Synthesis of 2,6-diphenylpyrazine derivatives and their DNA binding and cytotoxic properties

A series of 2,6-diphenylpyrazine derivatives was synthesized from 2,6-dichloropyrazine and 4-methoxyphenylboronic acid using palladium(0) as catalyst in a Suzuki methodology. After deprotection of the hydroxyl, alkylation reactions with different halides afforded compounds 5-8 bearing hydrophilic chains. DNA binding and cytotoxic properties were investigated. Compound 11 bearing imidazoline terminal groups was found to be a potent AT-specific DNA minor groove binder but there was no relationship between DNA interaction and cytotoxicity. However, in all cases the incorporation of the pyrazine ring was found to promote the cytotoxicity of the molecules compared to the corresponding pyridine analogues, previously synthesized.