2. Academic Validation
  3. Design, synthesis, biological evaluation and molecular docking study on peptidomimetic analogues of XK469

Design, synthesis, biological evaluation and molecular docking study on peptidomimetic analogues of XK469

  • Eur J Med Chem. 2016 Nov 29:124:311-325. doi: 10.1016/j.ejmech.2016.08.010.
Qiao-Hong Xia 1,  Wei Hu 2,  Chen Li 3,  Ji-Feng Wu 4,  Liang Yang 1,  Xue-Mei Han 1,  Yue-Mao Shen 1,  Zhi-Yu Li 5,  Xun Li 6
Affiliations

Affiliations

  • 1 Department of Medicinal Chemistry, Key Laboratory of Chemistry and Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, Ji'nan, Shandong 250012, PR China.
  • 2 State Key Laboratory of Microbial Technology, School of Life Science, Shandong University, Ji'nan, Shandong 250100, PR China.
  • 3 School of Bethune Medical Sciences, Jilin University, Changchun, PR China.
  • 4 Institute of Criminal Science and Technology, Ji'nan Public Security Bureau, Ji'nan, 250100, PR China.
  • 5 Department of Pharmaceutical Sciences, Philadelphia College of Pharmacy, Philadelphia, PA 19104, USA. Electronic address: Zh.Li@usciences.edu.
  • 6 Department of Medicinal Chemistry, Key Laboratory of Chemistry and Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, Ji'nan, Shandong 250012, PR China. Electronic address: tjulx2004@sdu.edu.cn.
PMID: 27597408 DOI: 10.1016/j.ejmech.2016.08.010
Abstract

XK469 is identified as a potent quinoxaline antineoplastic agent based on its significant clinical efficacy. It probably exerts its activity via DNA Topoisomerase II (Topo II) inhibition. To obtain more effective antineoplastic agents, a spectrum of peptidomimetic-type quinoxaline analogues of XK469 was herein designed, synthesized, and evaluated. Few compounds (e.g. 13a and 13b) exhibited obvious cytotoxicity indicated by in vitro anti-proliferative assay. SAR investigation revealed that introducing of hydrophobic tert-butylamine or dodecylamine moiety at the 3-position of quinoxaline core is favorable for achieving a better anti-proliferative potency, while peptidomimetic derivatives only yielded moderate cytotoxicity. Compounds with improved anti-proliferative activities also demonstrated decent anti-metastatic potencies comparable with that of doxorubicin (Doxo) based on in vivo mouse model study. The topo II-mediated kinetoplast DNA (kDNA) decatenation assay as well as molecular docking studies implicated that these compounds tend to be potent Topo II inhibitors. Overall, compounds 13a and 13b, 13b in particular, standed out from various assessments and might be promising candidates for further chemical optimization.

Keywords

Antineoplastic agents; Hydrophobic chain; Quinoxaline peptidomimetic analogues; Topoisomerase II inhibitor; XK469.

Figures