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Synthesis of Sequence-Selective C8-Linked Pyrrolo[2,1-c][1,4]benzodiazepine DNA Interstrand Cross-Linking Agents
David E. Thurston1, D. Subhas Bose, Andrew S. Thompson
1CRC Gene Targeted Drug Design Research Group, School of Pharmacy and Biomedical Science, University of Portsmouth, St Michael's Building, White Swan Road, Portsmouth, Hants. PO1 2DT, U.K., CRC Biomolecular Structure Unit, Institute of Cancer Research, Sutton, Surrey SM2 5NG, U.K., CRC Drug-DNA Interactions Research Group, Department of Oncology, University College London Medical School, 91 Riding House Street, London W1P 8BT, U.K., and College of Pharmacy, University of Texas at Austin, Austin, Texas 78712.
Abstract:
An 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 alpha,omega-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.