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Design, synthesis, biological evaluation and molecular docking study on peptidomimetic analogues of XK469.
- Source :
-
European Journal of Medicinal Chemistry . Nov2016, Vol. 124, p311-325. 15p. - Publication Year :
- 2016
-
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 ( k DNA) 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. [ABSTRACT FROM AUTHOR]
Details
- Language :
- English
- ISSN :
- 02235234
- Volume :
- 124
- Database :
- Academic Search Index
- Journal :
- European Journal of Medicinal Chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 119220358
- Full Text :
- https://doi.org/10.1016/j.ejmech.2016.08.010