Çapan İrfan, Hawash Mohammed, Qaoud Mohammed T, Gülüm Levent, Tunoglu Ezgi Nurdan Yenilmez, Çifci Kezban Uçar, Çevrimli Bekir Sıtkı, Sert Yusuf, Servi Süleyman, Koca İrfan, Tutar Yusuf
Department of Pharmaceutical Basic Sciences, Faculty of Pharmacy, Gazi University, 06330, Ankara, Türkiye.
Sente Kimya Research and Development Inc., 06200, Ankara, Türkiye.
BMC Chem. 2024 May 21;18(1):102. doi: 10.1186/s13065-024-01207-1.
Carbazole-based molecules containing thiosemicarbazide functional groups are recognized for their diverse biological activities, particularly in enhancing therapeutic anticancer effects through inhibiting crucial pathways. These derivatives also exhibit noteworthy antioxidant properties.
This study aims to synthesize, characterize, and evaluate the antioxidant and anticancer activities of 18 novel carbazole derivatives.
The radical scavenging capabilities of the compounds were assessed using the 2,2-diphenyl-1-picrylhydrazyl assay. Antiproliferative activities were evaluated on MCF-7 cancer cell lines through viability assays. Additionally, the modulation of the PI3K/Akt/mTOR pathway, apoptosis/necrosis induction, and cell cycle analysis were conducted for the most promising anticancer agents.
nine compounds showed potent antioxidant activities with IC values lower than the positive control acarbose, with compounds 4 h and 4y exhibiting the highest potency (IC values of 0.73 and 0.38 µM, respectively). Furthermore, compounds 4o and 4r displayed significant anticancer effects, with IC values of 2.02 and 4.99 µM, respectively. Compound 4o, in particular, exhibited promising activity by targeting the PI3K/Akt/mTOR signaling pathway, inhibiting tumor survival, inducing apoptosis, and causing cell cycle arrest in MCF-7 cell lines. Furthermore, compound 4o was showed significant antimicrobial activities against S. aureus and E. coli, and antifungal effect against C. albicans. Its potential to overcome drug resistance through this pathway inhibition highlights its promise as an anticancer agent. Molecular docking simulations supported these findings, revealing favorable binding profiles and interactions within the active sites of the enzymes PI3K, AKT1, and mTOR. Moreover, assessing the druggability of the newly synthesized thiosemicarbazide derivatives demonstrated optimal physicochemical properties, further endorsing their potential as drug candidates.
含有硫代氨基脲官能团的咔唑类分子因其多样的生物活性而受到认可，特别是通过抑制关键途径增强治疗性抗癌效果。这些衍生物还具有显著的抗氧化性能。
本研究旨在合成、表征和评估18种新型咔唑衍生物的抗氧化和抗癌活性。
使用2,2-二苯基-1-苦基肼测定法评估化合物的自由基清除能力。通过活力测定评估对MCF-7癌细胞系的抗增殖活性。此外，对最有前景的抗癌剂进行PI3K/Akt/mTOR途径的调节、凋亡/坏死诱导和细胞周期分析。
9种化合物表现出强大的抗氧化活性，IC值低于阳性对照阿卡波糖，化合物4h和4y表现出最高活性（IC值分别为0.73和0.38μM）。此外，化合物4o和4r显示出显著的抗癌效果，IC值分别为2.02和4.99μM。特别是化合物4o，通过靶向PI3K/Akt/mTOR信号通路、抑制肿瘤存活、诱导凋亡并使MCF-7细胞系中的细胞周期停滞，表现出有前景的活性。此外，化合物4o对金黄色葡萄球菌和大肠杆菌表现出显著的抗菌活性，对白色念珠菌表现出抗真菌作用。其通过这种途径抑制克服耐药性的潜力突出了其作为抗癌剂的前景。分子对接模拟支持了这些发现，揭示了在PI3K、AKT1和mTOR酶活性位点内的有利结合模式和相互作用。此外，评估新合成的硫代氨基脲衍生物的成药性显示出最佳的物理化学性质，进一步支持了它们作为候选药物的潜力。
