Design and in Vitro Characterization of Tricyclic Benzodiazepine Derivatives as Potent and Selective Antileukemic Agents
| Autor: | Pawel Siedlecki, Adam Mieczkowski, Marcin Wilczek, Krzysztof Woźniak, Tomasz Frączyk, Patrycja Wińska, Mateusz Psurski, Bartosz Bieszczad, Maciej Baginski, Monika Dziełak, Damian Trzybiński |
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| Rok vydání: | 2020 |
| Předmět: |
Molecular Conformation
Antineoplastic Agents Apoptosis Bioengineering Crystallography X-Ray 01 natural sciences Biochemistry Cell Line Benzodiazepines Mice Structure-Activity Relationship Catalytic Domain medicine Animals Humans Cytotoxic T cell Cytotoxicity Molecular Biology IC50 Cell Proliferation chemistry.chemical_classification Binding Sites Phosphoric Diester Hydrolases 010405 organic chemistry Stereoisomerism General Chemistry General Medicine medicine.disease Molecular biology In vitro 0104 chemical sciences 010404 medicinal & biomolecular chemistry Leukemia Enzyme chemistry Cell culture Drug Design Molecular Medicine Drug Screening Assays Antitumor Autotaxin |
| Zdroj: | Chemistry & Biodiversity. 18 |
| ISSN: | 1612-1880 1612-1872 |
| Popis: | Currently available chemotherapeutic treatments for blood cancers (leukemia) usually have strong side effects. More selective, efficient and less toxic anticancer agents are needed. We synthesized seven, new, optically pure (12aS)-1,3,4,12a-tetrahydropyrazino[2,1-c][1,4]benzodiazepine-6,12-(2H,11H)-dione derivatives and examined their cytotoxicity towards eight cancer cell lines, including urinary bladder (TCC-SUP, UM-UC-3, KU-19-9), colon (LoVo), and breast (MCF-7, MDA-MB-231) cancer representatives, as well as two leukemic cell lines (MV-4-11, CCRF-CEM) and normal murine fibroblasts (Balb/3T3) as a reference cell line. Three of the seven newly-obtained compounds ((12aS)-8-bromo-2-(3-phenylbenzoyl)-1,3,4,12a-tetrahydropyrazino[2,1-c][1,4]benzodiazepine-6,12(2H,11H)-dione, (12aS)-8,9-dimethoxy-2-(4-phenylbenzoyl)-1,3,4,12a-tetrahydropyrazino[2,1-c][1,4]benzodiazepine-6,12(2H,11H)-dione and (12aS)-8-nitro-2-(4-phenylbenzoyl)-1,3,4,12a-tetrahydropyrazino[2,1-c][1,4]benzodiazepine-6,12(2H,11H)-dione, showed enhanced activity and selectivity toward the leukemic MV-4-11 cell line when compared to our previously reported compounds, with IC50 values in the range of 2.9-5.6 µM. Additionally, (12aS)-9-nitro-2-(4-phenylbenzoyl)-1,3,4,12a-tetrahydropyrazino[2,1-c][1,4]benzodiazepine-6,12(2H,11H)-dione exhibited a strong cytotoxic effect against the leukemic CCRF-CEM (IC50 = 6.1 µM) and MV-4-11 (IC50 = 11.0 µM) cell lines, a moderate cytotoxic effect toward other tumor lines (IC50 = 31.8-55.0 µM) and very weak cytotoxic effect toward the Balb/3T3 reference cell line. Selected compounds were further evaluated for their potential to induce apoptotic cell death in MV-4-11 cells by measuring caspase-3 activity. We also obtained the crystal structure of three products and investigated the effect of 22 derivatives of 1,3,4,12a-tetrahydropyrazino[2,1-c][1,4]benzodiazepine-6,12-(2H,11H)-dione on the activity of the cancer-associated enzyme autotaxin. All compounds proved to be weak inhibitors of autotaxin, although some (R) and (S) enantiomers had Ki values of 10-19 µM. The obtained results showed that the tested compounds exhibited a selective anti-leukemic effect, which appeared not to be related directly to autotaxin. Molecular targets responsible for this effect remain to be identified. The newly obtained compounds can be used in the search for new, selective anticancer therapies. |
| Databáze: | OpenAIRE |
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