Synthesis of novel ursolic acid heterocyclic derivatives with improved abilities of antiproliferation and induction of p53, p21waf1 and NOXA in pancreatic cancer cells

Bioorg Med Chem. 2012 Oct 1;20(19):5774-86. doi: 10.1016/j.bmc.2012.08.010. Epub 2012 Aug 16.

Abstract

A series of new heterocyclic derivatives of ursolic acid 1 were synthesized and evaluated for their antiproliferative activity against AsPC-1 pancreatic cancer cells. Compounds 24-32, with an α,β unsaturated ketone in conjugation with an heterocyclic ring in ring A have improved antiproliferative activities. Compound 32 is the most active compound with an IC(50) of 1.9 μM which is sevenfold more active than ursolic acid 1. Compound 32 arrests cell cycle in G1 phase and induces apoptosis in AsPC-1 cells with upregulation of p53, p21(waf1) and NOXA protein levels.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents, Phytogenic / chemical synthesis
  • Antineoplastic Agents, Phytogenic / chemistry*
  • Antineoplastic Agents, Phytogenic / pharmacology*
  • Cell Line, Tumor
  • Cell Proliferation / drug effects*
  • Cyclin-Dependent Kinase Inhibitor p21 / metabolism
  • Humans
  • Pancreatic Neoplasms / drug therapy*
  • Pancreatic Neoplasms / metabolism
  • Proto-Oncogene Proteins c-bcl-2 / metabolism
  • Triterpenes / chemical synthesis
  • Triterpenes / chemistry*
  • Triterpenes / pharmacology*
  • Tumor Suppressor Protein p53 / metabolism*
  • Ursolic Acid

Substances

  • Antineoplastic Agents, Phytogenic
  • Cyclin-Dependent Kinase Inhibitor p21
  • PMAIP1 protein, human
  • Proto-Oncogene Proteins c-bcl-2
  • Triterpenes
  • Tumor Suppressor Protein p53