Table 1. Cellular Antiproliferative Activity of Compounds 16–21 in HCT116 and H1299 Isogenic Cell Lines.

				HCT116 IC50 (μM)c			HCT116 ratiosd		H1299 IC50 (μM)c			H1299 ratiosd
compd	R1	R2	LogD7.4a	WT	AKR1C3	NfsA_Ec	WT:1C3	WT:NfsA	WT	AKR1C3	NfsA_Ec	WT:1C3	WT:NfsA
1	NA	NA	1.0	66	1.1	0.016	60	4125	114	7.4	0.048	15	2375
16	Me	Me	1.4	102	70	0.089	1.5	1146	98	102	0.154	1.0	636
17	Me	Et	1.7	77	49	0.104	1.6	740	71	71	0.175	1.0	406
18	Me	i-Pr	1.9b	61	53	0.132	1.2	462	59	69	0.287	0.9	206
19	Et	Me	2.2b	83	73	0.231	1.1	359	85	58	0.546	1.5	156
20	Et	Et	2.1	95	62	0.186	1.5	511	67	54	0.552	1.2	121
21	Et	i-Pr	2.5b	65	70	0.496	0.9	131	49	67	0.685	0.7	73

^aOctanol–water partition coefficient, measured using a shake-flask method at pH 7.4.

^bCalculated using measured samples.

^cRelative sensitivity of HCT116 and H1299 monolayer cell lines determined as the concentration of prodrug required to inhibit cell growth by 50% compared to the untreated controls following 4 h drug exposure and 5 days’ regrowth. Mean IC₅₀ values are shown. The coefficient of variation (CV) was <20% across all samples (standard error of the mean (SEM) values are included in Supplementary Table 1).

^dRatio values were determined as the ratio of the average IC₅₀ values between the nontransfected (wild-type, WT) and transfected (AKR1C3- or NfsA_Ec-expressing) cell lines.