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Open AccessArticle

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

Laboratory of Functional Genomics, Biological Research Centre, Hungarian Academy of Sciences, Temesvári krt. 62, H-6726 Szeged, Hungary
Department of Physiology, Anatomy and Neuroscience, Faculty of Science and Informatics, University of Szeged, Közép fasor 52, H-6726 Szeged, Hungary
Avidin Ltd., Alsó kikötő sor 11/D, H-6726 Szeged, Hungary
Department of Dermatology and Allergology, University of Szeged, Korányi fasor 6, H-6720 Szeged, Hungary
Department of Hematology, Institute of Internal Medicine, University of Debrecen, Nagyerdei Körút 98, 4032 Debrecen, Hungary
Author to whom correspondence should be addressed.
Academic Editor: Wolfgang Holzer
Molecules 2018, 23(11), 2845;
Received: 29 September 2018 / Revised: 25 October 2018 / Accepted: 29 October 2018 / Published: 1 November 2018
(This article belongs to the Special Issue Pyrazole Derivatives)
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. View Full-Text
Keywords: imidazole; pyrazole; acute myeloid leukemia; apoptosis; toxicogenomics imidazole; pyrazole; acute myeloid leukemia; apoptosis; toxicogenomics
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MDPI and ACS Style

Szebeni, G.J.; Balog, J.A.; Demjén, A.; Alföldi, R.; Végi, V.L.; Fehér, L.Z.; Mán, I.; Kotogány, E.; Gubán, B.; Batár, P.; Hackler, L., Jr.; Kanizsai, I.; Puskás, L.G. Imidazo[1,2-b]pyrazole-7-carboxamides Induce Apoptosis in Human Leukemia Cells at Nanomolar Concentrations. Molecules 2018, 23, 2845.

AMA Style

Szebeni GJ, Balog JA, Demjén A, Alföldi R, Végi VL, Fehér LZ, Mán I, Kotogány E, Gubán B, Batár P, Hackler L Jr., Kanizsai I, Puskás LG. Imidazo[1,2-b]pyrazole-7-carboxamides Induce Apoptosis in Human Leukemia Cells at Nanomolar Concentrations. Molecules. 2018; 23(11):2845.

Chicago/Turabian Style

Szebeni, Gábor J.; Balog, József A.; Demjén, András; Alföldi, Róbert; Végi, Vanessza L.; Fehér, Liliána Z.; Mán, Imola; Kotogány, Edit; Gubán, Barbara; Batár, Péter; Hackler, László, Jr.; Kanizsai, Iván; Puskás, László G. 2018. "Imidazo[1,2-b]pyrazole-7-carboxamides Induce Apoptosis in Human Leukemia Cells at Nanomolar Concentrations" Molecules 23, no. 11: 2845.

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