Synthetic studies on mitotic kinesin Eg5 inhibitors: Synthesis and structure–activity relationships of novel 2,4,5-substituted-1,3,4-thiadiazoline derivatives

The optimization of an HTS hit (1a) leading to the identification of novel and orally active mitotic kinesin Eg5 inhibitor is described. The 2,4,5-substituted-1,3,4-thiadiazoline derivative 1a has been identified as a new class of mitotic kinesin Eg5 inhibitor. With the aim of enhancement of the mitotic phase accumulation activity, structure optimization of side chains at the 2-, 4-, and 5-positions of the 1,3,4-thiadiazoline ring of 1a was performed. The introduction of sulfonylamino group at the side chain at the 5-position and bulky acyl group at the 2- and 4-position contributed to a significant increase in the mitotic phase accumulation activity and Eg5 inhibitory activity. As a result, a series of optically active compounds exhibited an increased antitumor activity in a human ovarian cancer xenograft mouse model that was induced by oral administration.