.…”

Section: Introductionmentioning

confidence: 99%

“…[5][6][7] Compound 2 was reported to be an effective anti-tumour agent and a scaffold to adenosine (ATP) binding receptor in several kinases. 6 Moreover, various (3,4-dimethoxyphenyl)-5-fluorobenzothiazole (PMX610) [12][13][14][15] are famous with their potency that enable them to be effective anti-cancer agents. Based on these findings, and as a continuation of previous work, [16][17][18][19][20] we synthesized new expected drug hybrid of two active moieties pyrazolopyrimidine and benzothiazole or oxazole.…”

Section: Introductionmentioning

confidence: 99%

Synthesis and cytotoxic activity of new pyrazolo[1,5-a]pyrimidines and determination of pyrimidine regiospecific ring formation with 2D NMR

Abdelall¹,

Philoppes²

2016

Arkivoc

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Novel pyrazolo [1,5-a]pyrimidines (9a, 9b, and 10a-c) were synthesized in high and efficient yields. Their pathway involves the formation of N,S-ketene derivatives (7a and 7b) that reacted with hydrazine hydrate to get the key intermediate aminopyrazolo derivatives (8a and 8b). These aminopyrazoles were further reacted with either acetylacetoneor β-ketoesters resulting in the targeted pyrazolopyrimidines (9a, 9b, and 10a-c). All prepared compounds were fully characterized by spectral methods and the cyclization of 10a-d was proved by 2D NMR such as HMBC, HSQC and NOESY. The targeted pyrazolopyrimidines were subjected to in vitro anticancer screening and all of them showed promising cytotoxic activity when compared to doxorubicin. Compound 10d was the most active with IC50= 1.98, 2.20 and 2.61µM against MCF-7, BT474 and A549 cancer cell lines.

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“…PD166236,21 AP23846,22 and benzotriazine23) have been studied preclinically for their ability to inhibit both c‐Src and Abl in recent years. Recently, Schenone and coworker have synthesized a novel series of pyrazolo[3,4‐ d ]pyrimidine derivatives and assessed their activities 24–28. They discovered that these compounds potently inhibited c‐Src and Abl enzymes at low nanomolar concentrations and had potent growth inhibition on several human cancer cell lines, demonstrating the great potential of developing pyrazolo[3,4‐ d ]pyrimidine derivatives as a novel class of dual Src/Abl inhibitors for cancer therapy.…”

Section: Introductionmentioning

confidence: 99%

Theoretical Studies on Pyrazolo[3,4‐d]pyrimidine Derivatives as Potent Dual c‐Src/Abl Inhibitors Using 3D‐QSAR and Docking Approaches

Zeng

Fang

et al. 2014

Molecular Informatics

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In recent years, the development of dual or multi-targeted inhibitors has captured extensive attention of research for treating of malignancies. In this paper, three-dimensional quantitative structure-activity relationship and docking studies were performed on 87 pyrazolo[3,4-d]pyrimidines as dual Src/Abl inhibitors. The appropriate binding orientations and conformations of these compounds interacting with both Src and Abl kinases were revealed by docking studies, and the established optimum CoMFA models yielded q(2) =0.856, R(2) =0.966 for Src and q(2) =0.869, R(2) =0.974 for Abl, and the best CoMSIA models gave q(2) =0.877, R(2) =0.979 for Src and q(2) =0.885, R(2) =0.982 for Abl. Systemic external validations further confirm the satisfactory predictive power of these models, producing R(2) pred values of 0.872 and 0.865 for Src, 0.876 and 0.867 for Abl, r(2) m values of 0.832 and 0.928 for Src, 0.838 and 0.904 for Abl, respectively. In addition, through a comparison between 3D-QSAR contour maps and docking results, it is revealed that the hydrophobic and electrostatic interactions of compounds play significant roles for the inhibitory activity against both Src and Abl kinases. Some structural factors influencing the activities of these compounds were discussed in detail. The key amino acids impacting the receptor-ligand interactions have been identified. These theoretical results can offer useful references for designing novel potential dual Src/Abl inhibitors.

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Design, Synthesis, Biological Activity, and ADME Properties of Pyrazolo[3,4-d]pyrimidines Active in Hypoxic Human Leukemia Cells: A Lead Optimization Study

Cited by 77 publications

References 67 publications

SI113, a Specific Inhibitor of the Sgk1 Kinase Activity that Counteracts Cancer Cell Proliferation

SI113, a Specific Inhibitor of the Sgk1 Kinase Activity that Counteracts Cancer Cell Proliferation

Synthesis and cytotoxic activity of new pyrazolo[1,5-a]pyrimidines and determination of pyrimidine regiospecific ring formation with 2D NMR

Theoretical Studies on Pyrazolo[3,4‐d]pyrimidine Derivatives as Potent Dual c‐Src/Abl Inhibitors Using 3D‐QSAR and Docking Approaches

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