{"title":"通过抑制 CDK1 逆转金属药物抗性的同手性 Ir(III)-Metallohelices 的可编程模块组装","authors":"Xuezhao Li, Xing Zhao, Xingyun Wang, Anxian Xiong, Zhicheng Wang, Zhuolin Shi, Jingyi Zhang, Hanlin Wang, Wei Wei, Cheng He, Jiajia Ma, Zijian Guo, Chunying Duan, Jing Zhao, Xiuxiu Wang","doi":"10.1002/anie.202419292","DOIUrl":null,"url":null,"abstract":"Drug resistance is a major cause of cancer recurrence and poor prognosis. The innovative design and synthesis of inhibitors to target drug-resistance-specific proteins is highly desirable. However, challenges remain in precisely adjusting their conformation and stereochemistry to adapt the chiral regions of target proteins. Herein, using a stepwise programmable modular assembly approach, we precisely engineered two pairs of homochiral dinuclear Ir(III) metallohelices (Λ2S4-Hbpy and Δ2R4-Hbpy, Δ2S4-Hbpy and Λ2R4-Hbpy) functionalized with flexible dithiourea linkages. The resulting homochiral metallohelices exhibited significant chirality-dependent photocytotoxicities, and the enhanced structural compatibility ofΔ2S4-Hbpywith the target cyclin-dependent kinase 1 (CDK1) contributed to its superior photodynamic therapy efficacy, achieving an outstanding photocytotoxicity index (PI) value of 2.3×104. Interestingly, emerging as a critical mediator in the development of oxaliplatin resistance, CDK1 targeting by Δ2S4-Hbpyachieved enhanced cellular uptake, anticancer activity, and oncosis-mediated cell death in oxaliplatin-resistant HCT8/L cells. Mechanistic investigations, including proteomic profiling and CDK1 gene silencing, confirmed the pivotal role of chirality-selective CDK1 targeting in reversing metallodrug resistance. This study introduces a promising platform for constructing and customizing flexible metallohelices with precise conformation and stereochemistry to target drug-resistance-specific proteins, offering innovative insights into the designability of metallodrugs to overcome drug resistance.","PeriodicalId":125,"journal":{"name":"Angewandte Chemie International Edition","volume":"16 1","pages":""},"PeriodicalIF":16.1000,"publicationDate":"2024-12-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Programmable Modular Assembly of Homochiral Ir(III)-Metallohelices to Reverse Metallodrug Resistance by Inhibiting CDK1\",\"authors\":\"Xuezhao Li, Xing Zhao, Xingyun Wang, Anxian Xiong, Zhicheng Wang, Zhuolin Shi, Jingyi Zhang, Hanlin Wang, Wei Wei, Cheng He, Jiajia Ma, Zijian Guo, Chunying Duan, Jing Zhao, Xiuxiu Wang\",\"doi\":\"10.1002/anie.202419292\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"Drug resistance is a major cause of cancer recurrence and poor prognosis. The innovative design and synthesis of inhibitors to target drug-resistance-specific proteins is highly desirable. However, challenges remain in precisely adjusting their conformation and stereochemistry to adapt the chiral regions of target proteins. Herein, using a stepwise programmable modular assembly approach, we precisely engineered two pairs of homochiral dinuclear Ir(III) metallohelices (Λ2S4-Hbpy and Δ2R4-Hbpy, Δ2S4-Hbpy and Λ2R4-Hbpy) functionalized with flexible dithiourea linkages. The resulting homochiral metallohelices exhibited significant chirality-dependent photocytotoxicities, and the enhanced structural compatibility ofΔ2S4-Hbpywith the target cyclin-dependent kinase 1 (CDK1) contributed to its superior photodynamic therapy efficacy, achieving an outstanding photocytotoxicity index (PI) value of 2.3×104. Interestingly, emerging as a critical mediator in the development of oxaliplatin resistance, CDK1 targeting by Δ2S4-Hbpyachieved enhanced cellular uptake, anticancer activity, and oncosis-mediated cell death in oxaliplatin-resistant HCT8/L cells. Mechanistic investigations, including proteomic profiling and CDK1 gene silencing, confirmed the pivotal role of chirality-selective CDK1 targeting in reversing metallodrug resistance. This study introduces a promising platform for constructing and customizing flexible metallohelices with precise conformation and stereochemistry to target drug-resistance-specific proteins, offering innovative insights into the designability of metallodrugs to overcome drug resistance.\",\"PeriodicalId\":125,\"journal\":{\"name\":\"Angewandte Chemie International Edition\",\"volume\":\"16 1\",\"pages\":\"\"},\"PeriodicalIF\":16.1000,\"publicationDate\":\"2024-12-14\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Angewandte Chemie International Edition\",\"FirstCategoryId\":\"92\",\"ListUrlMain\":\"https://doi.org/10.1002/anie.202419292\",\"RegionNum\":1,\"RegionCategory\":\"化学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"CHEMISTRY, MULTIDISCIPLINARY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Angewandte Chemie International Edition","FirstCategoryId":"92","ListUrlMain":"https://doi.org/10.1002/anie.202419292","RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CHEMISTRY, MULTIDISCIPLINARY","Score":null,"Total":0}
Programmable Modular Assembly of Homochiral Ir(III)-Metallohelices to Reverse Metallodrug Resistance by Inhibiting CDK1
Drug resistance is a major cause of cancer recurrence and poor prognosis. The innovative design and synthesis of inhibitors to target drug-resistance-specific proteins is highly desirable. However, challenges remain in precisely adjusting their conformation and stereochemistry to adapt the chiral regions of target proteins. Herein, using a stepwise programmable modular assembly approach, we precisely engineered two pairs of homochiral dinuclear Ir(III) metallohelices (Λ2S4-Hbpy and Δ2R4-Hbpy, Δ2S4-Hbpy and Λ2R4-Hbpy) functionalized with flexible dithiourea linkages. The resulting homochiral metallohelices exhibited significant chirality-dependent photocytotoxicities, and the enhanced structural compatibility ofΔ2S4-Hbpywith the target cyclin-dependent kinase 1 (CDK1) contributed to its superior photodynamic therapy efficacy, achieving an outstanding photocytotoxicity index (PI) value of 2.3×104. Interestingly, emerging as a critical mediator in the development of oxaliplatin resistance, CDK1 targeting by Δ2S4-Hbpyachieved enhanced cellular uptake, anticancer activity, and oncosis-mediated cell death in oxaliplatin-resistant HCT8/L cells. Mechanistic investigations, including proteomic profiling and CDK1 gene silencing, confirmed the pivotal role of chirality-selective CDK1 targeting in reversing metallodrug resistance. This study introduces a promising platform for constructing and customizing flexible metallohelices with precise conformation and stereochemistry to target drug-resistance-specific proteins, offering innovative insights into the designability of metallodrugs to overcome drug resistance.
期刊介绍:
Angewandte Chemie, a journal of the German Chemical Society (GDCh), maintains a leading position among scholarly journals in general chemistry with an impressive Impact Factor of 16.6 (2022 Journal Citation Reports, Clarivate, 2023). Published weekly in a reader-friendly format, it features new articles almost every day. Established in 1887, Angewandte Chemie is a prominent chemistry journal, offering a dynamic blend of Review-type articles, Highlights, Communications, and Research Articles on a weekly basis, making it unique in the field.