Studies on some novel nitroimidazole-polyamine drug conjugates.

This thesis is a study of the synthesis of various polyamine-drug conjugates, the evaluation of their abilities to protect DNA solutions from the effects of radiation and their abilities to act as substrates for a cellular polyamine uptake system. Synthetic methods were developed to synthesise an N1, N8-diderivatised spermidine- nitroimidazole conjugate and three structurally isomeric monoderivatised spermidine- nitroimidazole conjugates (N1, and N4 and N8 respectively). Also synthesised were an N1, N7-diderivatised norspermidine-nitroimidazole conjugate, an N4-monoderivatised spermidine-ascorbic acid conjugate and the radioprotecting agent N1-mercaptoethylspeimidine. All synthetic routes involved alkylating the polyamines, facilitated by the regioselective introduction of various protecting groups including DPP and BOC. All compounds demonstrated the ability to protect PBR322 DNA in aqueous solution (25 mug. ul-1) from the damage caused by radiation in terms of strand breaks, both over a range of drug concentrations ([0.0005] - [5.0] mmol) irradiating at 6.72 Gy and at drug concentrations of [0.05] mmol over a range of radiation doses (0 - 8.35 Gy). Under these conditions of indirect damage, the polyamine-nitroimidazole conjugates and the polyamine-ascorbic acid conjugate were not found to enhance the protection offered by misonidazole or ascorbic acid, respectively. A range of variously charged thiols were also tested, showing that the magnitude or sign of charge had no apparent effect on the level of protection. It was concluded that bulk scavenging of hydroxyl radicals is at least as important as scavenging in the local vicinity of DNA. The compounds were examined for their abilities to serve as substrates for the polyamine uptake system in A549 lung carcinoma cells, by measuring their inhibition of [14C]-spermidine uptake. Marked differences were observed between the nitroimidazole-polyamine conjugates. For maximum recognition of the substrate by the polyamine transport system, the amino-butyl unit of spermidine should remain underivatised. The preferred site(s) of spermidine amino derivatisation was in the order: N1>N8>N4~N1,N8.