硫代乙内酰脲衍生物作为具有抗癌活性的强效拓扑异构酶I（Top1）抑制剂的设计、合成与评价
Design, synthesis and evaluation of thiohydantoin derivatives as potent topoisomerase I (Top1) inhibitors with anticancer activity.
作者信息
Majumdar Papiya, Bathula Chandramohan, Basu Suparna M, Das Subhendu K, Agarwal Rahul, Hati Santanu, Singh Ashutosh, Sen Subhabrata, Das Benu Brata
机构信息
Laboratory of Molecular Biology, Department of Physical Chemistry, Indian Association for the Cultivation of Science, 2A and 2B Raja S. C. Mullick Road, Jadavpur, Kolkata, 700032, India.
Department of Chemistry, Shiv Nadar University, Post Office Shiv Nadar University, Gautam Buddha Nagar, 201314, Uttar Pradesh, India.
出版信息
Eur J Med Chem. 2015 Sep 18;102:540-51. doi: 10.1016/j.ejmech.2015.08.032. Epub 2015 Aug 18.
DNA topoisomerase I is a potential chemotherapeutic target. Here, we designed and synthesized a library comprising of hydantoin and thiohydantoin derivatives and tested them against human and Leishmania Top1. One of the thiohydantoin compounds with substituted thiophenyl as the central moiety (compound 15) exhibited potent inhibition of human Top1 (HTop1) through stabilization of Top1-DNA cleavage complexes and showed selective anticancer activity against human cervical carcinoma (HeLa) and breast carcinoma (MCF-7) cell lines. Molecular modeling studies with HTop1 rationalized the inhibitory mechanism of compound 15.
DNA拓扑异构酶I是一个潜在的化疗靶点。在此，我们设计并合成了一个包含乙内酰脲和硫代乙内酰脲衍生物的文库，并对它们针对人和利什曼原虫Top1进行了测试。其中一种以取代噻吩基为中心部分的硫代乙内酰脲化合物（化合物15）通过稳定Top1-DNA切割复合物对人Top1（HTop1）表现出强效抑制作用，并对人宫颈癌（HeLa）和乳腺癌（MCF-7）细胞系显示出选择性抗癌活性。对HTop1进行的分子模拟研究阐明了化合物15的抑制机制。
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