The Bispidinone Derivative 3,7-Bis-[2-(S)-amino-3-(1H-indol-3-yl)-propionyl]-1,5-diphenyl-3,7-diazabicyclo[3.3.1]nonan-9-one Dihydrochloride Induces an Apoptosis-Mediated Cytotoxic Effect on Pancreatic Cancer Cells In Vitro
| Autor: | Danielle R. Bond, Joshua S. Brzozowski, Judith Weidenhofer, Mark Tarleton, Christopher J. Scarlett, Melanie J. Predebon, Aron A Shaw, Michael C. Bowyer, Fiona M. Deane, Adam McCluskey, Helen Jankowski |
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| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
Cell Survival
Pharmaceutical Science Antineoplastic Agents 01 natural sciences Article Analytical Chemistry Flow cytometry lcsh:QD241-441 03 medical and health sciences chemistry.chemical_compound cytotoxic 0302 clinical medicine lcsh:Organic chemistry Cell Line Tumor Drug Discovery medicine Humans Cytotoxic T cell Viability assay DAPI Physical and Theoretical Chemistry Cytotoxicity Cells Cultured Molecular Structure medicine.diagnostic_test 010405 organic chemistry Organic Chemistry apoptosis bispidinone in vitro Pancreatic cancer Bridged Bicyclo Compounds Heterocyclic Molecular biology drug development In vitro 0104 chemical sciences Pancreatic Neoplasms chemistry Chemistry (miscellaneous) Apoptosis Cell culture 030220 oncology & carcinogenesis Molecular Medicine |
| Zdroj: | Molecules, Vol 24, Iss 3, p 524 (2019) Molecules Volume 24 Issue 3 |
| ISSN: | 1420-3049 |
| Popis: | Pancreatic cancer (PC) is a complex, heterogeneous disease with a dismal prognosis. Current therapies have failed to improve survival outcomes, urging the need for discovery of novel targeted treatments. Bispidinone derivatives have yet to be investigated as cytotoxic agents against PC cells. The cytotoxic effect of four bispidinone derivatives (BisP1: 1,5-diphenyl-3,7-bis(2-hydroxyethyl)-3,7-diazabicyclo[3.3.1]nonan-9-one BisP2: 3,7-bis-(2-(S)-amino-4-methylsulfanylbutyryl)-1,5-diphenyl-3,7-diazabicyclo[3.3.1]nonan-9-one dihydrochloride BisP3: [2-{7-[2-(S)-tert-butoxycarbonylamino-3-(1H-indol-3-yl)-propionyl]-9-oxo-1,5-diphenyl-3,7-diazabicyclo[3.3.1]non-3-yl}-1-(S)-(1H-indol-3-ylmethyl)-2-oxoethyl]-carbamic acid tertbutyl ester BisP4: 3,7-bis-[2-(S)-amino-3-(1H-indol-3-yl)-propionyl]-1,5-diphenyl-3,7-diazabicyclo[3.3.1]nonan-9-one dihydrochloride) was assessed against PC cell lines (MiaPaca-2, CFPAC-1 and BxPC-3). Cell viability was assessed using a Cell Counting Kit-8 (CCK-8) colorimetric assay, while apoptotic cell death was confirmed using fluorescence microscopy and flow cytometry. Initial viability screening revealed significant cytotoxic activity from BisP4 treatment (1 µ M&ndash 100 µ M) on all three cell lines, with IC50 values for MiaPaca-2, BxPC-3, and CFPAC-1 16.9 µ M, 23.7 µ M, and 36.3 µ M, respectively. Cytotoxic treatment time-response (4 h, 24 h, and 48 h) revealed a 24 h treatment time was sufficient to produce a cytotoxic effect on all cell lines. Light microscopy evaluation (DAPI staining) of BisP4 treated MiaPaca-2 PC cells revealed dose-dependent characteristic apoptotic morphological changes. In addition, flow cytometry confirmed BisP4 induced apoptotic cell death induction of activated caspase-3/-7. The bispidinone derivative BisP4 induced an apoptosis-mediated cytotoxic effect on MiaPaca-2 cell lines and significant cytotoxicity on CFPAC-1 and BxPC-3 cell lines. Further investigations into the precise cellular mechanisms of action of this class of compounds are necessary for potential development into pre-clinical trials. |
| Databáze: | OpenAIRE |
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