Slow self-activation enhances the potency of viridin prodrugs Academic Article uri icon

Overview

MeSH Major

  • Androstenes
  • Bacteriocins
  • Prodrugs

abstract

  • When the viridin wortmannin (Wm) is modified by reaction with certain nucleophiles at the C20 position, the compounds obtained exhibit an improved antiproliferative activity even though a covalent reaction between C20 and a lysine in the active site of PI3 kinase is essential to Wm's ability to inhibit this enzyme. Here we show that this improved potency results from an intramolecular attack by the C6 hydroxyl group that slowly converts these inactive prodrugs to the active species Wm over the 48 h duration of the antiproliferative assay. Our results provide a guide for selecting Wm-like compounds to maximize kinase inhibition with the variety of protocols used to assess the role of PI3 kinase in biological systems, or for achieving optimal therapeutic effects in vivo . In addition, the slow self-activation of WmC20 derivatives provides a mechanism that can be exploited to obtain kinase inhibitors endowed with physical and pharmacokinetic properties far different from man-made kinase inhibitors because they do not bind to kinase active sites.

publication date

  • August 14, 2008

Research

keywords

  • Academic Article

Identity

Language

  • eng

PubMed Central ID

  • PMC2663427

Digital Object Identifier (DOI)

  • 10.1021/jm800374f

PubMed ID

  • 18630894

Additional Document Info

start page

  • 4699

end page

  • 707

volume

  • 51

number

  • 15