İrfan Çapan, Mervenur Al, Mehmet Gümüş, Leyla Açik, Betül Aydin, Ayşe Büşranur Çelik, Levent Gülüm, Yusuf Sert, Ezgi Nurdan Yenilmez, İrfan Koca, Yusuf Tutar
{"title":"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","authors":"İrfan Çapan, Mervenur Al, Mehmet Gümüş, Leyla Açik, Betül Aydin, Ayşe Büşranur Çelik, Levent Gülüm, Yusuf Sert, Ezgi Nurdan Yenilmez, İrfan Koca, Yusuf Tutar","doi":"10.1002/ddr.70092","DOIUrl":null,"url":null,"abstract":"<div>\n \n <p>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 IC<sub>50</sub> 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.</p>\n </div>","PeriodicalId":11291,"journal":{"name":"Drug Development Research","volume":"86 3","pages":""},"PeriodicalIF":4.2000,"publicationDate":"2025-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Design, Synthesis, and Evaluation of Benzimidazole-Carbazole Hybrids Targeting Heat Shock Proteins-Mediated Apoptosis in Breast and Colon Cancer Cells\",\"authors\":\"İrfan Çapan, Mervenur Al, Mehmet Gümüş, Leyla Açik, Betül Aydin, Ayşe Büşranur Çelik, Levent Gülüm, Yusuf Sert, Ezgi Nurdan Yenilmez, İrfan Koca, Yusuf Tutar\",\"doi\":\"10.1002/ddr.70092\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div>\\n \\n <p>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 IC<sub>50</sub> 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.</p>\\n </div>\",\"PeriodicalId\":11291,\"journal\":{\"name\":\"Drug Development Research\",\"volume\":\"86 3\",\"pages\":\"\"},\"PeriodicalIF\":4.2000,\"publicationDate\":\"2025-05-09\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Drug Development Research\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://onlinelibrary.wiley.com/doi/10.1002/ddr.70092\",\"RegionNum\":4,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q2\",\"JCRName\":\"CHEMISTRY, MEDICINAL\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Drug Development Research","FirstCategoryId":"3","ListUrlMain":"https://onlinelibrary.wiley.com/doi/10.1002/ddr.70092","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"CHEMISTRY, MEDICINAL","Score":null,"Total":0}
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.
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.