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甲氧基、亚甲二氧基、羟基和卤代取代苯并菲啶酮衍生物的合成作为 DNA 拓扑异构酶 IB（TOP1）和酪氨酰-DNA 磷酸二酯酶 1（TDP1）抑制剂及其对耐药性癌症的生物学活性。

Synthesis of Methoxy-, Methylenedioxy-, Hydroxy-, and Halo-Substituted Benzophenanthridinone Derivatives as DNA Topoisomerase IB (TOP1) and Tyrosyl-DNA Phosphodiesterase 1 (TDP1) Inhibitors and Their Biological Activity for Drug-Resistant Cancer.

机构信息

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

Developmental Therapeutics Branch and Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda 20892, Maryland, United States.

出版信息

J Med Chem. 2021 Jun 10;64(11):7617-7629. doi: 10.1021/acs.jmedchem.1c00318. Epub 2021 May 19.

DOI:10.1021/acs.jmedchem.1c00318
PMID:34008967
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10087287/
Abstract

As a recently discovered DNA repair enzyme, tyrosyl-DNA phosphodiesterase 1 (TDP1) removes topoisomerase IB (TOP1)-mediated DNA protein cross-links. Inhibiting TDP1 can potentiate the cytotoxicity of TOP1 inhibitors and overcome cancer cell resistance to TOP1 inhibitors. On the basis of our previous study, herein we report the synthesis of benzophenanthridinone derivatives as TOP1 and TDP1 inhibitors. Seven compounds (, , , , , , and ) showed a robust TOP1 inhibitory activity (+++ or ++++), and four compounds (, , , and ) showed a TDP1 inhibition (half-maximal inhibitory concentration values of 15 or 19 μM). We also show that the dual TOP1 and TDP1 inhibitor induces both cellular TOP1cc, TDP1cc formation and DNA damage, resulting in cancer cell apoptosis at a sub-micromolar concentration. In addition, showed an enhanced activity in drug-resistant MCF-7/TDP1 cancer cells and was synergistic with topotecan in both MCF-7 and MCF-7/TDP1 cells.

摘要

作为一种新发现的 DNA 修复酶，酪氨酸-DNA 磷酸二酯酶 1（TDP1）可去除拓扑异构酶 IB（TOP1）介导的 DNA 蛋白交联。抑制 TDP1 可以增强 TOP1 抑制剂的细胞毒性，并克服癌细胞对 TOP1 抑制剂的耐药性。基于我们之前的研究，本文报道了苯并菲啶酮衍生物作为 TOP1 和 TDP1 抑制剂的合成。7 种化合物（、、、、、、和）表现出较强的 TOP1 抑制活性（++++或+++++），4 种化合物（、、、和）表现出 TDP1 抑制活性（半数最大抑制浓度值为 15 或 19 μM）。我们还表明，双重 TOP1 和 TDP1 抑制剂 可诱导细胞内 TOP1cc 和 TDP1cc 的形成以及 DNA 损伤，从而在亚微摩尔浓度下诱导癌细胞凋亡。此外，在耐药 MCF-7/TDP1 癌细胞中显示出增强的活性，并与拓扑替康在 MCF-7 和 MCF-7/TDP1 细胞中均具有协同作用。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3556/10087287/67829d7d7e90/nihms-1868161-f0008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3556/10087287/f0152bf6b2c8/nihms-1868161-f0001.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3556/10087287/14ba629dcf28/nihms-1868161-f0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3556/10087287/49cefe0666ee/nihms-1868161-f0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3556/10087287/109bd2e59428/nihms-1868161-f0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3556/10087287/cbaf72f6aba2/nihms-1868161-f0007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3556/10087287/67829d7d7e90/nihms-1868161-f0008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3556/10087287/f0152bf6b2c8/nihms-1868161-f0001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3556/10087287/9852ad12bb61/nihms-1868161-f0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3556/10087287/6bdc1efd89e2/nihms-1868161-f0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3556/10087287/14ba629dcf28/nihms-1868161-f0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3556/10087287/49cefe0666ee/nihms-1868161-f0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3556/10087287/109bd2e59428/nihms-1868161-f0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3556/10087287/cbaf72f6aba2/nihms-1868161-f0007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3556/10087287/67829d7d7e90/nihms-1868161-f0008.jpg

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