Synthesis and antiproliferative activity of 3-amino-N-phenyl-1H-indazole-1-carboxamides

Eur J Med Chem. 2009 Jan;44(1):165-78. doi: 10.1016/j.ejmech.2008.03.023. Epub 2008 Apr 8.

Abstract

A series of new 3-amino-N-phenyl-1H-indazole-1-carboxamides 10 have been prepared from commercially available phenyl isocyanate precursors 8 and 3-aminoindazole 9. Some of the synthesized compounds were evaluated for their in vitro antineoplastic activity against 60 human cell lines derived from seven clinically isolated cancer types (lung, colon, melanoma, renal, ovarian, brain, and leukemia) according to the NCI standard protocol. The test results indicated that 3-amino-1H-indazole-1-carboxamides 10 were endowed with an interesting antiproliferative activity. The most active compounds of this series, 10d,e, were able to inhibit cell growth of many neoplastic cell lines at concentrations lower than 1 microM (0.0153 microM in SR leukemia) causing a block in G0-G1 phase of cell cycle. Analysis of pRb expression showed that these two compounds increased the ratio between underphosphorylated pRb and total pRb. The X-ray structure of 10w, confirmed the 3-amino-N-phenyl-1H-indazole-1-carboxamide structure of compounds 10.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amides / chemical synthesis*
  • Amides / pharmacology
  • Antineoplastic Agents / chemical synthesis*
  • Antineoplastic Agents / pharmacology
  • Cell Cycle / drug effects
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Crystallography, X-Ray
  • Humans
  • Indazoles / chemical synthesis*
  • Indazoles / pharmacology
  • Molecular Structure
  • Neoplasms / drug therapy
  • Retinoblastoma Protein / metabolism
  • Structure-Activity Relationship

Substances

  • Amides
  • Antineoplastic Agents
  • Indazoles
  • Retinoblastoma Protein