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合成 11-氨烷氧基取代的二苯并菲啶衍生物作为酪氨酰-DNA 磷酸二酯酶 1 抑制剂及其抗癌活性。

Synthesis of 11-aminoalkoxy substituted benzophenanthridine derivatives as tyrosyl-DNA phosphodiesterase 1 inhibitors and their anticancer activity.

机构信息

School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China.

Developmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, United States.

出版信息

Bioorg Chem. 2022 Jun;123:105789. doi: 10.1016/j.bioorg.2022.105789. Epub 2022 Apr 4.

DOI:10.1016/j.bioorg.2022.105789
PMID:35429714
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10557912/
Abstract

Tyrosyl-DNA phosphodiesterase 1 (TDP1) is an enzyme that repairs DNA lesions caused by the trapping of DNA topoisomerase IB (TOP1)-DNA break-associated crosslinks. TDP1 inhibitors have synergistic effect with TOP1 inhibitors in cancer cells and can overcome cancer cell resistance to TOP1 inhibitors. Here, we report the synthesis of 11-aminoalkoxy substituted benzophenanthridine derivatives as selective TDP1 inhibitors and show that six compounds 14, 16, 18, 20, 25 and 27 exhibit high TDP1 inhibition potency. The most potent TDP1 inhibitor 14 (IC = 1.7 ± 0.24 μM) induces cellular TDP1cc formation and shows synergistic effect with topotecan in four human cancer cell lines MCF-7, A549, H460 and HepG2.

摘要

酪氨酰 DNA 磷酸二酯酶 1（TDP1）是一种修复由 DNA 拓扑异构酶 IB（TOP1）-DNA 断裂相关交联物捕获引起的 DNA 损伤的酶。TDP1 抑制剂与癌细胞中的 TOP1 抑制剂具有协同作用，并能克服癌细胞对 TOP1 抑制剂的耐药性。在这里，我们报告了 11-氨氧基取代的苯并菲啶衍生物的合成，作为选择性 TDP1 抑制剂，并表明六种化合物 14、16、18、20、25 和 27 表现出高 TDP1 抑制活性。最有效的 TDP1 抑制剂 14（IC=1.7±0.24μM）诱导细胞 TDP1cc 的形成，并与拓扑替康在 MCF-7、A549、H460 和 HepG2 四种人癌细胞系中表现出协同作用。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/55b1/10557912/55eb2e3fc8ef/nihms-1928133-f0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/55b1/10557912/3d119a51d41e/nihms-1928133-f0001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/55b1/10557912/f288caa5ea79/nihms-1928133-f0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/55b1/10557912/bab079a33562/nihms-1928133-f0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/55b1/10557912/55eb2e3fc8ef/nihms-1928133-f0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/55b1/10557912/3d119a51d41e/nihms-1928133-f0001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/55b1/10557912/f288caa5ea79/nihms-1928133-f0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/55b1/10557912/bab079a33562/nihms-1928133-f0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/55b1/10557912/55eb2e3fc8ef/nihms-1928133-f0004.jpg

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