Design and Synthesis of New Multi-Target Coumarin Analogues Acting as Carbonic Anhydrases IX/XII and Topoisomerase II Inhibitors With Apoptotic Potential

IF 3.6 3区 医学 Q2 CHEMISTRY, MEDICINAL
Ahmed A. Al-Karmalawy, Tarek A. Yousef, Ali Khalil Ali, Mohamed A. Zeidan, Marwa Sharaky, Arwa Omar Al Khatib, Hela Ferjani, Eslam M. Abbass
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Abstract

Through applying the hybridization technique, new coumarin derivatives (2–17) were prepared with substitution at coumarin C-3 utilizing various heterocyclic derivatives, aiming to afford multi-target carbonic anhydrases (CAs) IX/XII and topoisomerase II (Topo II) inhibitors with potent antiproliferative activity. Eight different cell lines were used to evaluate the growth inhibition percentages (GI%) of cancer cells determined by coumarin analogues 1–17. Analogues 16 and 17 had the most substantial cytotoxic effects, achieving mean GI% of 86.59% and 85.74%, respectively, exceeding doxorubicin (Dox), which demonstrated a mean GI% of 69.15. Furthermore, the CAs IX/XII and Topo II inhibitory potentials for compound 17 were evaluated according to the protein expression analysis in the MG-63 cancer cells. Analogue 17 downregulated the expression of CA IX, CA XII, and Topo II proteins by 0.43-, 0.51-, and 0.56-fold change, respectively, indicating frontier inhibitory potentials. Additionally, analogue 17 achieved upregulation of apoptotic proteins (Caspases 3, 7, and 9, and BAX by 1.52-, 3.10-, 1.67-, and 1.90-fold change, respectively). On the contrary, compound 17 induced downregulation of the antiapoptotic proteins BCL-2, MMP2, and MMP9 by 0.44-, 0.38-, and 0.45-fold change, respectively. Besides, compound 17 achieved an arrest at the G0–G1 phase of the cell cycle and elevated the cellular levels from 65.75% of the control cells to 92.54%. Finally, three molecular docking processes of the superior analogue 17 toward CA IX, CA XII, and Topo II targets were performed to investigate its molecular interactions.

具有凋亡潜能的碳酸酐酶IX/XII和拓扑异构酶II抑制剂的新型多靶点香豆素类似物的设计和合成。
通过杂交技术,利用各种杂环衍生物在香豆素C-3上进行取代,制备了新的香豆素衍生物(2-17),旨在获得具有强抗增殖活性的多靶点碳酸酐酶(CAs) IX/XII和拓扑异构酶II (Topo II)抑制剂。用香豆素类似物1-17测定了8种不同细胞系对癌细胞的生长抑制百分比(GI%)。类似物16和17具有最显著的细胞毒作用,平均GI%分别为86.59%和85.74%,超过阿霉素(Dox)的平均GI%为69.15。此外,根据MG-63癌细胞中的蛋白表达分析,评估化合物17对CAs IX/XII和Topo II的抑制潜力。类似物17对CA IX、CA XII和Topo II蛋白的表达下调幅度分别为0.43倍、0.51倍和0.56倍,显示出前沿抑制电位。此外,类似物17实现了凋亡蛋白(Caspases 3、7、9和BAX分别上调1.52倍、3.10倍、1.67倍和1.90倍)。相反,化合物17诱导抗凋亡蛋白BCL-2、MMP2和MMP9分别下调0.44倍、0.38倍和0.45倍。此外,化合物17在细胞周期的G0-G1期实现了阻滞,并将对照细胞的细胞水平从65.75%提高到92.54%。最后,进行了与caix、caxii和Topo II靶点的三个分子对接过程,研究了其分子相互作用。
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来源期刊
Archiv der Pharmazie
Archiv der Pharmazie 医学-化学综合
CiteScore
7.90
自引率
5.90%
发文量
176
审稿时长
3.0 months
期刊介绍: Archiv der Pharmazie - Chemistry in Life Sciences is an international journal devoted to research and development in all fields of pharmaceutical and medicinal chemistry. Emphasis is put on papers combining synthetic organic chemistry, structural biology, molecular modelling, bioorganic chemistry, natural products chemistry, biochemistry or analytical methods with pharmaceutical or medicinal aspects such as biological activity. The focus of this journal is put on original research papers, but other scientifically valuable contributions (e.g. reviews, minireviews, highlights, symposia contributions, discussions, and essays) are also welcome.
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