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A unique class of duocarmycin and CC-1065 analogues subject to reductive activation

Academic Article
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Overview

related to degree

  • Trzupek, John, Ph.D. in Chemistry, Scripps Research 2001 - 2006

authors

  • Jin, W.
  • Trzupek, John
  • Rayl, T. J.
  • Broward, M. A.
  • Vielhauer, G. A.
  • Weir, S. J.
  • Hwang, I.
  • Boger, Dale

publication date

  • December 2007

journal

  • Journal of the American Chemical Society  Journal

abstract

  • N-Acyl O-amino phenol derivatives of CBI-TMI and CBI-indole2 are reported as prototypical members of a new class of reductively activated prodrugs of the duocarmycin and CC-1065 class of antitumor agents. The expectation being that hypoxic tumor environments, with their higher reducing capacity, carry an intrinsic higher concentration of "reducing" nucleophiles (e.g., thiols) capable of activating such derivatives (tunable N-O bond cleavage) and increasing their sensitivity to the prodrug treatment. Preliminary studies indicate the prodrugs effectively release the free drug in functional cellular assays for cytotoxic activity approaching or matching the activity of the free drug, yet remain essentially stable and unreactive to in vitro DNA alkylation conditions (<0.1-0.01% free drug release) and pH 7.0 phosphate buffer, and exhibit a robust half-life in human plasma (t1/2 = 3 h). Characterization of a representative O-(acylamino) prodrug in vivo indicates that they approach the potency and exceed the efficacy of the free drug itself (CBI-indole2), indicating that not only is the free drug effectively released from the inactive prodrug but also that they offer additional advantages related to a controlled or targeted release in vivo.

subject areas

  • Alkylation
  • Animals
  • Antibiotics, Antineoplastic
  • Cell Line, Tumor
  • DNA
  • Humans
  • Indoles
  • Inhibitory Concentration 50
  • Leukemia L1210
  • Mice
  • Mice, Inbred DBA
  • Phenols
  • Prodrugs
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Identity

PubMed Central ID

  • PMC2519901

International Standard Serial Number (ISSN)

  • 0002-7863

Digital Object Identifier (DOI)

  • 10.1021/ja075398e

PubMed ID

  • 18020335
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Additional Document Info

start page

  • 15391

end page

  • 15397

volume

  • 129

issue

  • 49

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