The Leaving Group Strongly Affects H₂O₂-Induced DNA Cross-Linking by Arylboronates

Abstract

We evaluated the effects of the benzylic leaving group and core structure of arylboronates on H2O2-induced formation of bisquinone methides for DNA interstrand cross-linking. The mechanism of DNA cross-linking induced by these arylboronates involves generation of phenol intermediates followed by departure of benzylic leaving groups leading to QMs which directly cross-link DNA via alkylation. The QM formation is the rate-determining step for DNA cross-linking. A better leaving group (Br) and stepwise bisquinone methide formation increased interstrand cross-linking efficiency. These findings provide essential guidelines for designing novel anticancer prodrugs.