9-[3-(2-Nitro-1-imidazolyl)propylamino]-cyclopenteno[b]quinoline hydrochloride (NLCPQ-1). A novel DNA-affinic bioreductive agent as cytotoxin and radiosensitizer.

Our recent studies with 9-[3-(2-nitro-1-imidazolyl)propylamino]-1,2,3,4,-tetrahydroacridine++ + hydrochloride (a 2-nitroimidazole-linked 1,2,3,4-tetrahydroacridine derivative) shows that less effective DNA binding indeed leads to a hypoxic radiosensitizer and cytotoxin of superior in vitro therapeutic index to the fully aromatic nitroimidazole-linked acridine series, which strongly bind to DNA through intercalation. Extending our investigations in this area, we have synthesized and have been evaluating five more nitroimidazoles tethered to quinoline-based chromophores. Here, the in vitro and limited in vivo results of 9-[3-(2-nitro-1-imidazolyl)-propylamino]cyclopenteno[b]quinoline hydrochloride (NLCPQ-1) are presented. On a concentration basis, NLCPQ-1 was the most potent analog so far tested of the above mentioned small series as radiosensitizer or cytotoxin of hypoxic cells. It had a hypoxic selectivity of 9-12 in various cell lines, a C1.6 of approximately equal to 7 microM, and a sensitization enhancement ratio of 3.2 at 50 microM (approximately equal to 27% of the IC50(A)) in V79 cells. Its in vitro therapeutic index (defined as IC50(A)/C1.6) was 25-30 vs. 11 for 9-[3-(2-nitro-1-imidazolyl)propylamino]acridine hydrochloride. The partition coefficient in octanol/water was 0.30 +/- 0.01. The uptake factor (intracellular vs. extracellular concentration) was increased by increasing input concentration and reached 92 at 80 microM. When NLCPQ-1 was administered i.p. at 15 mg/kg, at various time-intervals before a single, 20 Gy radiation dose in Balb/c mice bearing EMT6 tumors, significant synergism was observed. The in vivo-in vitro assay was used as an endpoint, and the fractional product analysis was used to determine synergistic interactions. No toxicity was observed at doses up to 50 mg/kg NLCPQ-1 in nontumor-bearing Balb/c mice.