Tubulin-perturbing naphthoquinone spiroketals

Chem Biol Drug Des. 2008 Feb;71(2):117-24. doi: 10.1111/j.1747-0285.2007.00616.x. Epub 2008 Jan 9.


Several natural and synthetic naphthoquinone spiroketals are potent inhibitors of the thioredoxin-thioredoxin reductase redox system. Based on the antimitotic and weak antitubulin actions noted for SR-7 ([8-(furan-3-ylmethoxy)-1-oxo-1,4-dihydronaphthalene-4-spiro-2'-naphtho[1'',8''-de][1',3'][dioxin]), a library of related compounds was screened for tubulin-perturbing properties. Two compounds, TH-169 (5'-hydroxy-4'H-spiro[1,3-dioxolane-2,1'-naphthalen]-4'-one) and TH-223 (5'-methoxy-4'H-spiro[1,3-dioxane-2,1'-naphthalen]-4'-one), had substantial effects on tubulin assembly and were antiproliferative at low micromolar concentrations. TH-169 was the most potent at blocking GTP-dependent polymerization of 10 mum tubulin in vitro with a remarkable 50% inhibitory concentration of ca. 400 nm. It had no effect on paclitaxel-induced microtubule assembly and did not cause microtubule hypernucleation. TH-169 failed to compete with colchicine for binding to beta-tubulin. The 50% antiproliferative concentration of TH-169 against human cancer cells was at or slightly below 1 mum. Flow cytometry showed that 1 mum TH-169 caused an increase in G(2)/M and hypodiploid cells. TH-169 eliminated the PC-3 cells' polyploid population and increased their expression of p21(WAF1) and Hsp70 in a concentration-dependent manner. The antiproliferative effect of TH-169 was irreversible and independent of changes in caspases, actin, tubulin, glyceraldehyde phosphate dehydrogenase or Bcl-x(S/L). This structurally simple naphthoquinone spiroketal represents a small molecule, tubulin-interactive agent with a novel apoptotic pathway and attractive biological function.

Publication types

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

MeSH terms

  • Antineoplastic Agents / chemistry*
  • Antineoplastic Agents / pharmacology
  • Apoptosis / drug effects*
  • Cell Cycle / drug effects
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Cyclin-Dependent Kinase Inhibitor p21 / genetics
  • Drug Screening Assays, Antitumor*
  • Furans / pharmacology*
  • Guanosine Triphosphate / pharmacology
  • HSP70 Heat-Shock Proteins / genetics
  • Humans
  • Naphthoquinones / pharmacology*
  • Paclitaxel / pharmacology
  • Spiro Compounds / pharmacology*
  • Tubulin / drug effects*
  • Up-Regulation


  • Antineoplastic Agents
  • CDKN1A protein, human
  • Cyclin-Dependent Kinase Inhibitor p21
  • Furans
  • HSP70 Heat-Shock Proteins
  • Naphthoquinones
  • Spiro Compounds
  • Tubulin
  • spiroketal
  • Guanosine Triphosphate
  • Paclitaxel