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发现有效异喹啉醌-氧化物以克服癌症多药耐药性。

Discovery of Potent Isoquinolinequinone -Oxides to Overcome Cancer Multidrug Resistance.

机构信息

School of Chemistry, Analytical and Biological Chemistry Research Facility, University College Cork, Cork T12 K8AF, Ireland.

i3S-Instituto de Investigação e Inovação em Saúde, Universidade do Porto, 4200-135 Porto Portugal.

出版信息

J Med Chem. 2024 Aug 22;67(16):13909-13924. doi: 10.1021/acs.jmedchem.4c00705. Epub 2024 Aug 2.

DOI:10.1021/acs.jmedchem.4c00705
PMID:39093920
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11345829/
Abstract

Multidrug resistance (MDR) of human tumors has resulted in an immediate need to develop appropriate new drugs. This work outlines the development of 20 potent IQQ -oxide derivatives in two isomeric families, both exhibiting nanomolar GI against human tumor cell lines. Preliminary NCI-60 tumor screening sees the C(6) isomers achieve a mean GI > 2 times lower than the corresponding C(7) isomers. MDR evaluation of nine selected compounds reveals that each presents lower GI concentrations in two MDR tumor cell lines. Four of the series display nanomolar GI values against MDR cells, having selectivity ratios up to 2.7 versus the sensitive (parental) cells. The most potent compound inhibits the activity of drug efflux pumps in MDR cells, causes significant ROS accumulation, and potently inhibits cell proliferation, causing alterations in the cell cycle profile. Our findings are confirmed by 3D spheroid models, providing new candidates for studies against MDR cancers.

摘要

多药耐药（MDR）的人类肿瘤已经导致了对开发合适的新药的迫切需求。这项工作概述了两种异构族的 20 种有效 IQQ-氧化物衍生物的开发，它们都表现出对人类肿瘤细胞系的纳摩尔 GI 值。初步的 NCI-60 肿瘤筛选发现 C(6)异构体的平均 GI 值比相应的 C(7)异构体低 2 倍以上。对 9 种选定化合物的 MDR 评估表明，每种化合物在两种 MDR 肿瘤细胞系中的 GI 浓度都较低。该系列中有 4 种化合物对 MDR 细胞表现出纳摩尔 GI 值，对敏感（亲本）细胞的选择性比值高达 2.7。最有效的化合物 抑制了 MDR 细胞中药物外排泵的活性，导致 ROS 大量积累，并强烈抑制细胞增殖，导致细胞周期谱发生改变。我们的发现通过 3D 球体模型得到了证实，为研究针对 MDR 癌症的新候选药物提供了依据。

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Regioselection Switch in Nucleophilic Addition to Isoquinolinequinones: Mechanism and Origin of the Regioselectivity in the Total Synthesis of Ellipticine.区域选择性亲核加成到异喹啉醌：在椭圆叶紫堇碱全合成中区域选择性的机制和起源。
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