Parallel synthesis and biological evaluation of 837 analogues of procaspase-activating compound 1 (PAC-1)

ACS Comb Sci. 2012 Jan 9;14(1):44-50. doi: 10.1021/co2001372. Epub 2011 Oct 28.


Procaspase-Activating Compound 1 (PAC-1) is an ortho-hydroxy N-acyl hydrazone that enhances the enzymatic activity of procaspase-3 in vitro and induces apoptosis in cancer cells. An analogue of PAC-1, called S-PAC-1, was evaluated in a veterinary clinical trial in pet dogs with lymphoma and found to have considerable potential as an anticancer agent. With the goal of identifying more potent compounds in this promising class of experimental therapeutics, a combinatorial library based on PAC-1 was created, and the compounds were evaluated for their ability to induce death of cancer cells in culture. For library construction, 31 hydrazides were condensed in parallel with 27 aldehydes to create 837 PAC-1 analogues, with an average purity of 91%. The compounds were evaluated for their ability to induce apoptosis in cancer cells, and through this work, six compounds were discovered to be substantially more potent than PAC-1 and S-PAC-1. These six hits were further evaluated for their ability to relieve zinc-mediated inhibition of procaspase-3 in vitro. In general, the newly identified hit compounds are two- to four-fold more potent than PAC-1 and S-PAC-1 in cell culture, and thus have promise as experimental therapeutics for treatment of the many cancers that have elevated expression levels of procaspase-3.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Antineoplastic Agents / chemical synthesis*
  • Antineoplastic Agents / chemistry
  • Apoptosis / drug effects
  • Caspase 3 / biosynthesis
  • Caspase Inhibitors
  • Cell Culture Techniques
  • Cell Survival / drug effects
  • Chemistry Techniques, Synthetic / methods*
  • Drug Discovery
  • Drug Screening Assays, Antitumor
  • Enzyme Induction
  • Flow Cytometry
  • Humans
  • Hydrazones / chemistry*
  • Molecular Structure
  • Piperazines / chemistry*
  • Small Molecule Libraries / chemical synthesis*
  • Small Molecule Libraries / chemistry
  • U937 Cells


  • (4-benzylpiperazin-1-yl)acetic acid (3-allyl-2-hydroxybenzylidene)hydrazine
  • Antineoplastic Agents
  • Caspase Inhibitors
  • Hydrazones
  • Piperazines
  • Small Molecule Libraries
  • Caspase 3