靶向热休克蛋白介导的乳腺癌和结肠癌细胞凋亡的苯并咪唑-咔唑复合物的设计、合成和评价

IF 4.2 4区 医学 Q2 CHEMISTRY, MEDICINAL
İrfan Çapan, Mervenur Al, Mehmet Gümüş, Leyla Açik, Betül Aydin, Ayşe Büşranur Çelik, Levent Gülüm, Yusuf Sert, Ezgi Nurdan Yenilmez, İrfan Koca, Yusuf Tutar
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引用次数: 0

摘要

热休克蛋白(HSPs),特别是HSP70和HSP90,是参与癌症进展和耐药机制的关键分子伴侣蛋白。这些伴侣蛋白的双重抑制是一种很有前途的治疗方法。在这里,我们设计和合成了一系列新的靶向HSP70/90的苯并咪唑-咔唑杂交种。利用苯并咪唑的激酶抑制特性和咔唑的DNA干扰和细胞凋亡潜能,对这些杂种对乳腺癌(MCF-7)和结肠癌(HCT-116)癌细胞的抗癌活性进行了评估。大多数活性化合物显示亚微摩尔IC50值,并通过线粒体功能障碍和细胞骨架破坏诱导细胞凋亡,通过流式细胞术和荧光显微镜证实。分子对接发现与HSP70 (PDB: 1S3X)和HSP90 (PDB: 1YC4)具有较高的结合亲和力,与实验结果相关。此外,DNA相互作用研究证实了化合物诱导结构不稳定和断裂的能力,为其作用机制提供了深入的见解。这些发现突出了苯并咪唑-咔唑混合物作为克服癌症耐药的有希望的HSP抑制剂的潜力。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Design, Synthesis, and Evaluation of Benzimidazole-Carbazole Hybrids Targeting Heat Shock Proteins-Mediated Apoptosis in Breast and Colon Cancer Cells

Heat shock proteins (HSPs), particularly HSP70 and HSP90, are pivotal molecular chaperones implicated in cancer progression and resistance mechanisms. Dual inhibition of these chaperones represents a promising therapeutic approach. Here, we report the design and synthesis of a novel series of benzimidazole-carbazole hybrids aimed at targeting HSP70/90. Leveraging the kinase inhibitory properties of benzimidazole and the DNA interfering and apoptotic potential of carbazole, these hybrids were evaluated for their anticancer activity against breast (MCF-7) and colon (HCT-116) cancer cell lines. The most active compounds demonstrated submicromolar IC50 values and induced apoptosis through mitochondrial dysfunction and cytoskeletal disruption, confirmed via flow cytometry and fluorescence microscopy. Molecular docking revealed high binding affinities to HSP70 (PDB: 1S3X) and HSP90 (PDB: 1YC4), correlating with experimental outcomes. Furthermore, DNA interaction studies confirmed the compounds' ability to induce structural destabilization and fragmentation, providing insight into their mechanism of action. These findings highlight the potential of benzimidazole-carbazole hybrids as promising HSP inhibitors for overcoming cancer resistance.

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来源期刊
CiteScore
6.40
自引率
2.60%
发文量
104
审稿时长
6-12 weeks
期刊介绍: Drug Development Research focuses on research topics related to the discovery and development of new therapeutic entities. The journal publishes original research articles on medicinal chemistry, pharmacology, biotechnology and biopharmaceuticals, toxicology, and drug delivery, formulation, and pharmacokinetics. The journal welcomes manuscripts on new compounds and technologies in all areas focused on human therapeutics, as well as global management, health care policy, and regulatory issues involving the drug discovery and development process. In addition to full-length articles, Drug Development Research publishes Brief Reports on important and timely new research findings, as well as in-depth review articles. The journal also features periodic special thematic issues devoted to specific compound classes, new technologies, and broad aspects of drug discovery and development.
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