One-Pot Synthesis and Biological Evaluation of Piperidinium-3,3'-(arylmethylene) bis-lawsone derivatives by targeting caspase-7
Keywords:
bis-lawsone, caspase-7 inhibitors, Alzheimer’s
Abstract
Caspase-7, an effector enzyme activated by the initiator caspase-1, plays a crucial role in triggering apoptosis. It is also a significant factor in neurodegenerative conditions like Alzheimer's and Huntington's diseases. While both peptide and nonpeptide caspase inhibitors have shown promise in preclinical research, peptide inhibitors face challenges such as poor cell permeability, brief half-life, limited efficacy, and complex structures that are difficult to optimize. Additionally, they encounter bioavailability issues. Consequently, the development of nonpeptide-based caspase inhibitors remains an area of interest for researchers. Using a multicomponent reaction, eight lawsone derivatives, specifically piperidinium-3,3'-(arylmethylene) bis-lawsone, were successfully synthesized. This group included five novel compounds (2, 3, 4, 7, 8) and three previously known ones (1, 5, 6). The products were analyzed using Nuclear Magnetic Resonance (NMR) 1-2D spectroscopy and High Resolution Mass Spectrometry (HRMS), followed by an evaluation of their inhibitory activity against caspase-7. Notably, this study marks the first instance of piperidinium-3,3'-(arylmethylene) bis-lawsone being investigated for its potential to target the caspase-7 enzyme. Among the eight compounds, compound 8 demonstrated the most promising results, exhibiting an inhibitory activity of approximately 29.80% against caspase-7. This finding suggests that compound 8 could serve as a valuable fragment molecule for future development of caspase-7 inhibitors.
References
Abcam. (2023, August 17). Caspase-7 Inhibitor Assay Kit (ab102495). Abcam. Retrieved from https://www.abcam.com/products/assay-kits/caspase-7-inhibitor-assay-kit-ab102495.html
Basu, S., Rajakaruna, S., & Menko, A. S. (2012). Insulin-like growth factor receptor-1 and nuclear factor κB are crucial survival signals that regulate caspase-3-mediated lens epithelial cell differentiation initiation. Journal of Biological Chemistry, 287(11), 8384-8397.
https://doi.org/10.1074/jbc.M112.341586
Boucher, D., Blais, V., & Denault, J.-B. (2012). Caspase-7 uses an exosite to promote poly(ADP ribose) polymerase 1 proteolysis. Proceedings of the National Academy of Sciences, 109(15), 5669-5674. https://doi.org/10.1073/pnas.1200934109
Brahmachari, G. 2015. Sulfamic acid-catalyzed one-pot room temperature synthesis of biologically relevant bis-lawsone derivatives. ACS Sustainable Chemistry & Engineering, 3(9), 2058-2066.
https://doi.org/10.1021/acssuschemeng.5b00325.
Brentnall, M., Rodriguez-Menocal, L., De Guevara, R. L., Cepero, E., & Boise, L. H. (2013). Caspase-9, caspase-3 and caspase-7 have distinct roles during intrinsic apoptosis. BMC Cell Biology, 14, 32. https://doi.org/10.1186/1471-2121-14-32
Chinnapaka, S., Zheng, G., Chen, A., & Munirathinam, G. (2019). Nitro aspirin (NCX4040) induces apoptosis in PC3 metastatic prostate cancer cells via hydrogen peroxide (H2O2)-mediated oxidative stress. Free Radical Biology and Medicine, 143, 494-509. https://doi.org/https://doi.org/10.1016/j.freeradbiomed.2019.08.025
Fatahpour, M., Hazeri, N., Maghsoodlou, M. T., Sadeh, F. N., & Lshkari, M. (2018). One-pot multicomponent synthesis of piperidinium 3, 3'-(arylmethylene) bis (2-hydroxynaphthalene-1, 4-diones): NMR spectroscopic and X-ray~ structure characterization. Turkish Journal of Chemistry, 42(3), 908-917.
https://doi.org/10.3906/kim-1712-52
Fernando, P., Kelly, J. F., Balazsi, K., Slack, R. S., & Megeney, L. A. (2002). Caspase 3 activity is required for skeletal muscle differentiation. Proceedings of the National Academy of Sciences, 99(17), 11025-11030. https://doi.org/10.1073/pnas.162172899
Fiorucci, S. (2001). NO-releasing NSAIDs are caspase inhibitors. Trends in Immunology, 22(5), 232-235.
https://doi.org/10.1016/s1471-4906(01)01904-4
Fujita, J., Crane, A. M., Souza, M. K., Dejosez, M., Kyba, M., Flavell, R. A., Thomson, J. A., & Zwaka, T. P. (2008). Caspase activity mediates the differentiation of embryonic stem cells. Cell stem cell, 2(6), 595-601.
https://doi.org/10.1016/j.stem.2008.04.001
Hermel, E., Gafni, J., Propp, S. S., Leavitt, B. R., Wellington, C. L., Young, J. E., Hackam, A. S., Logvinova, A. V., Peel, A. L., Chen, S. F., Hook, V., Singaraja, R., Krajewski, S., Goldsmith, P. C., Ellerby, H. M., Hayden, M. R., Bredesen, D. E., & Ellerby, L. M. (2004). Specific caspase interactions and amplification are involved in selective neuronal vulnerability in Huntington's disease. Cell Death & Differentiation, 11(4), 424-438. https://doi.org/10.1038/sj.cdd.4401358
Ivachtchenko, A. V., Okun, I., Tkachenko, S. E., Kiselyov, A. S., Ivanenkov, Y. A., & Balakin, K. V. (2009). Nonpeptide small molecule inhibitors of caspases. In Design of Caspase Inhibitors as Potential Clinical Agents (pp. 93-122). CRC Press Boca Raton, FL.
https://doi.org/10.1201/9781420045413.ch5
Jentzsch, J., Koko, W. S., Al Nasr, I. S., Khan, T. A., Schobert, R., Ersfeld, K., & Biersack, B. (2020). New Antiparasitic Bis‐Naphthoquinone Derivatives. Chemistry & biodiversity, 17(2), e1900597.
https://doi.org/10.1002/cbdv.201900597
Jiang, Y., & Hansen, T. V. (2011). Isatin 1,2,3-triazoles as potent inhibitors against caspase-3. Bioorganic & Medicinal Chemistry Letters., 21(6), 1626-1629. https://doi.org/https://doi.org/10.1016/j.bmcl.2011.01.110
Julien, O., & Wells, J. A. (2017). Caspases and their substrates. Cell Death & Differentiation,., 24, 1380-1389. https://doi.org/10.1038/cdd.2017.44
Kashyap, D., Garg, V. K., & Goel, N. (2021). Chapter Four - Intrinsic and extrinsic pathways of apoptosis: Role in cancer development and prognosis. In R. Donev (Ed.), Advances in Protein Chemistry and Structural Biology (Vol. 125, pp. 73-120). Academic Press. https://doi.org/https://doi.org/10.1016/bs.apcsb.2021.01.003
Lamkanfi, M., & Kanneganti, T. D. Caspase-7: a protease involved in apoptosis and inflammation. (1878-5875 (Electronic)).
Larsen, B. D., Rampalli, S., Burns, L. E., Brunette, S., Dilworth, F. J., & Megeney, L. A. (2010). Caspase 3/caspase-activated DNase promote cell differentiation by inducing DNA strand breaks. Proceedings of the National Academy of Sciences, 107(9), 4230-4235. https://doi.org/doi:10.1073/pnas.0913089107
Lee, D., Long, S. A., Adams, J. L., Chan, G., Vaidya, K. S., Francis, T. A., Kikly, K., Winkler, J. D., Sung, C.-M., & Debouck, C. (2000). Potent and selective nonpeptide inhibitors of caspases 3 and 7 inhibit apoptosis and maintain cell functionality. Journal of Biological Chemistry, 275(21), 16007-16014.
https://doi.org/10.1074/jbc.275.21.16007
Lee, D., Long, S. A., Murray, J. H., Adams, J. L., Nuttall, M. E., Nadeau, D. P., Kikly, K., Winkler, J. D., Sung, C.-M., Ryan, M. D., Levy, M. A., Keller, P. M., & DeWolf, W. E. (2001). Potent and Selective Nonpeptide Inhibitors of Caspases 3 and 7. Journal of Medicinal Chemistry, 44(21), 2015-2026. https://doi.org/10.1021/jm0100537
Limpachayaporn, P., Schäfers, M., & Haufe, G. (2015). Isatin sulfonamides: potent caspases-3 and-7 inhibitors, and promising PET and SPECT radiotracers for apoptosis imaging. Future Med. Chem., 7(9), 1173-1196. https://doi.org/https://doi.org/10.4155/fmc.15.52
O'Brien, T., & Lee, D. (2004). Prospects for caspase inhibitors. Mini-Reviews in Medicinal Chemistry, 4(2), 153-165. https://doi.org/https://doi.org/10.2174/1389557043487448
Ramasamy, K., Sisy Sam, S., & Chandrasekaran, A. (2006). Allele and Genotype Frequency of MDR1 C3435T in Tamilian Population. Drug Metabolism and Pharmacokinetics., 21(6), 506-508. https://doi.org/https://doi.org/10.2133/dmpk.21.506
Riaz, M. T., Yaqub, M., Shafiq, Z., Ashraf, A., Khalid, M., Taslimi, P., Tas, R., Tuzun, B., & Gulcin, I. (2021). Synthesis, biological activity and docking calculations of bis-naphthoquinone derivatives from Lawsone. Bioorganic Chemistry, 114, 105069.
https://doi.org/10.1016/j.bioorg.2021.105069
Sanchez, C., Reines, E. H., & Montgomery, S. A. (2014). A comparative review of escitalopram, paroxetine, and sertraline: are they all alike? International clinical psychopharmacology, 29(4), 185.
https://doi.org/10.1097/YIC.0000000000000023
Tezcan, B., Gök, Y., Sevinçek, R., Taslimi, P., Taskin‐Tok, T., Aktaş, A., Güzel, B., Aygün, M., & Gülçin, İ. (2022). Benzimidazolium salts bearing the trifluoromethyl group as organofluorine compounds: Synthesis, characterization, crystal structure, in silico study, and inhibitory profiles against acetylcholinesterase and α‐glycosidase. Journal of Biochemical and Molecular Toxicology, 36(4), e23001.
https://doi.org/10.1002/jbt.23001
Vickers, C. J., González-Páez, G. E., & Wolan, D. W. (2013). Selective Detection and Inhibition of Active Caspase-3 in Cells with Optimized Peptides. Journal of The American Chemical Society, 135(34), 12869-12876. https://doi.org/10.1021/ja406399r
Walsh, J. G., Cullen, S. P., Sheridan, C., Lüthi, A. U., Gerner, C., & Martin, S. J. (2008). Executioner caspase-3 and caspase-7 are functionally distinct proteases. Proceedings of the National Academy of Sciences, 105(35), 12815-12819. https://doi.org/doi:10.1073/pnas.0707715105
Zengin, R., Gök, Y., Demir, Y., Şen, B., Taskin-Tok, T., Aktaş, A., Demirci, Ö., Gülçin, İ., & Aygün, M. (2023). Fluorinated benzimidazolium salts: Synthesis, characterization, molecular docking studies and inhibitory properties against some metabolic enzymes. Journal of Fluorine Chemistry, 267,110094. https://doi.org/10.1016/j.jfluchem.2023.110094
Basu, S., Rajakaruna, S., & Menko, A. S. (2012). Insulin-like growth factor receptor-1 and nuclear factor κB are crucial survival signals that regulate caspase-3-mediated lens epithelial cell differentiation initiation. Journal of Biological Chemistry, 287(11), 8384-8397.
https://doi.org/10.1074/jbc.M112.341586
Boucher, D., Blais, V., & Denault, J.-B. (2012). Caspase-7 uses an exosite to promote poly(ADP ribose) polymerase 1 proteolysis. Proceedings of the National Academy of Sciences, 109(15), 5669-5674. https://doi.org/10.1073/pnas.1200934109
Brahmachari, G. 2015. Sulfamic acid-catalyzed one-pot room temperature synthesis of biologically relevant bis-lawsone derivatives. ACS Sustainable Chemistry & Engineering, 3(9), 2058-2066.
https://doi.org/10.1021/acssuschemeng.5b00325.
Brentnall, M., Rodriguez-Menocal, L., De Guevara, R. L., Cepero, E., & Boise, L. H. (2013). Caspase-9, caspase-3 and caspase-7 have distinct roles during intrinsic apoptosis. BMC Cell Biology, 14, 32. https://doi.org/10.1186/1471-2121-14-32
Chinnapaka, S., Zheng, G., Chen, A., & Munirathinam, G. (2019). Nitro aspirin (NCX4040) induces apoptosis in PC3 metastatic prostate cancer cells via hydrogen peroxide (H2O2)-mediated oxidative stress. Free Radical Biology and Medicine, 143, 494-509. https://doi.org/https://doi.org/10.1016/j.freeradbiomed.2019.08.025
Fatahpour, M., Hazeri, N., Maghsoodlou, M. T., Sadeh, F. N., & Lshkari, M. (2018). One-pot multicomponent synthesis of piperidinium 3, 3'-(arylmethylene) bis (2-hydroxynaphthalene-1, 4-diones): NMR spectroscopic and X-ray~ structure characterization. Turkish Journal of Chemistry, 42(3), 908-917.
https://doi.org/10.3906/kim-1712-52
Fernando, P., Kelly, J. F., Balazsi, K., Slack, R. S., & Megeney, L. A. (2002). Caspase 3 activity is required for skeletal muscle differentiation. Proceedings of the National Academy of Sciences, 99(17), 11025-11030. https://doi.org/10.1073/pnas.162172899
Fiorucci, S. (2001). NO-releasing NSAIDs are caspase inhibitors. Trends in Immunology, 22(5), 232-235.
https://doi.org/10.1016/s1471-4906(01)01904-4
Fujita, J., Crane, A. M., Souza, M. K., Dejosez, M., Kyba, M., Flavell, R. A., Thomson, J. A., & Zwaka, T. P. (2008). Caspase activity mediates the differentiation of embryonic stem cells. Cell stem cell, 2(6), 595-601.
https://doi.org/10.1016/j.stem.2008.04.001
Hermel, E., Gafni, J., Propp, S. S., Leavitt, B. R., Wellington, C. L., Young, J. E., Hackam, A. S., Logvinova, A. V., Peel, A. L., Chen, S. F., Hook, V., Singaraja, R., Krajewski, S., Goldsmith, P. C., Ellerby, H. M., Hayden, M. R., Bredesen, D. E., & Ellerby, L. M. (2004). Specific caspase interactions and amplification are involved in selective neuronal vulnerability in Huntington's disease. Cell Death & Differentiation, 11(4), 424-438. https://doi.org/10.1038/sj.cdd.4401358
Ivachtchenko, A. V., Okun, I., Tkachenko, S. E., Kiselyov, A. S., Ivanenkov, Y. A., & Balakin, K. V. (2009). Nonpeptide small molecule inhibitors of caspases. In Design of Caspase Inhibitors as Potential Clinical Agents (pp. 93-122). CRC Press Boca Raton, FL.
https://doi.org/10.1201/9781420045413.ch5
Jentzsch, J., Koko, W. S., Al Nasr, I. S., Khan, T. A., Schobert, R., Ersfeld, K., & Biersack, B. (2020). New Antiparasitic Bis‐Naphthoquinone Derivatives. Chemistry & biodiversity, 17(2), e1900597.
https://doi.org/10.1002/cbdv.201900597
Jiang, Y., & Hansen, T. V. (2011). Isatin 1,2,3-triazoles as potent inhibitors against caspase-3. Bioorganic & Medicinal Chemistry Letters., 21(6), 1626-1629. https://doi.org/https://doi.org/10.1016/j.bmcl.2011.01.110
Julien, O., & Wells, J. A. (2017). Caspases and their substrates. Cell Death & Differentiation,., 24, 1380-1389. https://doi.org/10.1038/cdd.2017.44
Kashyap, D., Garg, V. K., & Goel, N. (2021). Chapter Four - Intrinsic and extrinsic pathways of apoptosis: Role in cancer development and prognosis. In R. Donev (Ed.), Advances in Protein Chemistry and Structural Biology (Vol. 125, pp. 73-120). Academic Press. https://doi.org/https://doi.org/10.1016/bs.apcsb.2021.01.003
Lamkanfi, M., & Kanneganti, T. D. Caspase-7: a protease involved in apoptosis and inflammation. (1878-5875 (Electronic)).
Larsen, B. D., Rampalli, S., Burns, L. E., Brunette, S., Dilworth, F. J., & Megeney, L. A. (2010). Caspase 3/caspase-activated DNase promote cell differentiation by inducing DNA strand breaks. Proceedings of the National Academy of Sciences, 107(9), 4230-4235. https://doi.org/doi:10.1073/pnas.0913089107
Lee, D., Long, S. A., Adams, J. L., Chan, G., Vaidya, K. S., Francis, T. A., Kikly, K., Winkler, J. D., Sung, C.-M., & Debouck, C. (2000). Potent and selective nonpeptide inhibitors of caspases 3 and 7 inhibit apoptosis and maintain cell functionality. Journal of Biological Chemistry, 275(21), 16007-16014.
https://doi.org/10.1074/jbc.275.21.16007
Lee, D., Long, S. A., Murray, J. H., Adams, J. L., Nuttall, M. E., Nadeau, D. P., Kikly, K., Winkler, J. D., Sung, C.-M., Ryan, M. D., Levy, M. A., Keller, P. M., & DeWolf, W. E. (2001). Potent and Selective Nonpeptide Inhibitors of Caspases 3 and 7. Journal of Medicinal Chemistry, 44(21), 2015-2026. https://doi.org/10.1021/jm0100537
Limpachayaporn, P., Schäfers, M., & Haufe, G. (2015). Isatin sulfonamides: potent caspases-3 and-7 inhibitors, and promising PET and SPECT radiotracers for apoptosis imaging. Future Med. Chem., 7(9), 1173-1196. https://doi.org/https://doi.org/10.4155/fmc.15.52
O'Brien, T., & Lee, D. (2004). Prospects for caspase inhibitors. Mini-Reviews in Medicinal Chemistry, 4(2), 153-165. https://doi.org/https://doi.org/10.2174/1389557043487448
Ramasamy, K., Sisy Sam, S., & Chandrasekaran, A. (2006). Allele and Genotype Frequency of MDR1 C3435T in Tamilian Population. Drug Metabolism and Pharmacokinetics., 21(6), 506-508. https://doi.org/https://doi.org/10.2133/dmpk.21.506
Riaz, M. T., Yaqub, M., Shafiq, Z., Ashraf, A., Khalid, M., Taslimi, P., Tas, R., Tuzun, B., & Gulcin, I. (2021). Synthesis, biological activity and docking calculations of bis-naphthoquinone derivatives from Lawsone. Bioorganic Chemistry, 114, 105069.
https://doi.org/10.1016/j.bioorg.2021.105069
Sanchez, C., Reines, E. H., & Montgomery, S. A. (2014). A comparative review of escitalopram, paroxetine, and sertraline: are they all alike? International clinical psychopharmacology, 29(4), 185.
https://doi.org/10.1097/YIC.0000000000000023
Tezcan, B., Gök, Y., Sevinçek, R., Taslimi, P., Taskin‐Tok, T., Aktaş, A., Güzel, B., Aygün, M., & Gülçin, İ. (2022). Benzimidazolium salts bearing the trifluoromethyl group as organofluorine compounds: Synthesis, characterization, crystal structure, in silico study, and inhibitory profiles against acetylcholinesterase and α‐glycosidase. Journal of Biochemical and Molecular Toxicology, 36(4), e23001.
https://doi.org/10.1002/jbt.23001
Vickers, C. J., González-Páez, G. E., & Wolan, D. W. (2013). Selective Detection and Inhibition of Active Caspase-3 in Cells with Optimized Peptides. Journal of The American Chemical Society, 135(34), 12869-12876. https://doi.org/10.1021/ja406399r
Walsh, J. G., Cullen, S. P., Sheridan, C., Lüthi, A. U., Gerner, C., & Martin, S. J. (2008). Executioner caspase-3 and caspase-7 are functionally distinct proteases. Proceedings of the National Academy of Sciences, 105(35), 12815-12819. https://doi.org/doi:10.1073/pnas.0707715105
Zengin, R., Gök, Y., Demir, Y., Şen, B., Taskin-Tok, T., Aktaş, A., Demirci, Ö., Gülçin, İ., & Aygün, M. (2023). Fluorinated benzimidazolium salts: Synthesis, characterization, molecular docking studies and inhibitory properties against some metabolic enzymes. Journal of Fluorine Chemistry, 267,110094. https://doi.org/10.1016/j.jfluchem.2023.110094
Published
2025-03-27
How to Cite
hermawati, elvira, Taufik, M., Danova, A., Chavasiri, W., & Mujahidin, D. (2025). One-Pot Synthesis and Biological Evaluation of Piperidinium-3,3’-(arylmethylene) bis-lawsone derivatives by targeting caspase-7. Indonesian Journal of Pharmacy. https://doi.org/10.22146/ijp.16734
Issue
Section
Research Article
