Synthesis and biological evaluation of chromium bioorganometallics based on the antibiotic platensimycin lead structure

ChemMedChem. 2009 Nov;4(11):1930-8. doi: 10.1002/cmdc.200900347.

Abstract

The recent discovery of the natural product platensimycin as a new antibiotic lead structure has triggered the synthesis of numerous organic derivatives for structure-activity relationship studies. Herein, we describe the synthesis, characterization and biological evaluation of the first organometallic antibiotic inspired by platensimycin. Two bioorganometallic compounds containing (eta(6)-pentamethylbenzene)Cr(CO)(3) (2) and (eta(6)-benzene)Cr(CO)(3) (3), linked by an amide bond to the aromatic part of platensimycin, were synthesized. Their antibiotic activities were tested against B. subtilis 168 (Gram positive) and E. coli W3110 (Gram negative) bacterial strains. Both compounds were found to be inactive against E. coli but derivative 2 inhibits B. subtilis growth at a moderate MIC value of 0.15 mM. To test the intrinsic toxicity of chromium, several chromium salts along with {eta(6)-(3-pentamethylphenyl propionic acid)}Cr(CO)(3) (5) and {eta(6)-(3-phenyl propionic acid)}Cr(CO)(3) (6) were tested against both bacterial strains. No activity was observed against E. coli for any of the compounds; B. subtilis growth was not inhibited by Cr(NO(3))(3) and only very weakly by 5, K(2)Cr(2)O(7) and Na(2)CrO(4) at MIC values of 0.5, 0.68 and 1.24 mM, respectively. Compounds 2, 3, 5 and 4 (the pure organic analogue of 2) show similar cytotoxicity against HeLa, HepG2 and HT-29 mammalian cell lines. Furthermore, the cellular uptake and the intracellular distribution of compounds 2, 3 and Cr(NO(3))(3) in B. subtilis were studied using atomic absorption spectroscopy to gain insight in to the possible cellular targets. Compound 2 was found to be readily taken up and distributed almost equally among cytosol, cell debris and cell membrane in B. subtilis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adamantane / chemical synthesis*
  • Adamantane / chemistry
  • Adamantane / toxicity
  • Aminobenzoates / chemical synthesis*
  • Aminobenzoates / chemistry
  • Aminobenzoates / toxicity
  • Anilides / chemical synthesis*
  • Anilides / chemistry
  • Anilides / toxicity
  • Anti-Bacterial Agents / chemical synthesis*
  • Anti-Bacterial Agents / chemistry
  • Anti-Bacterial Agents / toxicity
  • Cell Line, Tumor
  • Chromium / chemistry*
  • Chromium / toxicity
  • Crystallography, X-Ray
  • HeLa Cells
  • Humans
  • Microbial Sensitivity Tests
  • Molecular Conformation
  • Organometallic Compounds / chemical synthesis*
  • Organometallic Compounds / chemistry
  • Organometallic Compounds / toxicity
  • Spectrophotometry, Atomic

Substances

  • Aminobenzoates
  • Anilides
  • Anti-Bacterial Agents
  • Organometallic Compounds
  • Chromium
  • Adamantane
  • platensimycin