Nitroimidazole-based bioreductive compounds bearing a quinazoline or a naphthyridine chromophore

Abstract

In our search for novel bioreductive agents with weak DNA-binding characteristics, we have synthesized two new 2-nitroimidazolyl derivatives tethered to a fused aromatic-ring chromophore with two nitrogen atoms: 4-[3-(2-nitro-1-imidazolyl)-propylamino]-2-methyl-quinazoline hydrochloride (NLQZ-1) and 4-[3-(2-nitro-1-imidazolyl)-propylamino]-1,5-naphthyridine hydrochloride (NLPP-1). DNA binding was evaluated by using the ethidium bromide displacement assay. Cytotoxicity, radiosensitization, and interaction with chemotherapeutic agents were evaluated in V79 and A549 cells by using the clonogenic assay. Both compounds are not DNA intercalators and showed relatively low uptake characteristics in V79 cells. A slightly increasing hypoxic selectivity [HS = IC(50)(A)/IC(50)(H) (IC(50) is the product of a compound's concentration and the time necessary for 50% reduction in clonogenicity under aerobic (A) or hypoxic (H) conditions)] was observed with incubation time in the case of NLPP-1 (12-19 and 15-26 in V79 and A549 cells, respectively, with 1-3 h of incubation). The HS of NLQZ-1 was approximately 14, independently of incubation time. Good radiosensitization of hypoxic V79 cells was obtained with both compounds at nontoxic concentrations [the concentration for a sensitization enhancement ratio of 1.6 (C(1.6)) was 61.4 and 75.0 micromol/l for NLQZ-1 and NLPP-1, respectively]. For NLPP-1, a C(1.6) of 44.1 micromol/l was obtained in A549 cells. Both compounds interacted synergistically with cisplatin or melphalan in V79 cells, under hypoxic preexposure conditions and dose modification factors values of approximately 2.5 were obtained at 10% survival. It is concluded that although compounds that do not bind to DNA are in general less potent hypoxic cytotoxins, they can still show good HS values and interact synergistically with radiation/chemotherapeutic agents. Therefore, a further in-vivo evaluation of NLQZ-1 and NLPP-1 is worthwhile.