Synthesis and Evaluation of New 1, 4-Dihydropyridine Derivatives as Potential Breast Cancer Therapeutics: HER2 Inhibition Efficacy Study Using MCF-7 and SK-BR-3 Cells and Molecular Docking

Abdulrhman Y. Khalifa

Abstract

The derivatives of 1,4-Dihydropyridine compound have gained significant interest for their potential-anticancer properties particularly in targeting breast-cancer. The study aimed to synthesize and evaluate the anticancer activity of four novel 1,4-dihydropyridine derivatives (5a–d) against breast cancer cell lines MCF-7 and SK-BR-3. The derivatives were synthesized via the reaction of N-(4-nitrophenyl)-3-oxobutanamide with substituted benzaldehyde and ammonium acetate. Cytotoxic activity was assessed using MCF-7 and SK-BR-3 cells, and IC₅₀ values were determined. Molecular docking was performed to evaluate the binding affinity of the compounds to the HER2 receptor. Structural characterization was conducted using FT-IR, ¹H-NMR, ¹³C-NMR, and mass spectrometry. All four derivatives (5a–d) demonstrated higher inhibition rates in SK-BR-3 cells (72%, 83%, 89%, and 85%, respectively) compared to MCF-7 cells (51%, 54%, 58%, and 55%) at a concentration of 100 μg. Compound 5c exhibited the highest cytotoxicity, with the lowest IC₅₀ value (18.5 μg/mL) against SK-BR-3 cells, followed by 5b and 5d, while 5a showed the weakest effect. Molecular docking results supported the potential of these compounds as HER2-targeted agents. The synthesized 1,4-dihydropyridine derivatives, particularly compound 5c, demonstrated promising anticancer activity, especially against HER2-positive SK-BR-3 cells.

Keywords

1,4-dihydropyridine derivatives; breast cancer; MCF-7 cells; SK-BR-3 cells; HER2 receptors.

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References

Abdullah, H. T., Al-Bayati, A. M., Saleh, A. N. A., Alsalihi, K. A., and Abed, H. H., 2025. Effect of Ocimum basilicum Herbs Extract on Pro-Inflammatory Cytokines in Ethanol-Induced Liver Damage in Rats. Wiadomości Lekarskie, 1522–1529. https://doi.org/10.36740/WLek/208443.

Ades, F., Zardavas, D., Bozovic-Spasojevic, I., Pugliano, L., Fumagalli, D., De Azambuja, E., Viale, G., Sotiriou, C., and Piccart, M., 2014. Luminal B Breast Cancer: Molecular Characterization, Clinical Management, and Future Perspectives. Journal of Clinical Oncology, 32, 2794–2803. https://doi.org/10.1200/JCO.2013.54.1870.

Aertgeerts, K., Skene, R., Yano, J., Sang, B.-C., Zou, H., Snell, G., Jennings, A., Iwamoto, K., Habuka, N., Hirokawa, A., Ishikawa, T., Tanaka, T., Miki, H., Ohta, Y., and Sogabe, S., 2011. Structural Analysis of the Mechanism of Inhibition and Allosteric Activation of the Kinase Domain of HER2 Protein. Journal of Biological Chemistry, 286, 18756–18765. https://doi.org/10.1074/jbc.M110.206193.

Arienti, C., Pignatta, S., and Tesei, A., 2019. Epidermal Growth Factor Receptor Family and Its Role in Gastric Cancer. Frontiers in Oncology, 9, 1308. https://doi.org/10.3389/fonc.2019.01308.

Bergin, A. R. T. and Loi, S., 2019. Triple-Negative Breast Cancer: Recent Treatment Advances. F1000Research, 8, 1342. https://doi.org/10.12688/f1000research.18888.1.

Bilani, N., Zabor, E. C., Elson, L., Elimimian, E. B., and Nahleh, Z., 2020. Breast Cancer in the United States: A Cross-Sectional Overview. Journal of Cancer Epidemiology, 2020, 1–8. https://doi.org/10.1155/2020/6387378.

Desai, B., Sureja, D., Naliapara, Y., Shah, A., and Saxena, A. K., 2001. Synthesis and QSAR Studies of 4-Substituted Phenyl-2,6-Dimethyl-3, 5-Bis-N-(Substituted Phenyl)Carbamoyl-1,4-Dihydropyridines as Potential Antitubercular Agents. Bioorganic & Medicinal Chemistry, 9, 1993–1998. https://doi.org/10.1016/S0968-0896(01)00141-9.

Faizan, S., Hani, U., Haider, N., Vadivel, V., and Prashantha Kumar, B. R., 2024. N-Substituted Dihydropyridines as Promising EGFR Tyrosine Kinase Inhibitors against Breast Cancer: Design, Synthesis, Biological Evaluation, Docking, and Molecular Dynamics Simulations. Results in Chemistry, 7, 101502. https://doi.org/10.1016/j.rechem.2024.101502.

Gao, J. J. and Swain, S. M., 2018. Luminal a Breast Cancer and Molecular Assays: A Review. The Oncologist, 23, 556–565. https://doi.org/10.1634/theoncologist.2017-0535.

Gaudio, A. C., Korolkovas, A., and Takahata, Y., 1994. Quantitative Structure-Activity Relationships for 1,4-Dihydropyridine Calcium Channel Antagonists (Nifedipine analogues): A Quantum Chemicalklassical Approach. Journal of Pharmaceutical Sciences, 83, 1110–1115. https://doi.org/10.1002/jps.2600830809.

Iatrakis, G. and Zervoudis, S., 2021. Epidemiology of Ductal Carcinoma in Situ. Chirurgia, 116, S15. https://doi.org/10.21614/chirurgia.116.5.suppl.S15.

Joshi, H. and Press, M.F., 2018. Molecular Oncology of Breast Cancer. The Breast, Elsevier, e285, 282–307.

Kamińska, M., Ciszewski, T., Łopacka-Szatan, K., Miotła, P., and Starosławska, E., 2015. Breast Cancer Risk Factors. Menopausal Review, 3, 196–202. https://doi.org/10.5114/pm.2015.54346.

Liu, H., Zhu, S., Xia, G., Huang, Z., Han, W., Li, Z., and Liu, C., 2024. Effects of 1,4-Dihydropyridine Derivatives on Cell Injury and mTOR of HepG2 and 3d-QSAR Study. Computational Biology and Chemistry, 109, 108010. https://doi.org/10.1016/j.compbiolchem.2023.108010.

Loibl, S. and Gianni, L., 2017. HER2-Positive Breast Cancer. The Lancet, 389, 2415–2429. https://doi.org/10.1016/S0140-6736(16)32417-5.

Mannhold, R., Jablonka, B., Voigt, W., Schönafinger, K., and Schraven, E., 1992. Calcium- and Calmodulin-Antagonism of Elnadipine Derivatives: Comparative Sar. European Journal of Medicinal Chemistry, 27, 229–235. https://doi.org/10.1016/0223-5234(92)90006-M.

Mehany, M. M., Hammam, O. A., Selim, A. A., Sayed, G. H., and Anwer, K. E., 2024. Novel Pyridine Bearing Pentose Moiety-Based Anticancer Agents: Design, Synthesis, Radioiodination and Bioassessments. Scientific Reports, 14, 2738. https://doi.org/10.1038/s41598-024-53228-4.

Mishra, A. P., Bajpai, A., and Rai, A. K., 2019. 1,4-Dihydropyridine: A Dependable Heterocyclic Ring with the Promising and the Most Anticipable Therapeutic Effects. Mini-Reviews in Medicinal Chemistry, 19, 1219–1254. https://doi.org/10.2174/1389557519666190425184749.

Moradipoodeh, B., Jamalan, M., Zeinali, M., Fereidoonnezhad, M., and Mohammadzadeh, G., 2020. Specific Targeting of HER2-Positive Human Breast Carcinoma SK-BR-3 Cells by Amygdaline-ZHER2 Affibody Conjugate. Molecular Biology Reports, 47, 7139-7151. https://doi.org/10.1007/s11033-020-05782-z.

Obeagu, E., Abdi, Y., Obeagu, G., Bunu, U. O., P.C, U., and Alum, E., 2023. Biomakers of Breast Cancer: Overview. International Journal of Current Research in Biological Medicine, 8, 8–16. https://doi.org/10.22192/ijcrbm.2023.08.01.002.

Oliveira, T. a. S., Silva, J. B. A., Esperandim, T. R., Acésio, N. O., Tavares, D. C., and Crotti, A. E. M., 2024. Anticancer Activity of 4-Aryl-1,4-Dihydropyridines. Future Pharmacology, 4, 564–573. https://doi.org/10.3390/futurepharmacol4030031.

Radadiya, A., Khedkar, V., Bavishi, A., Vala, H., Thakrar, S., Bhavsar, D., Shah, A., and Coutinho, E., 2014. Synthesis and 3d-Qsar Study of 1,4-Dihydropyridine Derivatives as MDR Cancer Reverters. European Journal of Medicinal Chemistry, 74, 375–387. https://doi.org/10.1016/j.ejmech.2014.01.011.

Rubin, E., Shan, K., Dalal, S., Vu, D., Milillo-Naraine, A., Guaqueta, D., and Ergle, A., 2024. Molecular Targeting of the Human Epidermal Growth Factor Receptor-2 (HER2) Genes across Various Cancers. International Journal of Molecular Sciences, 25, 1064. https://doi.org/10.3390/ijms25021064.

Safak, C. and Simsek, R., 2006. Fused 1,4-Dihydropyridines as Potential Calcium Modulatory Compounds. Mini-Reviews in Medicinal Chemistry, 6, 747–755. https://doi.org/10.2174/138955706777698606.

Singh, R. P., Kaur, R., and Singh, K., 2016. A Review on Synthesis of Aminoacetanilides. ScienceIn Publishing, 4, 111–120.

Sruthi, A. S. V. L., Faizan, S., Vikram, H., Veena, N. G., Susil, A., Harindranath, H., Vasanth Kumar, S., Kumar Shivaraju, V., and Prashantha Kumar, B. R., 2024. A Multifaceted Approach for the Development of Novel Hantzsch 1,4-Dihydropyridines as Anticancer Agents: Rational Design, Parallel Synthesis, Analysis, Cytotoxicity and EGFR/HER2 Inhibition Studies. Results in Chemistry, 7, 101413. https://doi.org/10.1016/j.rechem.2024.101413.

Sun, Y.-S., Zhao, Z., Yang, Z.-N., Xu, F., Lu, H.-J., Zhu, Z.-Y., Shi, W., Jiang, J., Yao, P.-P., and Zhu, H.-P., 2017. Risk Factors and Preventions of Breast Cancer. International Journal of Biological Sciences, 13, 1387–1397. https://doi.org/10.7150/ijbs.21635.

Taher, I., Hamzah, B., H. Abed, H., and Husseini, M., 2024. Synthesizing Novel Vanillin-Based Di-Schiff Compounds and Evaluating Their Antibacterial Properties Running Title: Novel Vanillin-Based Di-Schiff Compounds and Their Antibacterial Properties. 2, 54–63.

Tasneem, S., Sheikh, K. A., Naematullah, M., Mumtaz Alam, M., Khan, F., Garg, M., Amir, M., Akhter, M., Amin, S., Haque, A., and Shaquiquzzaman, M., 2022. Synthesis, Biological Evaluation and Docking Studies of Methylene Bearing Cyanopyrimidine Derivatives Possessing a Hydrazone Moiety as Potent Lysine Specific Demethylase-1 (Lsd1) Inhibitors: A Promising Anticancer Agents. Bioorganic Chemistry, 126, 105885. https://doi.org/10.1016/j.bioorg.2022.105885.

Vijayan, R. S. K., He, P., Modi, V., Duong-Ly, K. C., Ma, H., Peterson, J. R., Dunbrack, R. L., and Levy, R. M., 2015. Conformational Analysis Ofthe Dfg-out Kinase Motifand Biochemical Profiling of Structurally Validated Type Ii Inhibitors. Journal of Medicinal Chemistry, 58, 466–479. https://doi.org/10.1021/jm501603h.

Xie, H., Hu, Q.-Q., Zhang, Y.-L., Qin, X.-T., and Li, L., 2023. Simple and Efficient Synthesis of Diamino Derivatives of Bis-1,2,4-Oxadiazolevia Tandem Staudinger/Aza-Wittig Reaction. Current Organic Synthesis, 20, 589–594. https://doi.org/10.2174/1570179420666221006113032.

Zonouz, M. A. and Abedinpour, S., 2024. A Review on the Methods of Preparing 14-Dihydropyridine Derivatives. Communications in Catalysis, 2. https://doi.org/10.22049/cic.2024.29549.1038.

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DOI: https://doi.org/10.20961/alchemy.22.2.111224.504-517

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