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新型强效四氢喹唑啉类抑制剂，对人拓扑异构酶 IIα 具有高度选择性，而对 IIβ 选择性较低。

Novel, Potent, and Druglike Tetrahydroquinazoline Inhibitor That Is Highly Selective for Human Topoisomerase II α over β.

机构信息

Laboratory of Molecular Modeling and Drug Discovery, Istituto Italiano di Tecnologia, Via Morego 30, 16163 Genoa, Italy.

Department of Pharmacy and Biotechnology, Alma Mater Studiorum-University of Bologna, Via Belmeloro 6, 40126 Bologna, Italy.

出版信息

J Med Chem. 2020 Nov 12;63(21):12873-12886. doi: 10.1021/acs.jmedchem.0c00774. Epub 2020 Oct 20.

DOI:10.1021/acs.jmedchem.0c00774
PMID:33079544
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7668297/
Abstract

We disclose a novel class of 6-amino-tetrahydroquinazoline derivatives that inhibit human topoisomerase II (topoII), a validated target of anticancer drugs. In contrast to topoII-targeted drugs currently in clinical use, these compounds do not act as topoII poisons that enhance enzyme-mediated DNA cleavage, a mechanism that is linked to the development of secondary leukemias. Instead, these tetrahydroquinazolines block the topoII function with no evidence of DNA intercalation. We identified a potent lead compound [compound (ARN-21934) IC = 2 μM for inhibition of DNA relaxation, as compared to an IC = 120 μM for the anticancer drug etoposide] with excellent metabolic stability and solubility. This new compound also shows ~100-fold selectivity for topoIIα over topoβ, a broad antiproliferative activity toward cultured human cancer cells, a favorable in vivo pharmacokinetic profile, and the ability to penetrate the blood-brain barrier. Thus, ARN-21934 is a highly promising lead for the development of novel and potentially safer topoII-targeted anticancer drugs.

摘要

我们揭示了一类新型的 6-氨基四氢喹唑啉衍生物，它们能够抑制人类拓扑异构酶 II（topoII），这是一种已被证实的抗癌药物靶点。与目前临床使用的靶向 topoII 的药物不同，这些化合物不作为 topoII 毒物发挥作用，不会增强酶介导的 DNA 断裂，而这种机制与继发性白血病的发展有关。相反，这些四氢喹唑啉通过没有 DNA 嵌入的证据来阻断 topoII 的功能。我们鉴定出一种有效的先导化合物[化合物（ARN-21934）对 DNA 松弛的抑制作用的 IC = 2 μM，而抗癌药物依托泊苷的 IC = 120 μM]，具有良好的代谢稳定性和溶解度。这种新化合物对 topoIIα 的选择性也比 topoβ 高约 100 倍，对培养的人类癌细胞具有广泛的抗增殖活性，体内药代动力学特征良好，并且能够穿透血脑屏障。因此，ARN-21934 是开发新型、潜在更安全的拓扑异构酶 II 靶向抗癌药物的极具前景的先导化合物。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/46e0/7668297/72b3bf469465/jm0c00774_0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/46e0/7668297/66b9a923be8e/jm0c00774_0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/46e0/7668297/abbeb0f49e13/jm0c00774_0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/46e0/7668297/dbdeff90b182/jm0c00774_0007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/46e0/7668297/74b99354b147/jm0c00774_0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/46e0/7668297/a2ca624ea75c/jm0c00774_0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/46e0/7668297/72b3bf469465/jm0c00774_0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/46e0/7668297/66b9a923be8e/jm0c00774_0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/46e0/7668297/abbeb0f49e13/jm0c00774_0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/46e0/7668297/dbdeff90b182/jm0c00774_0007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/46e0/7668297/74b99354b147/jm0c00774_0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/46e0/7668297/a2ca624ea75c/jm0c00774_0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/46e0/7668297/72b3bf469465/jm0c00774_0006.jpg

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