Finally, the relative flexibility of the southern region binding domain allowed introducing a polyethyleneglycol-linked biotin to analog 48 without significantly sacrificing the selectivity, a tool compound that proved to be valuable in supporting our reported efforts in elucidating YC-1's mechanism of action. The SAR of the indazole core structure was also investigated. For ease of comparison, alternate cores with a benzyl group and furfuryl alcohol in the southern and northern regions, respectively, as embedded in YC-1, were prepared (Table ). Walking a nitrogen atom from the 4-to the 7position (compounds 49-52) showed very interesting SAR with analog 49 featuring the nitrogen at the 4-position being the only tolerated iteration. The introduction of nitrogen in compounds 49-52 improved the aqueous solubility in our kinetic solubility assay to >45 g/mL compared to YC-1's solubility of 3 g/mL in the same assay. The introduction of a halogen such as the 4-Cl derivative 53 showed a reduction of activity whereas a smaller 5-F in analog 54 maintained potency. Changing the core to indole 55 led to a 10-fold drop in potency compared to YC-1. Fusing a cyclohexyl ring to the indazole (56) caused a smaller two-fold potency decrease. The pyrazole core 57 was also synthesized and proved to be much weaker.