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  3. Structure-based discovery of cytotoxic dimeric tetrahydroxanthones as potential topoisomerase I inhibitors from a marine-derived fungus

Structure-based discovery of cytotoxic dimeric tetrahydroxanthones as potential topoisomerase I inhibitors from a marine-derived fungus

  • Eur J Med Chem. 2018 Mar 25:148:268-278. doi: 10.1016/j.ejmech.2018.02.041.
Guangwei Wu 1,  Xin Qi 1,  Xiaomei Mo 1,  Guihong Yu 2,  Qiang Wang 3,  Tianjiao Zhu 2,  Qianqun Gu 2,  Ming Liu 4,  Jing Li 5,  Dehai Li 6
Affiliations

Affiliations

  • 1 Key Laboratory of Marine Drugs, Chinese Ministry of Education; School of Medicine and Pharmacy, Ocean University of China, 5 Yushan Road, Qingdao, Shandong, 266003, PR China.
  • 2 Key Laboratory of Marine Drugs, Chinese Ministry of Education; School of Medicine and Pharmacy, Ocean University of China, 5 Yushan Road, Qingdao, Shandong, 266003, PR China; Laboratory for Marine Drugs and Bioproducts of Qingdao National Laboratory for Marine Science and Technology, Qingdao, 266237, PR China.
  • 3 College of Pharmacy, South Central University for Nationalities, Wuhan, 430074, PR China.
  • 4 Key Laboratory of Marine Drugs, Chinese Ministry of Education; School of Medicine and Pharmacy, Ocean University of China, 5 Yushan Road, Qingdao, Shandong, 266003, PR China; Laboratory for Marine Drugs and Bioproducts of Qingdao National Laboratory for Marine Science and Technology, Qingdao, 266237, PR China. Electronic address: lmouc@ouc.edu.cn.
  • 5 Key Laboratory of Marine Drugs, Chinese Ministry of Education; School of Medicine and Pharmacy, Ocean University of China, 5 Yushan Road, Qingdao, Shandong, 266003, PR China; Laboratory for Marine Drugs and Bioproducts of Qingdao National Laboratory for Marine Science and Technology, Qingdao, 266237, PR China. Electronic address: lijing_ouc@ouc.edu.cn.
  • 6 Key Laboratory of Marine Drugs, Chinese Ministry of Education; School of Medicine and Pharmacy, Ocean University of China, 5 Yushan Road, Qingdao, Shandong, 266003, PR China; Laboratory for Marine Drugs and Bioproducts of Qingdao National Laboratory for Marine Science and Technology, Qingdao, 266237, PR China. Electronic address: dehaili@ouc.edu.cn.
PMID: 29466776 DOI: 10.1016/j.ejmech.2018.02.041
Abstract

DNA Topoisomerase I (Topo I) is an important Anticancer drug target, and xanthone dimers are considered to be a new kind of Topo I Inhibitor chemotypes. Based on the characteristics of dimeric xanthone structures, five new dimeric Xanthones (1-5) and two known SAD isomers (6 and 7) were isolated from the mangrove-derived fungus Aspergillus vericolor. The absolute configurations of compounds 1-7, entailing both central and axial chirality elements, were established by a combination of ECD comparison, chemical conversions, and biogenetic considerations. Compounds 1-7 possessed high structural diversity and exhibited cytotoxicity at different levels. The selected new compounds 1, 2, and 5 showed Topo I inhibition properties and the most potent compound 1, an atropisomer of compound 2, was confirmed to inhibit Topo I-mediated DNA relaxation by targeting Topo I, thereby, arresting the cell cycle process and inducing necrosis in Cancer cells. Molecular docking studies showed that compound 1 could bind DNA by π-π interaction and DNA Topo I by hydrogen bonds to form a ternary complex.

Keywords

Aspergillus vericolor; Cytotoxicity; Dimeric xanthone; Topo I inhibitor.

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