Water-soluble benzoheterocycle triosmium clusters as potential inhibitors of telomerase enzyme

J Inorg Biochem. 2005 Feb;99(2):505-12. doi: 10.1016/j.jinorgbio.2004.10.027.

Abstract

We have studied the ability of several bioorganometallic clusters [(mu-H)Os(3)(CO)(9)(L)(mu(3)-eta(2)-(Q-H))], where L = [P(C(6)H(4)SO(3)Na)(3)] or [P(OCH(2)CH(2)NMe(3)I)(3)], and Q = quinoline, 3-aminoquinoline, quinoxaline or phenanthridine, of inhibiting telomerase, a crucial enzyme for cancer progression. In general, quinolines have shown interesting biological properties, especially in inhibiting enzymes. For example, the 2,3,7-trichloro-5-nitroquinoxaline (TNQX) exhibited strong anti-telomerase activity in vitro. Among the quinoline-clusters under study, only the negatively charged ones (by virtue of the sulfonated phosphines) exhibited good anti-telomerasic activity on semi-purified enzyme in a cell-free assay, while they were ineffective in vitro on Taq, a different DNA-polymerase. On the contrary, the treatment of breast cancer MCF-7 cell line did not evidence any activity of these clusters, suggesting a low aptitude for crossing cell membrane. Furthermore, all clusters exhibited non-specific, acute cytotoxicy, probably due to accumulation on cell membranes by virtue of their amphiphilic character. A detailed study of Os uptake and accumulation in MCF-7 cells supported this hypothesis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Biological Transport, Active
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Cell-Free System
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry*
  • Enzyme Inhibitors / pharmacokinetics
  • Enzyme Inhibitors / pharmacology*
  • Humans
  • In Vitro Techniques
  • Molecular Structure
  • Organometallic Compounds / chemical synthesis
  • Organometallic Compounds / chemistry*
  • Organometallic Compounds / pharmacokinetics
  • Organometallic Compounds / pharmacology*
  • Osmium / chemistry
  • Telomerase / antagonists & inhibitors*

Substances

  • Enzyme Inhibitors
  • Organometallic Compounds
  • Osmium
  • Telomerase