Design and Synthesis of Two Cytotoxic Analogs of the Novel Pyrrolo[1′,2′:1,2][1,4]diazepin [7,6-<i>b</i>]indol-5(6<i>H</i>)-one Nucleus

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  • Andrew Tsotinis
    University of Athens, School of Pharmacy, Department of Pharmaceutical ChemistryPanepistimiopolis-Zografou, GR-157 71, Athens , Greece
  • Margarita Vlachou
    University of Athens, School of Pharmacy, Department of Pharmaceutical ChemistryPanepistimiopolis-Zografou, GR-157 71, Athens , Greece
  • Konstantinos Kiakos
    CR-UK Gene Targeted Drug Design Research Group, The School of Pharmacy, University of London29/39 Brunswick Square, London WC1N 1AX, U.K
  • John A Hartley
    CR-UK Drug-DNA Interactions Research Group, Department of Oncology, Royal Free & University College Medical SchoolUCL, 91 Riding House Street, London WIP 8BT, U.K
  • David E Thurston
    CR-UK Gene Targeted Drug Design Research Group, The School of Pharmacy, University of London29/39 Brunswick Square, London WC1N 1AX, U.K

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Abstract

<jats:title>Abstract</jats:title> <jats:p>The design and synthesis of the two cytotoxic derivatives 15 and 16 of the novel pyrrolo[1′,2′:1,2][1,4]diazepin[7,6-b]indol-5(6H)-one nucleus is described. Readily available methyl 2-indolecarboxylates 5 and 6 are nitrosated with NaNO2 in AcOH to give the analogs 7 and 8, which are then oxidized with KMnO4 in aq. NaOH to provide the 3-NO2 acids 9 and 10. These, in turn, are subjected to amidation with (2S)-pyrrolidine-2-carboxaldehyde diethyl thioacetal in the presence of EDCI and HOBt and then to a 7-exo-trig cyclization reaction to give the target molecules 15 and 16. The new analogs were evaluated in the human leukemic K562 cell line and were shown to have micromolar potency.</jats:p>

Journal

  • Chemistry Letters

    Chemistry Letters 32 (6), 512-513, 2003-05-13

    Oxford University Press (OUP)

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