Table 2. Cellular Antiproliferative Activity of Compounds 16, 17, 20, and 25–27 in SiHa and HCT116 Isogenic Cell Lines under Aerobic and Anoxic Conditions.

					SiHa IC50 (μM)b			HCT116 IC50 (μM)b			HCT116 POR IC50 (μM)d
compd	R1	R2	X	LogD7.4a	aerobic	anoxic	HCRc	aerobic	anoxic	HCRc	aerobic	anoxic	HCRc
1	NA	NA	NA	1.0	19	2.7	7.0	38	2.5	15	41	0.14	293
16	Me	Me	Br	1.4	241	16	15	160	24	6.6	82	0.88	93
25	Me	Et	OMs	0.3	561	47	12	368	23	16	139	1.6	87
17	Me	Et	Br	1.7	164	10	16	145	21	6.9	54	0.66	82
26	Me	Et	OMs	0.6	459	22	21	288	14	21	112	1.2	93
20	Et	Et	Br	2.1	253	23	11	142	27	5.3	60	2.8	21
27	Et	Et	OMs	1.0	>300	15	>20	254	18	14	122	2.8	44

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

^bRelative sensitivity of SiHa, HCT116 (wild type), and HCT116 POR monolayer cell lines under aerobic and anoxic conditions. IC₅₀ values were determined as the concentration of prodrug required to inhibit cell growth by 50% compared to the untreated controls after 4 h drug exposure under aerobic or anoxic conditions followed by 5 days’ regrowth under aerobic conditions. Mean IC₅₀ values are shown. The CV was <20% across all samples (SEM values are included in Supplementary Table 2).

^cHCR = hypoxic cytotoxicity ratio, determined as the ratio of IC₅₀ values between aerobic and anoxic conditions.

^dHCT116 POR = HCT116 colon cancer cells transfected to overexpress human cytochrome P450 oxidoreductase (POR).