Research Article
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Cytotoxic effects of Mannich bases via induction of caspase-3 pathway on human oral squamous cell carcinoma

Year 2021, , 187 - 194, 28.02.2021
https://doi.org/10.18596/jotcsa.817007

Abstract

In anticancer drug research, there is a need for the synthesis of compounds with selective cytotoxicity compared to the drugs in the market. The current study aimed to determine the cytotoxicities of the bis Mannich bases 1-9 towards human oral squamous cell carcinoma (OSCC). Mannich bases showed cytotoxicity in low micromolar in the range of 1.7-27 µM against OSCC cell lines. The compounds 5 with the highest potency selectivity expression (PSE) value (318.1) and 7 with the highest tumor selectivity (TS) values (TS1:11.2, TS2:15.8) showed promising selective cytotoxicity towards cancer cell lines. According to Western blot analysis, representative compound 7 induced the activation of caspase-3 in HSC-2 cells. These results may suggest that the apoptosis pathway may be one of the possible mechanisms of the actions and lead compound 7 can be subjected to further bioassays.

Supporting Institution

Research Foundation of Ataturk University

Project Number

2015-322

Thanks

The authors are thankful to Hiroshi Sakagami (Meikai University, Japan) and Noriyuki Okudaira (Meikai University, Japan) for biological studies.

References

  • 1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2019. CA: A Cancer Journal for Clinicians. 2019;69(1):7-34. Doi:10.3322/caac.21551
  • 2. American Cancer Society. Cancer facts and figures 2020. 2020:1-76
  • 3. Tewari D, Rawat P, Singh PK. Adverse drug reactions of anticancer drugs derived from natural sources. Food and Chemical Toxicology. 2019;123:522-35. Doi:10.1016/j.fct.2018.11.041
  • 4. Roman G. Mannich bases in medicinal chemistry and drug design. European Journal of Medicinal Chemistry. 2015;89:743-816. Doi: 10.1016/j.ejmech.2014.10.076
  • 5. Dimmock JR, Chamankhah M, Seniuk A, Allen TM, Kao GY, Halleran S. Synthesis and cytotoxic evaluation of some Mannich bases of alicyclic ketones. Pharmazie. 1995;50(10):668-71.
  • 6. Dimmock JR, Kandepu NM, Hetherington M, Quail JW, Pugazhenthi U, Sudom AM, et al. Cytotoxic activities of Mannich bases of chalcones and related compounds. Journal of Medicinal Chemistry. 1998;41(7):1014-26. Doi: 10.1021/jm970432t
  • 7. Gul M, Gul HI, Das U, Hanninen O. Biological evaluation and structure-activity relationships of bis-(3-aryl-3-oxo-propyl)methylamine hydrochlorides and 4-aryl-3-arylcarbonyl-1-methyl-4-piperidinol hydrochlorides as potential cytotoxic agents and their alkylating ability towards cellular glutathione in human leukemic T cells. Arzneimittelforsch. 2005;55(6):332-7. Doi: 10.1055/s-0031-1296868.
  • 8. Gul M, Gul HI, Hanninen O. Effects of Mannich bases on cellular glutathione and related enzymes of Jurkat cells in culture conditions. Toxicology in Vitro. 2002;16(2):107-12. Doi: 10.1016/S0887-2333(01)00115-1
  • 9. Gul M, Gul HI, Vepsalainen J, Erciyas E, Hanninen O. Effect of acetophenone derived Mannich bases on cellular glutathione level in jurkat cells - A possible mechanism of action. Arzneimittel-Forsch. 2001;51(8):679-82. Doi: 10.1055/s-0031-1300100
  • 10. Yerdelen KO, Gul HI, Sakagami H, Umemura N. Synthesis and biological evaluation of 1,5-bis(4-hydroxy-3-methoxyphenyl)penta-1,4-dien-3-one and its aminomethyl derivatives. Journal of Enzyme Inhibition and Medicinal Chemistry. 2015;30(3):383-8. Doi: 10.3109/14756366.2014.940934
  • 11. Yamali C, Gul HI, Sakagami H, Supuran CT. Synthesis and bioactivities of halogen bearing phenolic chalcones and their corresponding bis Mannich bases. Journal of Enzyme Inhibition and Medicinal Chemistry. 2016;31(sup4):125-31. Doi: 10.1080/14756366.2016.1221825.
  • 12. Tugrak M, Yamali C, Sakagami H, Gul HI. Synthesis of mono Mannich bases of 2-(4-hydroxybenzylidene)-2,3-dihydroinden-1-one and evaluation of their cytotoxicities. Journal of Enzyme Inhibition and Medicinal Chemistry. 2016;31(5):818-23. Doi: 10.3109/14756366.2015.1070263
  • 13. Gul HI, Yerdelen KO, Gul M, Das U, Pandit B, Li PK, et al. Synthesis of 4'-hydroxy-3'-piperidinomethylchalcone derivatives and their cytotoxicity against PC-3 cell lines. Archiv der Pharmazie. 2007;340(4):195-201. Doi: 10.1002/ardp.200600072
  • 14. Gul HI, Tugrak M, Sakagami H. Synthesis of some acrylophenones with N-methylpiperazine and evaluation of their cytotoxicities. Journal of Enzyme Inhibition and Medicinal Chemistry. 2016;31(1):147-51. Doi: 10.3109/14756366.2015.1014474
  • 15. Bilginer S, Gul HI, Mete E, Das U, Sakagami H, Umemura N, et al. 1-(3-aminomethyl-4-hydroxyphenyl)-3-pyridinyl-2-propen-1-ones: a novel group of tumour-selective cytotoxins. Journal of Enzyme Inhibition and Medicinal Chemistry. 2013;28(5):974-80. Doi: 10.3109/14756366.2012.700927
  • 16. Das S, Das U, Sakagami H, Hashimoto K, Kawase M, Gorecki DK, et al. Sequential cytotoxicity: a theory examined using a series of 3,5-bis(benzylidene)-1-diethylphosphono-4-oxopiperidines and related phosphonic acids. Bioorganic and Medicinal Chemistry Letters. 2010;20(22):6464-8. Doi: 10.1016/j.bmcl.2010.09.051
  • 17. Yamali C, Gul HI, Ece A, Bua S, Angeli A, Sakagami H, et al. Synthesis, biological evaluation and in silico modelling studies of 1,3,5-trisubstituted pyrazoles carrying benzenesulfonamide as potential anticancer agents and selective cancer-associated hCA IX isoenzyme inhibitors. Bioorganic Chemistry. 2019;92:103222. Doi: 10.1016/j.bioorg.2019.103222
  • 18. Yamali C, Gul HI, Ozgun DO, Sakagami H, Umemura N, Kazaz C, et al. Synthesis and cytotoxic activities of difluoro-dimethoxy chalcones. Anticancer Agents in Medicinal Chemistry. 2017;17(10):1426-33. Doi: 10.2174/1871520617666170327123909
  • 19. Yamali C, Ozmen Ozgun D, Gul HI, Sakagami H, Kazaz C, Okudaira N. Synthesis and structure elucidation of 1-(2,5/3,5-difluorophenyl)-3-(2,3/2,4/2,5/3,4-dimethoxyphenyl)-2-propen-1-ones as anticancer agents. Medicinal Chemistry Research. 2017;26(9):2015-23. Doi: 10.1007/s00044-017-1911-0
  • 20. Yamali C, Gul HI, Cakir T, Demir Y, Gulcin I. Aminoalkylated phenolic chalcones: Investigation of biological effects on acetylcholinesterase and carbonic anhydrase I and II as potential lead enzyme ınhibitors. Letters in Drug Design and Discovery. 2020;17(10):1283-92. Doi: 10.2174/1570180817999200520123510
  • 21. Robles-Escajeda E, Das U, Ortega NM, Parra K, Francia G, Dimmock JR, et al. A novel curcumin-like dienone induces apoptosis in triple-negative breast cancer cells. Cellular Oncology (Dordr). 2016;39(3):265-77. Doi: 10.1007/s13402-016-0272-x
  • 22. Das U, Sakagami H, Chu Q, Wang Q, Kawase M, Selvakumar P, et al. 3,5-Bis(benzylidene)-1-[4-2-(morpholin-4-yl)ethoxyphenylcarbonyl]-4-piperidone hydrochloride: A lead tumor-specific cytotoxin which induces apoptosis and autophagy. Bioorganic and Medicinal Chemistry Letter. 2010;20(3):912-7. Doi: 10.1016/j.bmcl.2009.12.076
  • 23. Daina A, Michielin O, Zoete V. SwissADME: A free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules. Scientific Reports. 2017;7:42717. Doi: 10.1038/srep42717
  • 24. Fink SL, Cookson BT. Apoptosis, pyroptosis, and necrosis: Mechanistic description of dead and dying eukaryotic cells. Infection and Immunity. 2005;73(4):1907-16. Doi:10.1128/IAI.73.4.1907-1916.2005
Year 2021, , 187 - 194, 28.02.2021
https://doi.org/10.18596/jotcsa.817007

Abstract

Project Number

2015-322

References

  • 1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2019. CA: A Cancer Journal for Clinicians. 2019;69(1):7-34. Doi:10.3322/caac.21551
  • 2. American Cancer Society. Cancer facts and figures 2020. 2020:1-76
  • 3. Tewari D, Rawat P, Singh PK. Adverse drug reactions of anticancer drugs derived from natural sources. Food and Chemical Toxicology. 2019;123:522-35. Doi:10.1016/j.fct.2018.11.041
  • 4. Roman G. Mannich bases in medicinal chemistry and drug design. European Journal of Medicinal Chemistry. 2015;89:743-816. Doi: 10.1016/j.ejmech.2014.10.076
  • 5. Dimmock JR, Chamankhah M, Seniuk A, Allen TM, Kao GY, Halleran S. Synthesis and cytotoxic evaluation of some Mannich bases of alicyclic ketones. Pharmazie. 1995;50(10):668-71.
  • 6. Dimmock JR, Kandepu NM, Hetherington M, Quail JW, Pugazhenthi U, Sudom AM, et al. Cytotoxic activities of Mannich bases of chalcones and related compounds. Journal of Medicinal Chemistry. 1998;41(7):1014-26. Doi: 10.1021/jm970432t
  • 7. Gul M, Gul HI, Das U, Hanninen O. Biological evaluation and structure-activity relationships of bis-(3-aryl-3-oxo-propyl)methylamine hydrochlorides and 4-aryl-3-arylcarbonyl-1-methyl-4-piperidinol hydrochlorides as potential cytotoxic agents and their alkylating ability towards cellular glutathione in human leukemic T cells. Arzneimittelforsch. 2005;55(6):332-7. Doi: 10.1055/s-0031-1296868.
  • 8. Gul M, Gul HI, Hanninen O. Effects of Mannich bases on cellular glutathione and related enzymes of Jurkat cells in culture conditions. Toxicology in Vitro. 2002;16(2):107-12. Doi: 10.1016/S0887-2333(01)00115-1
  • 9. Gul M, Gul HI, Vepsalainen J, Erciyas E, Hanninen O. Effect of acetophenone derived Mannich bases on cellular glutathione level in jurkat cells - A possible mechanism of action. Arzneimittel-Forsch. 2001;51(8):679-82. Doi: 10.1055/s-0031-1300100
  • 10. Yerdelen KO, Gul HI, Sakagami H, Umemura N. Synthesis and biological evaluation of 1,5-bis(4-hydroxy-3-methoxyphenyl)penta-1,4-dien-3-one and its aminomethyl derivatives. Journal of Enzyme Inhibition and Medicinal Chemistry. 2015;30(3):383-8. Doi: 10.3109/14756366.2014.940934
  • 11. Yamali C, Gul HI, Sakagami H, Supuran CT. Synthesis and bioactivities of halogen bearing phenolic chalcones and their corresponding bis Mannich bases. Journal of Enzyme Inhibition and Medicinal Chemistry. 2016;31(sup4):125-31. Doi: 10.1080/14756366.2016.1221825.
  • 12. Tugrak M, Yamali C, Sakagami H, Gul HI. Synthesis of mono Mannich bases of 2-(4-hydroxybenzylidene)-2,3-dihydroinden-1-one and evaluation of their cytotoxicities. Journal of Enzyme Inhibition and Medicinal Chemistry. 2016;31(5):818-23. Doi: 10.3109/14756366.2015.1070263
  • 13. Gul HI, Yerdelen KO, Gul M, Das U, Pandit B, Li PK, et al. Synthesis of 4'-hydroxy-3'-piperidinomethylchalcone derivatives and their cytotoxicity against PC-3 cell lines. Archiv der Pharmazie. 2007;340(4):195-201. Doi: 10.1002/ardp.200600072
  • 14. Gul HI, Tugrak M, Sakagami H. Synthesis of some acrylophenones with N-methylpiperazine and evaluation of their cytotoxicities. Journal of Enzyme Inhibition and Medicinal Chemistry. 2016;31(1):147-51. Doi: 10.3109/14756366.2015.1014474
  • 15. Bilginer S, Gul HI, Mete E, Das U, Sakagami H, Umemura N, et al. 1-(3-aminomethyl-4-hydroxyphenyl)-3-pyridinyl-2-propen-1-ones: a novel group of tumour-selective cytotoxins. Journal of Enzyme Inhibition and Medicinal Chemistry. 2013;28(5):974-80. Doi: 10.3109/14756366.2012.700927
  • 16. Das S, Das U, Sakagami H, Hashimoto K, Kawase M, Gorecki DK, et al. Sequential cytotoxicity: a theory examined using a series of 3,5-bis(benzylidene)-1-diethylphosphono-4-oxopiperidines and related phosphonic acids. Bioorganic and Medicinal Chemistry Letters. 2010;20(22):6464-8. Doi: 10.1016/j.bmcl.2010.09.051
  • 17. Yamali C, Gul HI, Ece A, Bua S, Angeli A, Sakagami H, et al. Synthesis, biological evaluation and in silico modelling studies of 1,3,5-trisubstituted pyrazoles carrying benzenesulfonamide as potential anticancer agents and selective cancer-associated hCA IX isoenzyme inhibitors. Bioorganic Chemistry. 2019;92:103222. Doi: 10.1016/j.bioorg.2019.103222
  • 18. Yamali C, Gul HI, Ozgun DO, Sakagami H, Umemura N, Kazaz C, et al. Synthesis and cytotoxic activities of difluoro-dimethoxy chalcones. Anticancer Agents in Medicinal Chemistry. 2017;17(10):1426-33. Doi: 10.2174/1871520617666170327123909
  • 19. Yamali C, Ozmen Ozgun D, Gul HI, Sakagami H, Kazaz C, Okudaira N. Synthesis and structure elucidation of 1-(2,5/3,5-difluorophenyl)-3-(2,3/2,4/2,5/3,4-dimethoxyphenyl)-2-propen-1-ones as anticancer agents. Medicinal Chemistry Research. 2017;26(9):2015-23. Doi: 10.1007/s00044-017-1911-0
  • 20. Yamali C, Gul HI, Cakir T, Demir Y, Gulcin I. Aminoalkylated phenolic chalcones: Investigation of biological effects on acetylcholinesterase and carbonic anhydrase I and II as potential lead enzyme ınhibitors. Letters in Drug Design and Discovery. 2020;17(10):1283-92. Doi: 10.2174/1570180817999200520123510
  • 21. Robles-Escajeda E, Das U, Ortega NM, Parra K, Francia G, Dimmock JR, et al. A novel curcumin-like dienone induces apoptosis in triple-negative breast cancer cells. Cellular Oncology (Dordr). 2016;39(3):265-77. Doi: 10.1007/s13402-016-0272-x
  • 22. Das U, Sakagami H, Chu Q, Wang Q, Kawase M, Selvakumar P, et al. 3,5-Bis(benzylidene)-1-[4-2-(morpholin-4-yl)ethoxyphenylcarbonyl]-4-piperidone hydrochloride: A lead tumor-specific cytotoxin which induces apoptosis and autophagy. Bioorganic and Medicinal Chemistry Letter. 2010;20(3):912-7. Doi: 10.1016/j.bmcl.2009.12.076
  • 23. Daina A, Michielin O, Zoete V. SwissADME: A free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules. Scientific Reports. 2017;7:42717. Doi: 10.1038/srep42717
  • 24. Fink SL, Cookson BT. Apoptosis, pyroptosis, and necrosis: Mechanistic description of dead and dying eukaryotic cells. Infection and Immunity. 2005;73(4):1907-16. Doi:10.1128/IAI.73.4.1907-1916.2005
There are 24 citations in total.

Details

Primary Language English
Journal Section Articles
Authors

Cem Yamalı 0000-0002-4833-7900

Halise İnci Gül 0000-0001-6164-9602

Project Number 2015-322
Publication Date February 28, 2021
Submission Date October 27, 2020
Acceptance Date December 15, 2020
Published in Issue Year 2021

Cite

Vancouver Yamalı C, Gül Hİ. Cytotoxic effects of Mannich bases via induction of caspase-3 pathway on human oral squamous cell carcinoma. JOTCSA. 2021;8(1):187-94.