设计、合成及细胞色素 P4501B1 靶向螯合剂的结合亲和力评估。
Design, Synthesis and Binding Affinity Evaluation of Cytochrome P450 1B1 Targeted Chelators.
机构信息
School of Pharmacy, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, China.
Department of Breast Disease, The International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, 1961 Huashan Road, Shanghai 200030, China | Shanghai Key Laboratory of Embryo Original Diseases, 1961 Huashan Road, Shanghai 200030, China | Shanghai Municipal Key Clinical Specialty, 1961 Huashan Road, Shanghai 200030, China.
出版信息
Anticancer Agents Med Chem. 2022;22(2):261-269. doi: 10.2174/1871520621666210405091645.
BACKGROUND
Cytochrome P450 1B1 (CYP1B1) is specifically expressed in a variety of tumors which makes it a promising imaging target of tumor.
OBJECTIVE
We aimed to design and synthesize CYP1B1 targeted chelators for the potential application in positron emission tomography (PET) imaging of tumor.
METHODS
1,4,7-triazacyclononane-1,4-diiacetic acid (NODA) was connected to the CYP1B1 selective inhibitor we developed before through polyethylene glycol (PEG) linkers with different lengths. The inhibitory activities of chelators 6a-c against CYP1 family were evaluated by 7-ethoxyresorufin o-deethylation (EROD) assay. The manual docking between the chelators and the CYP1B1 was conducted subsequently. To determine the binding affinities of 6a-c to CYP1B1 in cells, we further performed a competition study at the cellular level.
RESULTS
Among three chelators, 6a with the shortest linker showed the best inhibitory activity against CYP1B1. In the following molecular simulation study, protein-inhibitor complex of 6a showed the nearest F-heme distance which is consistent with the results of enzymatic assay. Finally, the cell based competitive assay proved the binding affinity of 6a-c to CYP1B1 enzyme.
CONCLUSION
We designed and synthesized a series of chelators which can bind to CYP1B1 enzyme in cancer cells.To our knowledge, this work is the first attempt to construct CYP1B1 targeted chelators for radiolabeling and we hope it will prompt the application of CYP1B1 imaging in tumor detection.
背景
细胞色素 P450 1B1（CYP1B1）特异性表达于多种肿瘤中，使其成为肿瘤成像的有前途的靶标。
目的
我们旨在设计和合成 CYP1B1 靶向螯合剂，用于肿瘤正电子发射断层扫描（PET）成像的潜在应用。
方法
通过聚乙二醇（PEG）接头将 1,4,7-三氮杂环壬烷-1,4-二乙酸（NODA）连接到我们之前开发的 CYP1B1 选择性抑制剂上，接头的长度不同。通过 7-乙氧基resorufin o-脱乙基（EROD）测定评估螯合剂 6a-c 对 CYP1 家族的抑制活性。随后进行螯合剂与 CYP1B1 之间的手动对接。为了确定 6a-c 与 CYP1B1 在细胞中的结合亲和力，我们在细胞水平上进一步进行了竞争研究。
结果
在这三种螯合剂中，最短接头的 6a 对 CYP1B1 表现出最好的抑制活性。在随后的分子模拟研究中，6a 的蛋白-抑制剂复合物显示出最近的 F-血红素距离，这与酶测定的结果一致。最后，基于细胞的竞争性测定证明了 6a-c 与 CYP1B1 酶的结合亲和力。
结论
我们设计并合成了一系列能够与癌细胞中 CYP1B1 酶结合的螯合剂。据我们所知，这是首次尝试构建用于放射性标记的 CYP1B1 靶向螯合剂，我们希望它将推动 CYP1B1 成像在肿瘤检测中的应用。
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