Scripps VIVO scripps research logo

  • Index
  • Log in
  • Home
  • People
  • Organizations
  • Research
  • Events
Search form

Design, synthesis, and evaluation of duocarmycin O-amino phenol prodrugs subject to tunable reductive activation

Academic Article
uri icon
  • Overview
  • Identity
  • Additional Document Info
  • View All
scroll to property group menus

Overview

related to degree

  • Lajiness, James, Ph.D. in Organic Chemistry, Scripps Research 2007 - 2012

authors

  • Lajiness, James
  • Robertson, W. M.
  • Dunwiddie, I.
  • Broward, M. A.
  • Vielhauer, G. A.
  • Weir, S. J.
  • Boger, Dale

publication date

  • November 2010

journal

  • Journal of Medicinal Chemistry  Journal

abstract

  • A series of N-acyl O-amino derivatives of seco-CBI-indole(2) are reported and examined as prototypical members of a unique class of reductively activated (cleaved) prodrugs of the duocarmycin and CC-1065 family of antitumor agents. These prodrugs were designed to be potentially preferentially activated in hypoxic tumor environments which carry an intrinsically higher concentration of "reducing" nucleophiles (e.g., thiols) capable of activating such derivatives by nucleophilic cleavage of a weak N-O bond. A remarkable range of stabilities and a resulting direct correlation with in vitro/in vivo biological potencies was observed for these prodrugs, even enlisting subtle variations in the electronic and steric environment around the weak N-O bond. An in vivo evaluation of several of the prodrugs demonstrates that some approach the potency and exceed the efficacy of the free drug itself (CBI-indole(2)), suggesting the prodrugs may offer an additional advantage related to a controlled or targeted release.

subject areas

  • Animals
  • Antineoplastic Agents, Alkylating
  • Drug Screening Assays, Antitumor
  • Indoles
  • Leukemia L1210
  • Mice
  • Mice, Inbred DBA
  • Neoplasm Transplantation
  • Phenols
  • Prodrugs
  • Pyrroles
  • Stereoisomerism
  • Structure-Activity Relationship
scroll to property group menus

Identity

PubMed Central ID

  • PMC2974002

International Standard Serial Number (ISSN)

  • 0022-2623

Digital Object Identifier (DOI)

  • 10.1021/jm1010397

PubMed ID

  • 20942408
scroll to property group menus

Additional Document Info

start page

  • 7731

end page

  • 7738

volume

  • 53

issue

  • 21

©2021 The Scripps Research Institute | Terms of Use | Powered by VIVO

  • About
  • Contact Us
  • Support