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Bioorg Med Chem. 2011 Sep 15;19(18):5446-53. doi: 10.1016/j.bmc.2011.07.054. Epub 2011 Jul 30.

Synthesis and characterization of tritylthioethanamine derivatives with potent KSP inhibitory activity.

Author information

1
Department of Biology, New Mexico State University, Las Cruces, NM 88003, USA.

Abstract

Assembly of a bipolar mitotic spindle requires the action of class 5 kinesins, and inhibition or depletion of this motor results in mitotic arrest and apoptosis. S-Trityl-l-cysteine is an allosteric inhibitor of vertebrate Kinesin Spindle Protein (KSP) that has generated considerable interest due to its anti-cancer properties, however, poor pharmacological properties have limited the use of this compound. We have modified the triphenylmethyl and cysteine groups, guided by biochemical and cell-based assays, to yield new cysteinol and cysteamine derivatives with increased inhibitory activity, greater efficacy in model systems, and significantly enhanced potency against the NCI60 tumor panel. These results reveal a promising new class of conformationally-flexible small molecules as allosteric KSP inhibitors for use as research tools, with activities that provide impetus for further development as anti-tumor agents.

PMID:
21855351
PMCID:
PMC3171608
DOI:
10.1016/j.bmc.2011.07.054
[Indexed for MEDLINE]
Free PMC Article

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