Synthesis of novel pyrazoline derivatives and the evaluation of death mechanisms involved in their antileukemic activity
| Autor: | Bruna Fischer Duarte, Iris Mattos Santos Pirath, Jessica Toigo, Alisson Bigolin, Natália Marceli Stefanes, Maria Cláudia Santos-Silva, Louise Domeneghini Chiaradia-Delatorre, Daiane Mari Perondi, Amanda Abdalla Biasi Ribeiro, Mariana Franzoni Maioral, Amanda Virtuoso Jacques, Ricardo José Nunes |
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| Rok vydání: | 2019 |
| Předmět: |
Survivin
Clinical Biochemistry Pharmaceutical Science Antineoplastic Agents Apoptosis 01 natural sciences Biochemistry Cell Line Tumor Drug Discovery medicine Humans Cytotoxic T cell Cytotoxicity Molecular Biology Cell Proliferation bcl-2-Associated X Protein Membrane Potential Mitochondrial Acute leukemia Leukemia Caspase 3 010405 organic chemistry Cell growth Chemistry Organic Chemistry Apoptosis Inducing Factor 0104 chemical sciences 010404 medicinal & biomolecular chemistry medicine.anatomical_structure Proto-Oncogene Proteins c-bcl-2 Acute Disease S Phase Cell Cycle Checkpoints Cancer research Pyrazoles Molecular Medicine DNA fragmentation Bone marrow Drug Screening Assays Antitumor |
| Zdroj: | Bioorganic & Medicinal Chemistry. 27:375-382 |
| ISSN: | 0968-0896 |
| DOI: | 10.1016/j.bmc.2018.12.012 |
| Popis: | Malignant neoplasms are one of the leading causes of death worldwide and hematologic malignancies, including acute leukemia (AL) is one of the most relevant cancer types. Current available chemotherapeutics are associated with high morbidity and mortality rates, therefore, the search for new molecules with antitumor activity, specific and selective for neoplastic cells, became a great challenge for researchers in the oncology field. As pyrazolines stand out in the literature for their great variety of biological activities, the aim of this study was to synthesize and evaluate the antileukemic activity of five new pyrazoline derivatives. All pyrazolines showed adequate physicochemical properties for a good oral bioavailability. The two unpublished and most effective pyrazoline derivatives have been selected for further experiments. These compounds are highly selective for leukemic cells when compared to non-neoplastic cells and did not cause lysis on human red blood cells. Additionally, selected pyrazolines induced cell cycle arrest at G0/G1 phase and decreased cell proliferation marker KI67. Apoptotic cell death induced by selected pyrazolines was confirmed by morphological analysis, assessment of phosphatidylserine residue exposure and DNA fragmentation. Several factors indicate that both intrinsic and extrinsic apoptosis occurred. These were: increased FasR expression; the predominance of Bax in relation to Bcl-2; the loss of mitochondrial membrane potential; AIF release; decreased expression of survivin (an antiapoptotic protein); and the activation of caspase-3. The selected pyrazolines were also found to be cytotoxic against neoplastic cells collected from the peripheral blood and bone marrow of patients with different subtypes of acute leukemia. |
| Databáze: | OpenAIRE |
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