The synthesis of novel polyamine–nitroimidazole conjugates designed to probe the structural specificities of the polyamine uptake system in A549 lung carcinoma cells

Abstract

Synthetic routes were developed to synthesise an N ⁴-mono-derivatised spermidine–nitroimidazole conjugate and two novel structural isomers (N ¹- and N ⁸-spermidine–nitroimidazole conjugates). A synthetic method was developed to synthesise an N ¹,N ⁷-bis-derivatised norspermidine–nitroimidazole conjugate and further applied to the synthesis of an N ¹,N ⁸-bis-derivatised spermidine–nitroimidazole conjugate. The compounds were examined for their ability 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 as a substrate by the polyamine transport system, the aminobutyl unit of spermidine should remain underivatised. The preferred site(s) for spermidine amino derivatisation was in the order: N ¹ > N ⁸ ≈ N ¹, N ⁸ > N ⁴.