Synthesis of A83586C analogs with potent anticancer and beta-catenin/ TCF4/osteopontin inhibitory effects and insights into how A83586C modulates E2Fs and pRb

Org Lett. 2009 Feb 5;11(3):737-40. doi: 10.1021/ol802818f.

Abstract

The synthesis of three potent new antitumor agents is described: the A83586C-citropeptin hybrid (1), the A83586C-GE3 hybrid (2), and l-Pro-A83586C (3). Significantly, compounds 1 and 2 function as highly potent inhibitors of beta-catenin/TCF4 signaling within cancer cells, while simultaneously downregulating osteopontin (Opn) expression. A83586C antitumor cyclodepsipeptides also inhibit E2F-mediated transcription by downregulating E2F1 expression and inducing dephosphorylation of the oncogenic hyperphosphorylated retinoblastoma protein (pRb).

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / chemical synthesis*
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology*
  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
  • DNA-Binding Proteins / antagonists & inhibitors*
  • Depsipeptides / chemical synthesis*
  • Depsipeptides / chemistry
  • Depsipeptides / pharmacology*
  • Drug Screening Assays, Antitumor
  • E2F Transcription Factors / metabolism*
  • E2F1 Transcription Factor / metabolism
  • Humans
  • Inhibitory Concentration 50
  • Transcription Factor 4
  • Transcription Factors / antagonists & inhibitors*
  • beta Catenin / antagonists & inhibitors*

Substances

  • Antineoplastic Agents
  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
  • DNA-Binding Proteins
  • Depsipeptides
  • E2F Transcription Factors
  • E2F1 Transcription Factor
  • TCF4 protein, human
  • Transcription Factor 4
  • Transcription Factors
  • beta Catenin
  • A 83586C