Monopolar spindle 1 (Mps1) is essential for centrosome duplication, the spindle assembly check point, and the maintenance of chromosomal instability. Mps1 is highly expressed in cancer cells, and its expression levels correlate with the histological grades of cancers. Thus, selective Mps1 inhibitors offer an attractive opportunity for the development of novel cancer therapies. To design novel Mps1 inhibitors, we utilized the pan-kinase inhibitor anthrapyrazolone (4, SP600125) and its crystal structure bound to JNK1. Our design efforts led to the identification of indazole-based lead 6 with an Mps1 IC50 value of 498 nM. Optimization of the 3- and 6-positions on the indazole core of 6 resulted in 23c with improved Mps1 activity (IC50 = 3.06 nM). Finally, application of structure-based design using the X-ray structure of 23d bound to Mps1 culminated in the discovery of 32a and 32b with improved potency for cellular Mps1 and A549 lung cancer cells. Moreover, 32a and 32b exhibited reasonable selectivities over 120 and 166 kinases, respectively.

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Ther hodium(I)-catalyzed cycloisomerization of enynes with tethered (S)-2-methyl-2-propanesulfinyli mine affords 5-or 6-membered cyclic compoundsc ontaining exocyclic 1,3-diene moieties in as tereoselective manner. Ther eactionp roceeds through b-hydridee limination of a7 -membered azarhodacycle intermediate,w hich is generated from three unsaturated bonds (i.e., alkene,a lkyne, and C=Nb onds) anda nR h(I) complex. Ther esultant cycliccompounds could be reactedwith various dienophilest oa fford spiroamides as single isomers through the Diels-Alder reaction.