Some Benzoxazole Derivatives as Potential mTOR Inhibitors: Anticancer Activity and Molecular Docking Studies in Breast Cancer

Abstract

Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer with limited treatment options, highlighting the need for novel targeted therapies. The mechanistic target of rapamycin (mTOR) is a key regulator of cancer cell proliferation and survival, making it an attractive target for drug development. Based on this, we investigated the anticancer effects of four previously synthesized benzoxazole derivatives—2-(4-isopropylphenyl)-5-nitrobenzoxazole (i), 2-(2,3-dimethylphenyl)-6-nitrobenzoxazole (ii), 2-(2,4-dimethylphenyl)-5-nitrobenzoxazole (iii), and 2-(2,4-dimethylphenyl)-6-nitrobenzoxazole (iv)—through in vitro cytotoxicity assays and molecular docking studies. The cytotoxic effects of the compounds were evaluated using the MTT assay on MDA-MB-231 cells, which were treated with different concentrations (0–100 μM) for 48 hours. To further explore the mechanism of action, molecular docking was performed using mTOR as the target. There was a dose-dependent reduction in cell viability, with compound ii exhibiting the highest cytotoxic activity (IC50= 40.99±0.06 μM). According to molecular docking, all compounds demonstrated strong binding interactions with key residues such as Trp2239, Lys2187, Asp23357, and Val2240, as well as coordination with magnesium ions, supporting their role as mTOR inhibitors. Our results revealed that these benzoxazoles could function as potential candidates for exerting their anticarcinogenic effects on MDA-MB-231 cells through mTOR inhibition.

Keywords

• breast cancer
• mTOR inhibitors
• benzoxazole
• molecular docking
• anticancer activity

Bazı Benzoksazol Türevlerinin Potansiyel mTOR İnhibitör Olarak İncelenmesi: Meme Kanserinde Antikanser Aktivite ve Moleküler Yerleştirme Çalışmaları

Abstract

Üçlü negatif meme kanseri (TNBC), yeni hedefe yönelik tedavilere duyulan ihtiyacı vurgulayan, sınırlı tedavi seçeneklerine sahip agresif bir meme kanseri alt tipidir. Rapamisinin (mTOR) mekanik hedefi, kanser hücresi proliferasyonu ve canlılığının kilit bir düzenleyicisidir ve bu da onu ilaç geliştirme için ilgi çekici bir hedef haline getirmektedir. Bu nedenle, in vitro sitotoksisite deneyleri ve moleküler yerleştirme (docking) çalışmaları yoluyla daha önce sentezlenmiş dört benzoksazol türevinin —2- (4-izopropilfenil) -5-nitrobenzoksazol (i), 2- (2,3-dimetilfenil) -6-nitrobenzoksazol (ii), 2- (2,4-dimetilfenil) -5-nitrobenzoksazol (iii), ve 2- (2,4-dimetilfenil) —6-nitrobenzoksazol (iv) - antikanser potansiyeli araştırılmıştır. Bileşiklerin MDA-MB-231 hücreleri üzerindeki sitotoksik etkileri, 48 saat boyunca farklı konsantrasyonlarla (0-100 μM) muamele edilerek MTT deneyi ile değerlendirilmiştir. Etki mekanizmasını daha ayrıntılı araştırmak amacıyla, hedef protein olarak mTOR seçilerek moleküler docking çalışmaları gerçekleştirilmiştir. Hücre canlılığında doza bağlı bir azalma gözlemlenmiş ve bileşik ii en yüksek sitotoksik aktiviteyi göstermiştir (IC50 = 40,99 ± 0,06 μM). Moleküler docking çalışmaları sonucunda, tüm bileşiklerin mTOR proteininin Trp2239, Lys2187 ve Val2240 gibi anahtar kalıntıları ile güçlü bağlanma etkileşimleri gösterdiği ve ayrıca magnezyum iyonları ile koordinasyon sağladığı belirlenmiştir. Bu bulgular, bileşiklerin mTOR inhibitörleri olarak potansiyel rollerini desteklemektedir. Sonuçlarımız, bu benzoksazol türevlerinin, mTOR inhibisyonu yoluyla MDA-MB-231 hücreleri üzerinde antikarsinojenik etkilerini gösterebilecek potansiyel adaylar olabileceğini ortaya koymuştur.

Keywords

• meme kanseri
• mTOR inhibitörleri
• benzoksazol
• moleküler yerleştirme
• antikanser aktivite

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