Abstract
Currently, DNA topoisomerase I (Topo I) inhibitors constitute a family of antitumor agents with demonstrated clinical effects on human malignancies. However, the clinical uses of these agents have been greatly limited due to their severe toxic effects. Therefore, it is urgent to find and develop novel low toxic Topo I inhibitors. In recent years, during our ongoing research on natural antitumor products, a collection of low cytotoxic or non-cytotoxic compounds with various structures were identified from marine invertebrates, plants, and their symbiotic microorganisms. In the present study, new Topo I inhibitors were discovered from low cytotoxic and non-cytotoxic natural products by virtual screening with docking simulations in combination with bioassay test. In total, eight potent Topo I inhibitors were found from 138 low cytotoxic or non-cytotoxic compounds from coral-derived fungi and plants. All of these Topo I inhibitors demonstrated activities against Topo I-mediated relaxation of supercoiled DNA at the concentrations of 5–100 µM. Notably, the flavonoids showed higher Topo I inhibitory activities than other compounds. These newly discovered Topo I inhibitors exhibited structurally diverse and could be considered as a good starting point for the development of new antitumor lead compounds.
Highlights
DNA topoisomerase I (Topo I) is a crucial enzyme that works to relax supercoiled DNA during replication, transcription, and mitosis [1,2]
Non-cytotoxic activity were selected for inhibitors by virtualfungi screening combined the screening of Topo I inhibitors by virtual screening combined with bioassay test
Topo I inhibitors were discovered from natural products with low cytotoxic and non-cytotoxic activity by virtual screening with docking simulations in combination with bioassay test
Summary
DNA topoisomerase I (Topo I) is a crucial enzyme that works to relax supercoiled DNA during replication, transcription, and mitosis [1,2]. A large number of Topo-directed agents (e.g., camptothecin (CPT), topotecan, and. A large number of Topo-directed agents (e.g., camptothecin (CPT), topotecan, and irinotecan—Figure 1) are known which are currently in clinical use [10,11]. Their utilities irinotecan—Figure 1) are known which are currently in clinical use [10,11]. Epigallocatechin-3-gallate (EGCG)—a major polyphenolic constituent in green tea—has constituent in green tea—has received much attention as a potential cancer chemopreventive agent received much attention as a potential cancer chemopreventive agent with Topo I inhibitory activity with Topo I inhibitory activity (Figure 1) [14,15,16].
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