New lithocholic and chenodeoxycholic piperazinylcarboxamides with antiproliferative and pro-apoptotic effects on human cancer cell lines

Bioorg Med Chem. 2008 Sep 15;16(18):8737-44. doi: 10.1016/j.bmc.2008.07.046. Epub 2008 Jul 23.

Abstract

Six new synthetic bile acid derivatives were synthesized and tested in vitro against various human cancer cells (glioblastoma multiforme (GBM), multiple myeloma (KMS-11), and colonic carcinoma (HCT-116) cell lines. The best activity was obtained with compound IIIb on multiple myeloma cells (LD(50): 8.5+/-0.5 microM). This activity was associated with Mcl-1 and PARP-1 cleavage, inhibition of NFkappaB signaling, and DNA fragmentation, demonstrating an apoptotic cell death signaling pathway.

MeSH terms

  • Amides / chemical synthesis
  • Amides / pharmacology*
  • Apoptosis / drug effects*
  • Blotting, Western
  • Cell Line, Tumor
  • Cell Proliferation / drug effects*
  • Chenodeoxycholic Acid / analogs & derivatives
  • Chenodeoxycholic Acid / chemical synthesis
  • Chenodeoxycholic Acid / pharmacology*
  • Colonic Neoplasms / metabolism
  • Colonic Neoplasms / pathology
  • DNA Fragmentation
  • Glioblastoma / metabolism
  • Glioblastoma / pathology
  • Humans
  • Lithocholic Acid / analogs & derivatives
  • Lithocholic Acid / chemical synthesis
  • Lithocholic Acid / pharmacology*
  • Multiple Myeloma / metabolism
  • Multiple Myeloma / pathology
  • NF-kappa B / antagonists & inhibitors
  • NF-kappa B / genetics
  • NF-kappa B / metabolism
  • Neoplasms* / metabolism
  • Neoplasms* / pathology
  • Piperazines / chemical synthesis
  • Piperazines / pharmacology*
  • Signal Transduction

Substances

  • Amides
  • NF-kappa B
  • Piperazines
  • Chenodeoxycholic Acid
  • Lithocholic Acid