Hypoxic Selectivity and Solubility--Investigating the Properties of A-ring Substituted Nitro seco-1,2,9,9a-tetrahydrocyclopropa[c]benz[e]indol-4-ones (nitroCBIs) as Hypoxia-Activated Prodrugs for Antitumor Therapy

Bioorg Med Chem. 2010 Jul 15;18(14):4997-5006. doi: 10.1016/j.bmc.2010.06.001. Epub 2010 Jun 8.

Abstract

Nitro seco-1,2,9,9a-tetrahydrocyclopropa[c]benz[e]indol-4-ones (nitroCBIs) are a new class of prodrugs for antitumor therapy that undergo hypoxia-selective metabolism to form potent DNA minor groove alkylating agents. Although hindered by poor aqueous solubility, several examples have shown activity against hypoxic tumor cells in vivo. Here we investigate structural properties that influence hypoxic selectivity in vitro, and show that for high hypoxic selectivity nitroCBIs should combine an electron-withdrawing group of H-bond donor capacity on the A-ring, with a basic substituent on the minor groove-binding side chain. Substitution on the A-ring is compatible with the introduction of functionality that can improve water solubility.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents, Alkylating / chemistry*
  • Antineoplastic Agents, Alkylating / metabolism*
  • Antineoplastic Agents, Alkylating / pharmacokinetics
  • Antineoplastic Agents, Alkylating / pharmacology
  • Cell Hypoxia*
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Cyclopropanes / chemistry*
  • Cyclopropanes / metabolism*
  • Cyclopropanes / pharmacokinetics
  • Cyclopropanes / pharmacology
  • DNA / metabolism
  • Humans
  • Indoles / chemistry*
  • Indoles / metabolism*
  • Indoles / pharmacokinetics
  • Indoles / pharmacology
  • Mice
  • Neoplasms / drug therapy*
  • Prodrugs / chemistry*
  • Prodrugs / metabolism*
  • Prodrugs / pharmacokinetics
  • Prodrugs / pharmacology
  • Solubility

Substances

  • 1,2,9,9a-tetrahydrocyclopropa(c)benz(e)indol-4-one
  • Antineoplastic Agents, Alkylating
  • Cyclopropanes
  • Indoles
  • Prodrugs
  • DNA