Synthesis of sequence-selective C8-linked pyrrolo[2,1-c][1,4]benzodiazepine DNA interstrand cross-linking agents

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. Hurley

Research output: Contribution to journalArticle

107 Scopus citations

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 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.

Original languageEnglish (US)
Pages (from-to)8141-8147
Number of pages7
JournalJournal of Organic Chemistry
Volume61
Issue number23
DOIs
StatePublished - Nov 15 1996
Externally publishedYes

ASJC Scopus subject areas

  • Organic Chemistry

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    Thurston, D. E., Bose, D. S., Thompson, A. S., Howard, P. W., Leoni, A., Croker, S. J., Jenkins, T. C., Neidle, S., Hartley, J. A., & Hurley, L. H. (1996). Synthesis of sequence-selective C8-linked pyrrolo[2,1-c][1,4]benzodiazepine DNA interstrand cross-linking agents. Journal of Organic Chemistry, 61(23), 8141-8147. https://doi.org/10.1021/jo951631s