An optimized polyamine moiety boosts the potency of human type II topoisomerase poisons as quantified by comparative analysis centered on the clinical candidate F14512

Chem Commun (Camb). 2015 Oct 1;51(76):14310-3. doi: 10.1039/c5cc05065k. Epub 2015 Aug 3.

Abstract

Combined computational-experimental analyses explain and quantify the spermine-vectorized F14512's boosted potency as a topoII poison. We found that an optimized polyamine moiety boosts drug binding to the topoII/DNA cleavage complex, rather than to the DNA alone. These results provide new structural bases and key reference data for designing new human topoII poisons.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • DNA / metabolism
  • DNA Cleavage / drug effects
  • DNA Topoisomerases, Type II / metabolism*
  • Humans
  • Models, Molecular
  • Podophyllotoxin / analogs & derivatives*
  • Podophyllotoxin / chemistry
  • Podophyllotoxin / pharmacology
  • Spermine / chemistry*
  • Spermine / pharmacology*
  • Topoisomerase II Inhibitors / chemistry*
  • Topoisomerase II Inhibitors / pharmacology*

Substances

  • F14512
  • Topoisomerase II Inhibitors
  • Spermine
  • DNA
  • DNA Topoisomerases, Type II
  • Podophyllotoxin