The Nucleophilic Substitution Reaction of 2-Bromo-3-methoxy-1,4-naphthaquinone with Amino Acid Residues


Heather Crump

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Biologically active quinones benefit various aspects of medicine including anticancer and antibacterials. Through the derivation of 1,4-naphthoquinone with an amino acid residue and/or a peptide, we hope to enhance the medicinal value of 1,4-naphthoquinones, thereby facilitating the delivery of a 1,4-naphthoquinone derivative to specified locations in vivo . When exploring the reactivity of 2-bromo-3-methoxy-1,4-naphthoquinone with L -lysine ethyl ester dihydrochloride and L -cysteine ethyl ester hydrochloride, we find that the reactivity of the 2- and 3- positions of 2-bromo-3-methoxy-1,4-naphthaquinone depends on the reaction conditions. Triethylamine is added to deprotonate the ammonium salt to free amino acid. When one equivalent of triethylamine is added to a equimolar mixture of L -lysine ethyl ester dihydrochloride and quinone, a ?one-to-one? product, 2-bromo-3-(5-amino-5-ethoxycarbonylpentylamino)-1,4-naphthoquinone, is formed as a result of the substitution of the 3-methoxy group with the e-amino group of L -lysine ethyl ester. In the presence of two equivalents of triethylamine, both the a-amino group and the e-amino group of L -lysine ethyl ester are reacted with two quinone molecules, forming a ?one-to-two? product, N,N?-[bis(2-bromo-1,4-naphthaquinonyl)]lysine ethyl ester. Using a tandem substitution process, the ?one-to-one? product further reacts with L -cysteine ethyl ester, in which a thiolate anion replaces the bromine at the 2-position of the quinone residue, providing a disubstituted product, 2-(2-amino-2-ethoxycarbonylethylthio)-3-(5-amino-5-ethoxycarbonylpentylamino) -1,4-naphthoquinone. Further studies using peptide chains will help further tune the biological activity of a 1,4-naphthaquinone.


T. Otsuki




Support provided by:Sherman-Fairchild Foundation Grant Fellowship

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