Synthesis and Electrochemical Evaluation of Conjugates between 2′-Deoxyadenosine and Modified Anthraquinone: Probes for Hole-Transfer Studies in DNA

Abstract

Photoexcitation of anthraquinones (AQ) in association with DNA results in DNA damage mainly at guanine residues, with products from thymine oxidation also observed. Studies of adenine oxidation will be aided by systems with an increased driving force for charge transfer, achieved by adding electron-withdrawing groups to the AQ ring. Attaching AQ derivatives to adenine via a bridge with two carbon atoms should enable the intended regiocontrol within the DNA duplex structure. Herein we report the synthesis of conjugates between AQ and adenine in which the AQ moieties have been modified with a formyl, a trifluoroacetyl, and two methyl ester groups. These have been synthesized by palladium coupling of tert-butyldiphenylsilyl 5'-protected 8-ethynyl-2'-deoxyadenosine with the corresponding bromoanthraquinone intermediates. Bromo intermediates bearing formyl or trifluoroacetyl were prepared by monolithiation of 2,6-dibromoanthraquinone, a step that required protection of the anthraquinone carbonyls. A bromo intermediate bearing two methyl ester groups was obtained from 1,2,4-trimethylbenzene by Friedel-Crafts acylation with 4-bromobenzoyl chloride followed by oxidation to the tricarboxylic acid, cyclization to form the anthraquinone ring, and finally esterification. Hydrogenation of the ethynyl linker gave the ethanyl linker. Cyclic voltammetry showed that the conjugate with the two ester groups and ethynyl linker was the most easily reduced of the derivatives synthesized. These derivatives, with reduction potentials favorable for electron transfer, can be used in studies of adenine oxidation in DNA.