ABSTRACT
Human Eg5 is a mitotic kinesin that is essential for bipolar spindle formation and maintenance during mitosis. Recently, the discovery of compounds that inhibit Eg5 and cause mitotic arrest has attracted great interest, due to their potential use as the next generation of antimitotics. Here, we present the synthesis and biological investigation of 3,4-dihydrophenylquinazoline-2(1H)-thiones as selective and potent Eg5 inhibitors.
Subject(s)
Kinesins/antagonists & inhibitors , Quinazolines/pharmacology , Thiones/pharmacology , Algorithms , Animals , Antimitotic Agents/metabolism , Antimitotic Agents/pharmacology , Chlorocebus aethiops , Humans , Inhibitory Concentration 50 , Mitosis/drug effects , Molecular Structure , Quinazolines/metabolism , Thiones/metabolismABSTRACT
The mitotic kinesin Eg5 (or KSP) is a crucial player in the development and function of the mitotic spindle. Inhibition of this protein leads to cell cycle arrest and apoptosis without interfering with other microtubule-dependent processes. Therefore, it is a potential target in cancer therapy. Here, we report the synthesis and biological evaluation of a small library of molecules based on the structure of the known Eg5 inhibitor HR22C16. One of these derivatives (compound trans-24) proved to be a potent and specific Eg5 inhibitor.
