Design and synthesis of androgen receptor antagonists with bulky side chains for overcoming antiandrogen resistance

J Med Chem. 2009 Sep 10;52(17):5546-50. doi: 10.1021/jm801218k.

Abstract

Incorporation of curcumin and beta-ionone into one chemical entity led to identification of a novel antiandrogen with two bulky side chains, 6, which is a pure antagonist of the wild-type and the T877A, W741C, and H874Y mutated androgen receptors (AR), showing no cross-reactivity with progesterone receptor and low micromolar cytotoxicity in LNCaP, PCa-2b, 22Rv1, and C4-2B prostate cancer cells. Molecular modeling indicates 6 adopts a "Y"-shape conformation and forms multiple hydrogen bonds with AR backbone.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Androgen Antagonists / chemical synthesis
  • Androgen Antagonists / chemistry*
  • Androgen Antagonists / metabolism
  • Androgen Antagonists / pharmacology*
  • Androgen Receptor Antagonists*
  • Binding, Competitive
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Curcumin / chemistry
  • Dihydrotestosterone / pharmacology
  • Drug Design*
  • Drug Resistance / drug effects*
  • Humans
  • Hydrogen Bonding
  • Ligands
  • Models, Molecular
  • Molecular Conformation
  • Mutation
  • Norisoprenoids / chemistry
  • Protein Structure, Tertiary
  • Receptors, Androgen / chemistry
  • Receptors, Androgen / genetics
  • Receptors, Androgen / metabolism
  • Transcriptional Activation / drug effects

Substances

  • Androgen Antagonists
  • Androgen Receptor Antagonists
  • Ligands
  • Norisoprenoids
  • Receptors, Androgen
  • Dihydrotestosterone
  • Curcumin