4-[3-(2-nitro-1-imidazolyl)propylamino]-7-chloroquinoline hydrochloride (NLCQ-1), a novel bioreductive compound as a hypoxia-selective cytotoxin

A novel weakly DNA-intercalative bioreductive compound, 4-[3-(2-nitro-1-imi dazolyl)-propylamino]-7-chloroquinoline hydrochloride (NLCQ-1), has been sy nthesized and studied as a hypoxia-selective cytotoxin in vitro. NLCQ-1, wh ich shares a similar structure with the DNA-intercalative antimalarial drug chloroquine, bound more strongly to DNA than the nonchlorinated analog NLQ -1 (4-[3-(2-nitro-1-imidazolyl)propylamino] hydrochloride). Thus, NLCQ-1 ex hibited a C-50 [concentration for 50% displacement of the ethidium bromide (EB) from a DNA-EB complex] of 44 muM, whereas a C-50 value could not be re ached for NLQ-1 up to 225 muM. NLCQ-1 demonstrated significant hypoxic sele ctivity in several rodent (V79, EMT6, SCCVII) or human (A549, OVCAR-3) tumo r cell lines. Its potency as a hypoxic cytotoxin (expressed as the product of exposure time and concentration for 50% survival) ranged between 10 and 136 muM.h, for the cell lines tested, at 30 muM input concentration. Becaus e uptake in all cell lines was similar, the differences in potency may refl ect differences in the enzymatic profile or damage repair processes among t he cell lines. In addition, however, the most striking feature of NLCQ-1 wa s that hypoxic selectivity increased with exposure time, a common feature n ormally found in only bis-bioreductive agents carrying two moieties with di fferent redox potentials. Thus, hypoxic selectivity of NLCQ-1 in V79 cells at 50% survival was increased from fivefold up to 388-fold by increasing ex posure time from 1 to 4.5 h, as the result of a concomitant increase and de crease in its hypoxic and aerobic potency, respectively, over time. Because the nonchlorinated analog NLQ-1 did not demonstrate similar behavior, we h ypothesized that the C-7 chlorine of NLCQ-1 might play a significant role i n this phenomenon.