1. Academic Validation
  2. Design, synthesis, bioevaluation of LFC- and PA-tethered anthraquinone analogues of mitoxantrone

Design, synthesis, bioevaluation of LFC- and PA-tethered anthraquinone analogues of mitoxantrone

  • Bioorg Chem. 2020 Aug;101:104005. doi: 10.1016/j.bioorg.2020.104005.
Xin-Wen Xie 1 Zhao-Peng Liu 2 Xun Li 3
Affiliations

Affiliations

  • 1 Key Laboratory of Chemistry and Chemical Biology (Ministry of Education), Department of Medicinal Chemistry, School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Ji'nan, Shandong 250012, China.
  • 2 Key Laboratory of Chemistry and Chemical Biology (Ministry of Education), Department of Medicinal Chemistry, School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Ji'nan, Shandong 250012, China. Electronic address: liuzhaop@sdu.edu.cn.
  • 3 Key Laboratory of Chemistry and Chemical Biology (Ministry of Education), Department of Medicinal Chemistry, School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Ji'nan, Shandong 250012, China; Institute of Materia Medica, Shandong First Medical University & Shandong Academy of Medical Sciences, Ji'nan, Shandong, 250002, China. Electronic address: tjulx2004@sdu.edu.cn.
Abstract

The clinical application of mitoxantrone (MTZ), a DNA-intercalating Topoisomerase II (Topo II) poison, has been largely limited by the risk of secondary tumor and severe myelosuppression. To develop more effective antineoplastic agents with less toxicity, a spectrum of anthraquinone analogues of MTZ were herein designed and synthesized based on the concept of 'enhancing protein backbone-binding', by rationally introducing hydrophobic long fatty acid chain (LFC) and hydrophilic polyamine (PA) components, which are reported to function as effective tumor-targeting tethers. The SAR exploration implicated that in our synthesized molecules, the introduction of both lipophilic LFC and hydrophilic PA fragment is plausibly beneficial to the anti-proliferative potency, with a certain degree of selectivity between the hematopoietic and solid malignant cells, which still need to be further accurately confirmed. Meanwhile, many compounds, the LFC-tethered 5d2 and PA-bridged 8c in particular, provided satisfactory topo IIα inhibition by acting as DNA non-intercalators, largely attributable to their strong adaptability to three binding regions (pocket I, II and III) and also the generated H-bonding interactions between inhibitors and key residues of topo IIα. In brief, 5d2 and 8c might be promising hits for further exploitation of more potent topo IIα inhibitors.

Keywords

Anthraquinone analogues; LFC; Mitoxantrone (MTZ); PA; Topo IIα inhibitor.

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