摘要：

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 cytotoxinof 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 nitroimida-zoles tethered to quinoline-basedchromophores. 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 abovementioned small seriesas radiosensitizer or cytotoxin of hypoxic cells. It had a hypoxic selectivity of 9-12 in various cell lines, a C1.6 of 7 M, and a sensitization enhancement ratio of 3.2 at 50 M (27% of the IC^50(A)) in V79 cells. Its in vitro therapeutic index (defined as IC^50(A)/C^1.6)was 2530 vs. 11 for 9-[3-(2-nitro-1-imidazolyl)propylamino]acri-dine 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 M. When NLCPQ-1was administered IP 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 synergisticinteractions. No toxicity was observed at doses up to 50 mg/kg NLCPQ-1 in nontumor-bearing Balb/c mice.

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