Synthesis of Sequence-Selective C8-Linked Pyrrolo[2,1-c][1,4]benzodiazepine DNA Interstrand Cross-Linking Agents
journal contribution
posted on 1996-11-15, 00:00 authored by David E. Thurston, D. Subhas Bose, Andrew S. Thompson, Philip W. Howard, Alberto Leoni, Stephen J. Croker, Terrence C. Jenkins, Stephen Neidle, John A. Hartley, Laurence H. HurleyAn efficient convergent synthesis of a homologous series of
C8-linked pyrrolobenzodiazepine dimers
with remarkable DNA interstrand cross-linking activity and potent
in vitro cytotoxicity is reported.
The “amino thioacetal” cyclization procedure was used to
produce the electrophilic DNA-interactive
N10−C11 imine moiety during the final synthetic step. In order
to construct the key A-ring
fragments (9a−d), a versatile
convergent approach has been developed to join two units of
vanillic
acid with α,ω-dihaloalkanes of varying length to provide the
required bis(4-carboxy-2-methoxyphenoxy)alkanes while avoiding the formation of mixtures of
monoalkylated and bisalkylated products.
