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金（I）膦衍生物作为局部活性药物先导化合物，提高了选择性，可克服. 中的 5-硝基杂环药物耐药性。

Gold(I) Phosphine Derivatives with Improved Selectivity as Topically Active Drug Leads to Overcome 5-Nitroheterocyclic Drug Resistance in .

机构信息

Department of Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, California 92093, United States.

Department of Chemistry, Dornsife College of Letters, Arts and Sciences, University of Southern California, Los Angeles, California 90089, United States.

出版信息

J Med Chem. 2021 May 27;64(10):6608-6620. doi: 10.1021/acs.jmedchem.0c01926. Epub 2021 May 11.

DOI:10.1021/acs.jmedchem.0c01926
PMID:33974434
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9309012/
Abstract

causes the most common, nonviral sexually transmitted infection. Only metronidazole (Mz) and tinidazole are approved for treating trichomoniasis, yet resistance is a clinical problem. The gold(I) complex, auranofin, is active against and other protozoa but has significant human toxicity. In a systematic structure-activity exploration, we show here that diversification of gold(I) complexes, particularly as halides with simple C1-C3 trialkyl phosphines or as bistrialkyl phosphine complexes, can markedly improve potency against and selectivity over human cells compared to that of the existing antirheumatic gold(I) drugs. All gold(I) complexes inhibited the two most abundant isoforms of the presumed target enzyme, thioredoxin reductase, but a subset of compounds were markedly more active against live than the enzyme, suggesting that alternative targets exist. Furthermore, all tested gold(I) complexes acted independently of Mz and were able to overcome Mz resistance, making them candidates for the treatment of Mz-refractory trichomoniasis.

摘要

导致最常见的非病毒性性传播感染。只有甲硝唑（Mz）和替硝唑被批准用于治疗滴虫病，但耐药性是一个临床问题。金（I）配合物，金诺芬，对 和其他原生动物有效，但对人体有显著毒性。在系统的结构-活性探索中，我们在这里表明，金（I）配合物的多样化，特别是作为卤素与简单的 C1-C3 三烷基膦或作为双三烷基膦配合物，可以显著提高对 和对人细胞的选择性，与现有的抗风湿金（I）药物相比，其活性更高。所有金（I）配合物均抑制假定靶酶硫氧还蛋白还原酶的两种最丰富的同工酶，但一组化合物对活 的活性明显高于酶，表明存在替代靶标。此外，所有测试的金（I）配合物均不依赖 Mz 起作用，并且能够克服 Mz 耐药性，使它们成为治疗 Mz 耐药性滴虫病的候选药物。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/920b/9309012/b7b4f40ae7d2/nihms-1818375-f0008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/920b/9309012/c3d27a07516e/nihms-1818375-f0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/920b/9309012/20532949e017/nihms-1818375-f0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/920b/9309012/7640765ad6b7/nihms-1818375-f0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/920b/9309012/71b773e3bbe9/nihms-1818375-f0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/920b/9309012/4aa6129b45cf/nihms-1818375-f0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/920b/9309012/ac9c8fbf158b/nihms-1818375-f0007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/920b/9309012/b7b4f40ae7d2/nihms-1818375-f0008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/920b/9309012/c3d27a07516e/nihms-1818375-f0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/920b/9309012/20532949e017/nihms-1818375-f0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/920b/9309012/7640765ad6b7/nihms-1818375-f0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/920b/9309012/71b773e3bbe9/nihms-1818375-f0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/920b/9309012/4aa6129b45cf/nihms-1818375-f0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/920b/9309012/ac9c8fbf158b/nihms-1818375-f0007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/920b/9309012/b7b4f40ae7d2/nihms-1818375-f0008.jpg

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Auranofin Enhances Sulforaphane-Mediated Apoptosis in Hepatocellular Carcinoma Hep3B Cells through Inactivation of the PI3K/Akt Signaling Pathway.金诺芬通过使PI3K/Akt信号通路失活增强萝卜硫素介导的肝癌Hep3B细胞凋亡。
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