New microtubule polymerization inhibitors comprising a nitrooxymethylphenyl group

Bioorg Med Chem. 2011 Jul 1;19(13):3995-4003. doi: 10.1016/j.bmc.2011.05.031. Epub 2011 May 23.

Abstract

We have designed cancer antiproliferative compounds, starting from aniline or phenol derivative, which comprise one or two nitrooxymethylphenyl groups as do the hybrid drugs NCX4040 and NCX530. Compound 2a with p-nitrooxymethylbenzoyl-oxy and -amino groups as well as 8a with a p-nitrooxymethylbenzoylamino group showed more promising effects than NCX4040 against human colon and breast cancer cells. Since 2a and 8a, but not NCX4040, arrested human colon carcinoma HCT116 cells in the M phase, the former two compounds may inhibit cell growth differently from NCX4040. Merged images of immunofluorescence-stained α-tubulin and Hoechst-stained nuclei in human fibrosarcoma HT1080 cells showed that 2a and 8a disrupted microtubule formation just as did vincristine, the tubulin polymerization inhibitor. In experiments in vivo, the intraperitoneal administration of 8a at 80 mg/kg/day reduced the growth of HCT116 xenografts in nude mice to T/C 55%.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetates / chemistry
  • Animals
  • Aspirin / analogs & derivatives
  • Aspirin / chemistry
  • Benzoates / chemical synthesis
  • Benzoates / chemistry*
  • Benzoates / therapeutic use
  • Carbamates / chemical synthesis
  • Carbamates / chemistry*
  • Carbamates / therapeutic use
  • Cell Division
  • Cell Line, Tumor
  • Colonic Neoplasms / drug therapy
  • G2 Phase
  • Humans
  • Indoles / chemistry
  • Mice
  • Mice, Nude
  • Nitrates / chemical synthesis
  • Nitrates / chemistry*
  • Nitrates / therapeutic use
  • Nitro Compounds / chemistry
  • Structure-Activity Relationship
  • Transplantation, Heterologous
  • Tubulin / chemistry*
  • Tubulin / metabolism
  • Tubulin Modulators / chemical synthesis
  • Tubulin Modulators / chemistry*
  • Tubulin Modulators / therapeutic use
  • Vincristine / chemistry
  • Vincristine / therapeutic use

Substances

  • 1-(4-chlorobenzoyl)-5-methoxy-2-1H-indole-3-acetic acid 3-(nitrooxymethyl)phenyl ester
  • 2-(4-(nitrooxymethyl)benzamido)phenyl 4-(nitrooxymethyl)benzoate
  • 4-(phenylcarbamoyl)benzyl nitrate
  • Acetates
  • Benzoates
  • Carbamates
  • Indoles
  • NCX 4040
  • Nitrates
  • Nitro Compounds
  • Tubulin
  • Tubulin Modulators
  • Vincristine
  • Aspirin