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

Öz

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.

Anahtar Kelimeler

• Aromatase inhibition
• breast cancer
• CYP1 inhibition
• estrogen receptor antagonism
• melatonin analogues

Proje Numarası

117S065

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

Öz

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.

Anahtar Kelimeler

• Aromataz inhibisyonu
• CYP1 inhibisyonu
• melatonin analogları
• meme kanseri
• östrojen reseptör antagonizması

Proje Numarası

117S065

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