SYNTHESIS OF SEQUENCE-SELECTIVE C8-LINKED PYRROLO[2,1-C][1,4]BENZODIAZEPINE DNA INTERSTRAND CROSS-LINKING AGENTS

An efficient convergent synthesis of a homologous series of C8-linked pyrrolobenzodiazepine dimers with remarkable DNA interstrand cross-lin king activity and potent in vitro cytotoxicity is reported. The ''amin o thioacetal'' cyclization procedure was used to produce the electroph ilic DNA-interactive N10-C11 imine moiety during the final synthetic s tep. In order to construct the key A-ring fragments (9a-d), a versatil e convergent approach has been developed to join two units of vanillic acid with alpha,omega-dihaloalkanes of varying length to provide the required bis(4-carboxy-2-methoxyphenoxy)alkanes while avoiding the for mation of mixtures of monoalkylated and bisalkylated products.