Synthetic prodigiosenes and the influence of C-ring substitution on DNA cleavage, transmembrane chloride transport and basicity

Org Biomol Chem. 2013 Jun 21;11(23):3834-45. doi: 10.1039/c3ob40477c.


Analogues of the tripyrrolic natural product prodigiosin bearing an additional methyl and a carbonyl group at the C-ring were synthesised and evaluated. In vitro anticancer activity screening (NCI) and the study of modes of action (copper-mediated cleavage of double-stranded DNA and transmembrane transport of chloride anions) showed that the presence of the methyl group is not detrimental to activity. Furthermore, although the presence of an ester conjugated to the prodigiosene C-ring seems to decrease both pK(a) and chloride transport efficiency compared to the natural product, these analogues still exhibit a high rate of chloride transport. All analogues exhibit good in vitro anticancer activity and reduced toxicity compared to the natural product: compare an acute systemic toxicity of 100 mg kg(-1) in mice vs. 4 mg kg(-1) for prodigiosin, pointing towards a larger therapeutic window than for the natural product.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology
  • Biological Transport / drug effects
  • Carbon / chemistry*
  • Cell Line, Tumor
  • Cell Membrane / drug effects*
  • Cell Membrane / metabolism*
  • Chemistry Techniques, Synthetic
  • Chlorides / metabolism*
  • DNA Cleavage / drug effects*
  • Humans
  • Hydrogen-Ion Concentration
  • Mice
  • Prodigiosin / chemical synthesis*
  • Prodigiosin / chemistry
  • Prodigiosin / pharmacology*
  • Structure-Activity Relationship


  • Antineoplastic Agents
  • Chlorides
  • Carbon
  • Prodigiosin