5-Nitrofuran-2-ylmethyl group as a potential bioreductively activated pro-drug system

Abstract

5-Substituted isoquinolin-1-ones have been synthesised by one-pot Curtius rearrangement of the corresponding substituted 3-phenylpropenoyl azides and cyclisation. Arylmethylation of the anions of the isoquinolinones with benzyl halides [4-methoxybenzyl chloride, 2-(chloromethyl)furan and 5-nitro-2-(tosyloxymethyl)furan] takes place exclusively at nitrogen. Nitration of 2-(furan-2-ylmethyl)isoquinolin-1-one in strongly acidic medium gives 2-(5-nitrofuran-2-ylmethyl)isoquinolin-1-one, whereas weaker acidic conditions lead to dinitration. Curtius rearrangement of 3-carboranylbutanoyl azide and trapping with 5-nitrofuran-2-ylmethanol gives 5-nitrofuran-2-ylmethyl N-(3-carboranylpropyl)carbamate. Biomimetic reduction of these nitrofuranylmethyl derivatives of anticancer drugs triggers release of the parent drugs. Thus, these nitrofurans have potential applications as pro-drugs for selective release of therapeutic drugs in hypoxic solid tumours.