Boron neutron capture therapy : Synthesis of boronated amines- and DNA intercalating agents for potential use in cancer therapy

Abstract: Boron Neutron Capture Therapy is a binary cancer treatment modality, involving the delivery of a suitable boron compound to tumour cells followed by irradiation of the tumour by thermal neutrons. Boronated agents can selectively be delivered to tumour cells either directly with tumour-specific boron compounds, or by use of targeting strategies. However, the efficacy of this method would increase if the boron agents are localised in the cell nucleus rather than in the cell cytoplasm when neutron irradiation takes place. With these considerations in mind, some boronated DNA intercalating/interacting agents such as phenantbridine- acridine spermidine and naphthalimide derivatives were synthesised.Amincalkyl-o-carboranes were synthesised in order to be used both for coupling to macromolecules and also for halogenation of their corresponding nido- derivatives. The amino groups were introduced using the Gabriel reagent N, N-ditenzyl iminodicarboxylate to provide 1-(aminomethyl) and 1-(2-aminoethyl)-o-carboranes.The first attempt to achieve the possibility to accumulate a higher concentration of boron atoms in the cell nucleus was to synthesise carboranyl phenanthridinium analogues by reacting a p- or o- carboranyl moiety with phenanthridine, a chromophore with a planar aromatic ring system as DNA intercalator.Boronated acridine-spermidine, boronated diacridine, and boronated dispermidine were obtained in orderto 1) increase water solubility to avoid the interaction of these agents with non-DNA sides of the cell, especially membranes; 2) enhance the feasibility of a higher DNA-binding constant and also decrease the DNA-drug dissociation rate.Finally, the synthesis of a boronated naphthalimide derivative was carried out by nucleophilic reaction of a primary aminoalkyl-p-carborane with naphthalic anhydride.Biological evaluations on DNA-binding, toxicity, and cellular binding with carboranyl phenanthridiniumanalogues, boronated acridine- and spermidine are described.