Synthesis, cytotoxic characterization, and SAR study of imidazo[1,2‐<i>b</i>]pyrazole‐7‐carboxamides

Demjén, András; Alföldi, Róbert; Angyal, Anikó; Gyuris, Márió; Hackler, László; Szebeni, Gábor J.; Wölfling, János; Puskás, László G.; Kanizsai, Iván

doi:10.1002/ardp.201800062

Cited by 17 publications

(17 citation statements)

References 67 publications

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“…Boiling of 5‐chloro‐2‐(cyanoacetamido)pyridines 3 with dimethylformamide‐dimethylacetal (DMF‐DMA) in dioxane afforded N ‐(5‐chloropyridin‐2‐yl)‐2‐cyano‐3‐(dimethylamino)acrylamides 11 , which served as a precursor for synthesizing 3‐amino‐ N ‐(5‐chloropyridin‐2‐yl)‐1 H ‐pyrazole‐4‐carboxamides 12 upon heating with hydrazine hydrate in ethyl alcohol. These aminopyrazole‐carboxamides 12 a and 12 b are structurally related and similar structures are reported by Damjen et al . The structures of enamines 11 and their corresponding aminopyrazoles 12 were confirmed by their compatible elemental and spectral analyses.…”

Section: Resultssupporting

confidence: 80%

Utilization of 5‐Chloro‐2‐(cyanoacetamido)pyridines in the Synthesis of Biologically Active Heterocyclic Hybrids

et al. 2020

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A simple synthesis for a series of chloropyridine derivatives incorporating heterocyclic hybrids has been accomplished. The key reaction involving employment of 5-chloro-2-(cyanoacetamido)pyridines 3 in the synthesis of chloropyridinyl-pyridone, chloropyridinyl-pyrazole, chloropyridinyl-thiazole and chloropyridinyl-thiophene hybrids. The newly synthesized heterocycles were evaluated for their antioxidant and antibacterial activities against Gram-positive and Gram-negative bacterial strains. 3-Amino-N-(3,5-dichloropyridin-2-yl)-1H-pyrazole-4-carboxamide (12 b) was found to be the most potent compound against Escherichia coli and Staphylococcus aureus exhibiting inhibition percent of 92.3 % and 100 %, respectively, when compared to the standard drug ampicillin. Moreover, compound 12 b displayed the most significant antioxidant activity with percent inhibition 87.8 % which is close to the antioxidant activity of ascorbic acid.

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Section: Resultssupporting

confidence: 80%

Utilization of 5‐Chloro‐2‐(cyanoacetamido)pyridines in the Synthesis of Biologically Active Heterocyclic Hybrids

et al. 2020

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“…Synthesis was performed by the previously presented manner via Groebke-Blackburn-Bienaymé three component reaction (GBB-3CR) [ 17 ]. Briefly, to a suspension of pyrazole precursor (0.50 mmol) in MeCN (0.5 mL), pivaldehyde (0.55 mmol), HClO 4 (20 mol%), and the corresponding isocyanide (0.55 mmol) were added and stirred at room temperature for 6 h. Then the crude mixture was purified by filtration followed by washing with cold MeCN or by column chromatography on silica gel (eluent: hexane/EtOAc) to afford pure imidazo[1,2- b ]pyrazoles ( Figure 1 A).…”

Section: Resultsmentioning

confidence: 99%

“…Seven DU-compounds were prepared for antitumor characterization with a substitution pattern of C2 tert -butyl ( t Bu), C3 aliphatic ( t Bu, tert -octyl ( t Octyl) or cyclohexyl (Cy)), and C7 phenyl substituted secondary carboxamides with electron-donating (ED) groups, such as hydroxyl (OH) and amino (NH 2 ) functions (positioning in ortho -, meta - or para positions) ( Figure 1 B). In addition, one imidazo[1,2- b ]pyrazole (DU283) incorporating electron-withdrawing (EWG) function in para position (R 1 = 4-F) was selected among the investigated bicycles as an anti-tumor reference imidazo[1,2- b ]pyrazole-7-carboxamide [ 17 ]. Spectral analysis of imidazo[1,2- b ]pyrazole-7-carboxamides can be found in Figure S1 .…”

Section: Resultsmentioning

confidence: 99%

“…Moreover, the synthesis and the anticancer activity of N -fused pyrazoles, such as imidazo[1,2- b ]pyrazoles have also been reported [ 15 , 16 ]. We have recently published the synthesis of a library (67 compounds) of novel imidazo[1,2- b ]pyrazole-7-carboxamides, where among different cell lines, HL-60 leukemia cells showed the highest sensitivity upon treatment [ 17 ]. Based on the previous structure–activity relationship (SAR) experience, hit molecules have been further optimized by changing certain substituents to increase the cytotoxic effect against different leukemia cells.…”

Section: Introductionmentioning

confidence: 99%

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Imidazo[1,2-b]pyrazole-7-carboxamides Induce Apoptosis in Human Leukemia Cells at Nanomolar Concentrations

Szebeni

Balog

Demjén³

et al. 2018

Molecules

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Leukemia, the malignancy of the hematopoietic system accounts for 10% of cancer cases with poor overall survival rate in adults; therefore, there is a high unmet medical need for the development of novel therapeutics. Eight imidazo[1,2-b]pyrazole-7-carboxamides have been tested for cytotoxic activity against five leukemia cell lines: Acute promyelocytic leukemia (HL-60), acute monocytic leukemia (THP-1), acute T-lymphoblastic leukemia (MOLT-4), biphenotypic B myelomonocytic leukemia (MV-4-11), and erythroleukemia (K-562) cells in vitro. Imidazo[1,2-b]pyrazole-7-carboxamides hampered the viability of all five leukemia cell lines with different potential. Optimization through structure activity relationship resulted in the following IC50 values for the most effective lead compound DU385: 16.54 nM, 27.24 nM, and 32.25 nM on HL-60, MOLT-4, MV-4-11 cells, respectively. Human primary fibroblasts were much less sensitive in the applied concentration range. Both monolayer or spheroid cultures of murine 4T1 and human MCF7 breast cancer cells were less sensitive to treatment with 1.5–10.8 μM IC50 values. Flow cytometry confirmed the absence of necrosis and revealed 60% late apoptotic population for MV-4-11, and 50% early apoptotic population for HL-60. MOLT-4 cells showed only about 30% of total apoptotic population. Toxicogenomic study of DU385 on the most sensitive MV-4-11 cells revealed altered expression of sixteen genes as early (6 h), midterm (12 h), and late response (24 h) genes upon treatment. Changes in ALOX5AP, TXN, and SOD1 expression suggested that DU385 causes oxidative stress, which was confirmed by depletion of cellular glutathione and mitochondrial membrane depolarization induction. Imidazo[1,2-b]pyrazole-7-carboxamides reported herein induced apoptosis in human leukemia cells at nanomolar concentrations.

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“…Orthotopic transplantation of 4T1 cells offers a relevant tumor model to study efficacy of drug candidates or immune therapy regimens [8]. Previously, we showed the tumor promoting effect of mesenchymal stem cell (cancer associated fibroblast)-derived galectin-1 in the 4T1 model [9], and later on we screened an anti-cancer compound library of imidazo [1-2-b]pyrazole-7-carboxamides in both two-and three-dimensional cell cultures of 4T1 cells [10,11].…”

Section: Introductionmentioning

confidence: 99%

Single Cell Mass Cytometry Revealed the Immunomodulatory Effect of Cisplatin Via Downregulation of Splenic CD44+, IL-17A+ MDSCs and Promotion of Circulating IFN-γ+ Myeloid Cells in the 4T1 Metastatic Breast Cancer Model

Balog

Hackler²,

Kovács³

et al. 2019

IJMS

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The treatment of metastatic breast cancer remained a challenge despite the recent breakthrough in the immunotherapy regimens. Here, we addressed the multidimensional immunophenotyping of 4T1 metastatic breast cancer by the state-of-the-art single cell mass cytometry (CyTOF). We determined the dose and time dependent cytotoxicity of cisplatin on 4T1 cells by the xCelligence real-time electronic sensing assay. Cisplatin treatment reduced tumor growth, number of lung metastasis, and the splenomegaly of 4T1 tumor bearing mice. We showed that cisplatin inhibited the tumor stroma formation, the polarization of carcinoma-associated fibroblasts by the diminished proteolytic activity of fibroblast activating protein. The CyTOF analysis revealed the emergence of CD11b+/Gr-1+/CD44+ or CD11b+/Gr-1+/IL-17A+ myeloid-derived suppressor cells (MDSCs) and the absence of B220+ or CD62L+ B-cells, the CD62L+/CD4+ and CD62L+/CD8+ T-cells in the spleen of advanced cancer. We could show the immunomodulatory effect of cisplatin via the suppression of splenic MDSCs and via the promotion of peripheral IFN-γ+ myeloid cells. Our data could support the use of low dose chemotherapy with cisplatin as an immunomodulatory agent for metastatic triple negative breast cancer.

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Synthesis, cytotoxic characterization, and SAR study of imidazo[1,2‐b]pyrazole‐7‐carboxamides

Cited by 17 publications

References 67 publications

Utilization of 5‐Chloro‐2‐(cyanoacetamido)pyridines in the Synthesis of Biologically Active Heterocyclic Hybrids

Utilization of 5‐Chloro‐2‐(cyanoacetamido)pyridines in the Synthesis of Biologically Active Heterocyclic Hybrids

Imidazo[1,2-b]pyrazole-7-carboxamides Induce Apoptosis in Human Leukemia Cells at Nanomolar Concentrations

Single Cell Mass Cytometry Revealed the Immunomodulatory Effect of Cisplatin Via Downregulation of Splenic CD44+, IL-17A+ MDSCs and Promotion of Circulating IFN-γ+ Myeloid Cells in the 4T1 Metastatic Breast Cancer Model

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