Scripps VIVO scripps research logo

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

A novel, unusually efficacious duocarmycin carbamate prodrug that releases no residual byproduct

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

Overview

related to degree

  • Duncan, Katharine, Ph.D. in Chemistry, Scripps Research 2008 - 2014
  • Wolfe, Amanda, Ph.D. in Chemistry, Scripps Research 2008 - 2013

authors

  • Wolfe, Amanda
  • Duncan, Katharine
  • Parelkar, N. K.
  • Weir, S. J.
  • Vielhauer, G. A.
  • Boger, Dale

publication date

  • June 2012

journal

  • Journal of Medicinal Chemistry  Journal

abstract

  • A unique heterocyclic carbamate prodrug of seco-CBI-indole(2) that releases no residual byproduct is reported as a new member of a class of hydrolyzable prodrugs of the duocarmycin and CC-1065 family of natural products. The prodrug was designed to be activated by hydrolysis of a carbamate releasing the free drug without the cleavage release of a traceable extraneous group. Unlike prior carbamate prodrugs examined that are rapidly cleaved in vivo, the cyclic carbamate was found to be exceptionally stable to hydrolysis under both chemical and biological conditions providing a slow, sustained release of the exceptionally potent free drug. An in vivo evaluation of the prodrug found that its efficacy exceeded that of the parent drug, that its therapeutic window of efficacy versus toxicity is much larger than the parent drug, and that its slow free drug release permitted the safe and efficacious use of doses 150-fold higher than the parent compound.

subject areas

  • Animals
  • Antineoplastic Agents
  • Carbamates
  • Cell Line, Tumor
  • Cyclopropanes
  • Drug Design
  • Humans
  • Hydrolysis
  • Indoles
  • Inhibitory Concentration 50
  • Mice
  • Prodrugs
  • Pyrrolidinones
  • Xenograft Model Antitumor Assays
scroll to property group menus

Identity

PubMed Central ID

  • PMC3386426

International Standard Serial Number (ISSN)

  • 0022-2623

Digital Object Identifier (DOI)

  • 10.1021/jm300330b

PubMed ID

  • 22650244
scroll to property group menus

Additional Document Info

start page

  • 5878

end page

  • 5886

volume

  • 55

issue

  • 12

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

  • About
  • Contact Us
  • Support