Our SAR trend echoed an earlier report that similarly observed the critical role of the furfuryl alcohol motif to YC-1's HIF-1α inhibitory activities. The exquisite sensitivity of the furfuryl alcohol to minor structural perturbations provided an early indication that this motif might be directly involved in interactions with the target. Next, masking the primary alcohol with an ester group in compound 13 led to a 6-fold decrease in activity compared to parent 1; this suggested that the alcohol functionality in parent 1 was likely revealed through an esterase-catalyzed hydrolysis of ester 13 in cells. This hypothesis was also supported by compound 14 which had an ester directly attached to the furan and showed a 35% reduction of viability at 46 M. The corresponding acid 14a was also tested and found to be inactive. Consistent with the findings that a hydrogen-bond donor at the northern region of the scaffold was necessary for cytotoxic activity, we introduced a primary amine as shown in compound 15, which proved to be active, albeit 4-fold less potent than YC-1. Amongst all the compounds described in Table , compound 15 had the most attractive drug-like properties with kinetic solubility >45 g/mL in aqueous buffer and t 1/2 >30 min in our high-throughput single-point Rat Liver Microsome (RLM) stability assay. For comparison, YC-1 (1) has a solubility of 3g/mL and RLM t 1/2 6 min in the same assays. Finally, extension of the primary amine to methylamine 16 or hydroxylamine 17 led to >10-fold loss of potency, corroborating our observations of the delicate nature of the SAR.