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

Year 2021, Volume: 8 Issue: 1, 187 - 194, 28.02.2021

Cem Yamalı Halise İnci Gül

https://doi.org/10.18596/jotcsa.817007

Cited By: 2

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.

Keywords

Mannich, anticancer, apoptosis

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