The Bispidinone Derivative 3,7-Bis-[2-(<i>S</i>)-amino-3-(1<i>H</i>-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
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 cy...
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| Format: | Article |
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MDPI AG
2019-01-01
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| Series: | Molecules |
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| Online Access: | https://www.mdpi.com/1420-3049/24/3/524 |
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| author | Melanie J. Predebon Danielle R. Bond Joshua Brzozowski Helen Jankowski Fiona Deane Mark Tarleton Aron A. Shaw Adam McCluskey Michael C. Bowyer Judith Weidenhofer Christopher J. Scarlett |
| author_facet | Melanie J. Predebon Danielle R. Bond Joshua Brzozowski Helen Jankowski Fiona Deane Mark Tarleton Aron A. Shaw Adam McCluskey Michael C. Bowyer Judith Weidenhofer Christopher J. Scarlett |
| author_sort | Melanie J. Predebon |
| collection | DOAJ |
| description | 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 (<b>BisP1</b>: 1,5-diphenyl-3,7-bis(2-hydroxyethyl)-3,7-diazabicyclo[3.3.1]nonan-9-one; <b>BisP2</b>: 3,7-bis-(2-(S)-amino-4-methylsulfanylbutyryl)-1,5-diphenyl-3,7-diazabicyclo[3.3.1]nonan-9-one dihydrochloride; <b>BisP3:</b> [2-{7-[2-(<i>S</i>)-<i>tert</i>-butoxycarbonylamino-3-(1<i>H</i>-indol-3-yl)-propionyl]-9-oxo-1,5-diphenyl-3,7-diazabicyclo[3.3.1]non-3-yl}-1-(<i>S</i>)-(1<i>H</i>-indol-3-ylmethyl)-2-oxoethyl]-carbamic acid tertbutyl ester; <b>BisP4</b>: 3,7-bis-[2-(<i>S</i>)-amino-3-(1<i>H</i>-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 <b>BisP4</b> treatment (1 µM⁻100 µM) on all three cell lines, with IC<sub>50</sub> values for MiaPaca-2, BxPC-3, and CFPAC-1 16.9 µM, 23.7 µM, and 36.3 µM, 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 <b>BisP4</b> treated MiaPaca-2 PC cells revealed dose-dependent characteristic apoptotic morphological changes. In addition, flow cytometry confirmed <b>BisP4</b> induced apoptotic cell death induction of activated caspase-3/-7. The bispidinone derivative <b>BisP4</b> 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. |
| first_indexed | 2024-12-23T10:21:48Z |
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| institution | Directory Open Access Journal |
| issn | 1420-3049 |
| language | English |
| last_indexed | 2024-12-23T10:21:48Z |
| publishDate | 2019-01-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Molecules |
| spelling | doaj.art-56d49fd19e824b2ab53b775f8ba3d9302022-12-21T17:50:40ZengMDPI AGMolecules1420-30492019-01-0124352410.3390/molecules24030524molecules24030524The Bispidinone Derivative 3,7-Bis-[2-(<i>S</i>)-amino-3-(1<i>H</i>-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 VitroMelanie J. Predebon0Danielle R. Bond1Joshua Brzozowski2Helen Jankowski3Fiona Deane4Mark Tarleton5Aron A. Shaw6Adam McCluskey7Michael C. Bowyer8Judith Weidenhofer9Christopher J. Scarlett10Pancreatic Cancer Research Group, School of Environmental and Life Sciences, The University of Newcastle, Ourimbah, NSW 2258, AustraliaPancreatic Cancer Research Group, School of Environmental and Life Sciences, The University of Newcastle, Ourimbah, NSW 2258, AustraliaSchool of Biomedical Sciences and Pharmacy, The University of Newcastle, Callaghan, NSW 2308, AustraliaSchool of Biomedical Sciences and Pharmacy, The University of Newcastle, Callaghan, NSW 2308, AustraliaChemistry, School of Environmental and Life Sciences, The University of Newcastle, Callaghan, NSW 2308, AustraliaPancreatic Cancer Research Group, School of Environmental and Life Sciences, The University of Newcastle, Ourimbah, NSW 2258, AustraliaChemistry, School of Environmental and Life Sciences, The University of Newcastle, Callaghan, NSW 2308, AustraliaChemistry, School of Environmental and Life Sciences, The University of Newcastle, Callaghan, NSW 2308, AustraliaPancreatic Cancer Research Group, School of Environmental and Life Sciences, The University of Newcastle, Ourimbah, NSW 2258, AustraliaSchool of Biomedical Sciences and Pharmacy, The University of Newcastle, Callaghan, NSW 2308, AustraliaPancreatic Cancer Research Group, School of Environmental and Life Sciences, The University of Newcastle, Ourimbah, NSW 2258, AustraliaPancreatic 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 (<b>BisP1</b>: 1,5-diphenyl-3,7-bis(2-hydroxyethyl)-3,7-diazabicyclo[3.3.1]nonan-9-one; <b>BisP2</b>: 3,7-bis-(2-(S)-amino-4-methylsulfanylbutyryl)-1,5-diphenyl-3,7-diazabicyclo[3.3.1]nonan-9-one dihydrochloride; <b>BisP3:</b> [2-{7-[2-(<i>S</i>)-<i>tert</i>-butoxycarbonylamino-3-(1<i>H</i>-indol-3-yl)-propionyl]-9-oxo-1,5-diphenyl-3,7-diazabicyclo[3.3.1]non-3-yl}-1-(<i>S</i>)-(1<i>H</i>-indol-3-ylmethyl)-2-oxoethyl]-carbamic acid tertbutyl ester; <b>BisP4</b>: 3,7-bis-[2-(<i>S</i>)-amino-3-(1<i>H</i>-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 <b>BisP4</b> treatment (1 µM⁻100 µM) on all three cell lines, with IC<sub>50</sub> values for MiaPaca-2, BxPC-3, and CFPAC-1 16.9 µM, 23.7 µM, and 36.3 µM, 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 <b>BisP4</b> treated MiaPaca-2 PC cells revealed dose-dependent characteristic apoptotic morphological changes. In addition, flow cytometry confirmed <b>BisP4</b> induced apoptotic cell death induction of activated caspase-3/-7. The bispidinone derivative <b>BisP4</b> 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.https://www.mdpi.com/1420-3049/24/3/524Pancreatic cancerbispidinonecytotoxicin vitroapoptosisdrug development |
| spellingShingle | Melanie J. Predebon Danielle R. Bond Joshua Brzozowski Helen Jankowski Fiona Deane Mark Tarleton Aron A. Shaw Adam McCluskey Michael C. Bowyer Judith Weidenhofer Christopher J. Scarlett The Bispidinone Derivative 3,7-Bis-[2-(<i>S</i>)-amino-3-(1<i>H</i>-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 Molecules Pancreatic cancer bispidinone cytotoxic in vitro apoptosis drug development |
| title | The Bispidinone Derivative 3,7-Bis-[2-(<i>S</i>)-amino-3-(1<i>H</i>-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 |
| title_full | The Bispidinone Derivative 3,7-Bis-[2-(<i>S</i>)-amino-3-(1<i>H</i>-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 |
| title_fullStr | The Bispidinone Derivative 3,7-Bis-[2-(<i>S</i>)-amino-3-(1<i>H</i>-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 |
| title_full_unstemmed | The Bispidinone Derivative 3,7-Bis-[2-(<i>S</i>)-amino-3-(1<i>H</i>-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 |
| title_short | The Bispidinone Derivative 3,7-Bis-[2-(<i>S</i>)-amino-3-(1<i>H</i>-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 |
| title_sort | bispidinone derivative 3 7 bis 2 i s i amino 3 1 i h i 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 |
| topic | Pancreatic cancer bispidinone cytotoxic in vitro apoptosis drug development |
| url | https://www.mdpi.com/1420-3049/24/3/524 |
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