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Journals / Ankara Üniversitesi Eczacılık Fakültesi Dergisi / 2026 / Cilt: 50 Sayı: 3

MULTI-TARGETED EFFECTS OF NOVEL MELATONIN ANALOGUES: AROMATASE INHIBITION, ER ANTAGONISM AND CYP1 INHIBITORY ACTIVITY

YENİ MELATONİN ANALOGLARININ ÇOKLU HEDEFLİ ETKİLERİ: AROMATAZ İNHİBİSYONU, ER ANTAGONİZMASI VE CYP1 İNHİBİTÖR AKTİVİTESİ

Elif İnce Erguc(IZMIR KATIP CELEBI UNIVERSITY)0000-0003-0764-7694
Hanif Şirinzade(SELÇUK ÜNİVERSİTESİ, ECZACILIK FAKÜLTESİ, ECZACILIK PR.)0000-0001-9663-9199
Nil Bita Entezari Ökeer(EGE UNIVERSITY, FACULTY OF PHARMACY, PHARMACY PR.)0000-0003-1496-1091
Sibel Süzen(ANKARA UNIVERSITY, FACULTY OF PHARMACY, PHARMACY PR.)0000-0003-3413-6152
Hande Gürer-orhan(EGE ÜNİVERSİTESİ, ECZACILIK FAKÜLTESİ)0000-0002-4890-299X
Pages
705–716
Publication Date
2026-09-19
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AI Summary & Key Takeaways

AI Insight
⚡ TL;DR(Too Long; Didn't Read)

Compound 2f showed a favorable multi-target profile with selective cytotoxicity.

📌 3 Key Takeaways

🎯
Objective & Hypothesis:Objective: This study aimed to synthesize and evaluate novel chlorophenyl-substituted melatonin analogues for their potential multi-target effects in hormone-dependent breast cancer.
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Key Findings & Data:Their inhibitory activity on aromatase (CYP19A1), antagonistic potential on estrogen receptor (ER), inhibition of CYP1 enzymes, and selective cytotoxicity on cancer cells were investigated.
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Conclusion & Impact:Compound 2f showed a favorable multi-target profile with selective cytotoxicity.
🔬Design:Araştırma Makalesi
📍Scope:Comprehensive Sample
⚙️Variables:Aromataz inhibisyonu · CYP1 inhibisyonu · melatonin analogları

Abstract

Objective: This study aimed to synthesize and evaluate novel chlorophenyl-substituted melatonin analogues for their potential multi-target effects in hormone-dependent breast cancer. Their inhibitory activity on aromatase (CYP19A1), antagonistic potential on estrogen receptor (ER), inhibition of CYP1 enzymes, and selective cytotoxicity on cancer cells were investigated. Material and Method: Two groups of novel indole-based melatonin analogues (non-benzylated and benzylated) were synthesized and structurally characterized. Aromatase inhibition was assessed using a cell-free fluorescence-based assay. ER antagonism was evaluated in MCF-7 BUS cells using the E-Screen assay. CYP1 enzyme inhibition was determined via EROD assay using rat liver microsomes. Cytotoxicity was evaluated in MCF-7 BUS and MCF-10A cells using the MTT assay. Result and Discussion: Non-benzylated new compounds (2a–2f) showed higher aromatase and CYP1 inhibition compared to benzylated derivatives (4a–4e). Compound 2f exhibited the highest aromatase (78.5%) and CYP1 (79%) inhibition, and significant ER antagonism. New benzylated compounds displayed stronger cytotoxicity in MCF-7 BUS cells but less enzymatic inhibition. Compound 2f showed a favorable multi-target profile with selective cytotoxicity.

Özet

Amaç: Bu çalışmada, hormon bağımlı meme kanserinde potansiyel çoklu hedefli etkileri araştırılmak üzere klorofenil ikame edilmiş yeni melatonin analoglarının sentezlenmesi ve değerlendirilmesi amaçlanmıştır. Bu bileşiklerin aromataz (CYP19A1) inhibisyonu, östrojen reseptörü (ER) üzerindeki antagonistik potansiyeli, CYP1 enzim inhibisyonu ve kanser hücrelerine karşı seçici sitotoksisiteleri incelenmiştir. Gereç ve Yöntem: Yeni indol bazlı melatonin analoglarının iki grubu (benzillenmemiş ve benzillenmiş) sentezlenmiş ve yapısal olarak karakterize edilmiştir. Aromataz inhibisyonu hücresiz floresans tabanlı bir test ile değerlendirilmiştir. ER antagonizması, MCF-7 BUS hücrelerinde E- Screen testi ile incelenmiştir. CYP1 enzim inhibisyonu, sıçan karaciğer mikrozomları kullanılarak EROD testi ile belirlenmiştir. Sitotoksisite ise MCF-7 BUS ve MCF-10A hücrelerinde MTT testi ile değerlendirilmiştir. Sonuç ve Tartışma: Yeni benzillenmemiş bileşikler (2a–2f), benzillenmiş türevler (4a–4e) ile karşılaştırıldığında daha yüksek aromataz ve CYP1 inhibisyonu göstermiştir. 2f bileşiği en yüksek aromataz (%78.5) ve CYP1 (%79) inhibisyonunun yanı sıra anlamlı ER antagonizması sergilemiştir. Yeni benzillenmiş bileşikler, MCF-7 BUS hücrelerinde daha güçlü sitotoksisite göstermiş ancak enzimatik inhibisyon düzeyleri daha düşük bulunmuştur. 2f bileşiği, seçici sitotoksisite ile birlikte olumlu bir çoklu hedef profili ortaya koymuştur.

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Cite This Article

Erguc, E. İ., Şirinzade, H., Ökeer, N. B. E., Süzen, S., Gürer-orhan, H. (2026). MULTI-TARGETED EFFECTS OF NOVEL MELATONIN ANALOGUES: AROMATASE INHIBITION, ER ANTAGONISM AND CYP1 INHIBITORY ACTIVITY. Ankara Üniversitesi Eczacılık Fakültesi Dergisi, Cilt: 50 Sayı: 3, 705–716. https://doi.org/10.33483/jfpau.1770524

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References (32)

  1. Bray, F., Ferlay, J., Soerjomataram, I., et al. (2018). Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA: A Cancer Journal for Clinicians, 68(6), 394-424. [CrossRef]
  2. Clusan, L., Ferrière, F., Flouriot, G., et al. (2023). A basic review on estrogen receptor signaling pathways in breast cancer. International Journal of Molecular Sciences, 24(7), 6834. [CrossRef]
  3. Yager, J.D. (2015). Mechanisms of estrogen carcinogenesis: The role of E2/E1-quinone metabolites suggests new approaches to preventive intervention. Steroids, 99, 56-60. [CrossRef]
  4. Al-Shami, K., Awadi, S., Khamees, A., et al. (2023). Estrogens and the risk of breast cancer: A narrative review of literature. Heliyon, 9(9), e20224. [CrossRef]
  5. Id, K.U., Tomita, M. (2023). A mathematical model for cancer risk and accumulation of mutations caused by replication errors and external factors. PLOS ONE, 18(6), e0286499. [CrossRef]
  6. Dickson, R.B., Stancel, G.M. (2000). Estrogen receptor-mediated processes in normal and cancer cells. Journal of the National Cancer Institute Monographs, 2000(27), 135-145. [CrossRef]
  7. Yue, W., Yager, J.D., Wang, J.P., et al. (2013). Estrogen receptor-dependent and independent mechanisms of breast cancer carcinogenesis. Steroids, 78(2), 161-170. [CrossRef]
  8. Jin, Y., Choi, Y.J., Heo, K., et al. (2021). Melatonin as an oncostatic molecule based on its anti-aromatase role in breast cancer. International Journal of Molecular Sciences, 22(1), 438. [CrossRef]
  9. Yi, Y.J., Tang, H., Pi, P.L., et al. (2024). Melatonin in cancer biology: Pathways, derivatives, and the promise of targeted delivery. Drug Metabolism Reviews, 56(1), 62-79. [CrossRef]
  10. González-González, A., Mediavilla, M.D., Sánchez-Barceló, E.J. (2018). Melatonin: A molecule for reducing breast cancer risk. Molecules, 23(2), 336. [CrossRef]
  11. Mehrzadi, S., Pourhanifeh, M.H., Mirzaei, A., et al. (2021). An updated review of mechanistic potentials of melatonin against cancer: Pivotal roles in angiogenesis, apoptosis, autophagy, endoplasmic reticulum stress and oxidative stress. Cancer Cell International, 21, 314. [CrossRef]
  12. Kaur, K., Jaitak, V. (2019). Recent development in indole derivatives as anticancer agents for breast cancer. Anticancer Agents in Medicinal Chemistry, 19(8), 962-983. [CrossRef]
  13. Jin, Y., Choi, Y.J., Heo, K., et al. (2021). Melatonin as an oncostatic molecule based on its anti-aromatase role in breast cancer. International Journal of Molecular Sciences, 22(1), 438. [CrossRef]
  14. Maroufi, N.F., Ashouri, N., Mortezania, Z., et al. (2020). The potential therapeutic effects of melatonin on breast cancer: An invasion and metastasis inhibitor. Pathology Research and Practice, 216, 153226. [CrossRef]
  15. Motehaver, A.N., Sheida, F., Javadinia, S.A., et al. (2025). Melatonin and breast cancer: A review article. Chonnam Medical Journal, 61(2), 63-74. [CrossRef]
  16. Ozcan-Sezer, S., Ince, E., Akdemir, A., et al. (2019). Aromatase inhibition by 2-methyl indole hydrazone derivatives evaluated via molecular docking and in vitro activity studies. Xenobiotica, 49(5), 549-556. [CrossRef]
  17. Ince-Erguc, E., Fatullayev, H., Entezari, B., et al. (2024). In vitro evaluation of endocrine-related adverse effects of 5-fluoroindole derived melatonin analogues with antioxidant activity. Chemistry and Biodiversity, 21(5), e202402050. [CrossRef]
  18. Shirinzadeh, H., Neuhaus, E., Ince-Erguc, E., et al. (2020). New indole-7-aldehyde derivatives as melatonin analogues; synthesis and screening their antioxidant and anticancer potential. Bioorganic Chemistry, 104, 104219. [CrossRef]
  19. Büyükbingöl, E., Suzen, S., Klopman, G. (1994). Studies on the synthesis and structure-activity relationships of 5-(3’-indolal)-2-thiohydantoin derivatives as aldose reductase enzyme inhibitors. Farmaco, 49(6), 443-447.
  20. Anonymous. (1974). 1-Benzylindole. Organic Syntheses, 54, 58. [CrossRef]
  21. Kidwai, M., Negi, N., Gupta, S.D. (1994). Synthesis and antifertility activity of 1,5-diaryl-3-(3’-indolyl)formazans. Chemical and Pharmaceutical Bulletin, 42(11), 2363-2364. [CrossRef]
  22. Mosmann, T. (1983). Rapid colorimetric assay for cellular growth and survival: Application to proliferation and cytotoxicity assays. Journal of Immunological Methods, 65(1-2), 55-63. [CrossRef]
  23. Entezari, B., Bozdag, D., Gurer-Orhan, H. (2023). Evaluation of endocrine related adverse effects of non-endocrine targeted pharmaceuticals in cellular systems. Endocrine Metabolic and Immune Disorders Drug Targets, 23(2), 1740-1749. [CrossRef]
  24. Soto, A.M., Sonnenschein, C., Chung, K.L., et al. (1995). The E-SCREEN assay as a tool to identify estrogens: An update on estrogenic environmental pollutants. Environmental Health Perspectives, 103(Suppl 7), 113-122. [CrossRef]
  25. Ince-Erguc, E., Durgun, K., Akdemir, A., et al. (2024). Design, synthesis, and investigation of anticancer and antioxidant potential of novel indole-based melatonin analogues in breast cancer. ChemistrySelect, 9(21), e202400817. [CrossRef]
  26. Burke, M.D., Mayer, R.T. (1974). Ethoxyresorufin: Direct fluorimetric assay of a microsomal O-dealkylation which is preferentially inducible by 3-methylcholanthrene. Drug Metabolism and Disposition, 2(6), 583-588. [CrossRef]
  27. Bartolucci, A.A., Singh, K.P., Bae, S. (2015). Introduction to Statistical Analysis of Laboratory Data, Wiley, New Jersey, 1-238.
  28. Pasha, M.H., Gondal, H.Y., Munir, S., et al. (2024). New enantioenriched β-indolyl ketones as aromatase inhibitors: Unraveling heme-ligand interactions by MD simulation and MMPBSA analysis. Archiv der Pharmazie, 357(7), e2400010. [CrossRef]
  29. Chang, T.K.H., Chen, J., Yang, G., et al. (2010). Inhibition of procarcinogen-bioactivating human CYP1A1, CYP1A2 and CYP1B1 enzymes by melatonin. Journal of Pineal Research, 48(1), 55-64. [CrossRef]
  30. Gurer-Orhan, H., Ince, E., Konyar, D., et al. (2017). The role of oxidative stress modulators in breast cancer. Current Medicinal Chemistry, 24(14), 1601-1613. [CrossRef]
  31. Ozdemir, A., Turanli, S., Çalişkan, B., et al. (2020). Evaluation of cytotoxic activity of new benzimidazole-piperazine hybrids against human MCF-7 and A549 cancer cells. Pharmaceutical Chemistry Journal, 53, 1036-1046. [CrossRef]
  32. Bhatia, N., Thareja, S. (2024). Aromatase inhibitors for the treatment of breast cancer: An overview (2019-2023). Bioorganic Chemistry, 151, 107607. [CrossRef]