Structure-Activity Relationship Studies of β-Lactam-azide Analogues as Orally Active Antitumor Agents Targeting the Tubulin Colchicine Site

Sci Rep. 2017 Oct 6;7(1):12788. doi: 10.1038/s41598-017-12912-4.

Abstract

We have synthesized a series of new β-lactam-azide derivatives as orally active anti-tumor agents by targeting tubulin colchicine binding site and examined their structure activity relationship (SAR). Among them, compound 28 exhibited the most potent antiproliferative activity against MGC-803 cells with an IC50 value of 0.106 μM by induction of G2/M arrest and apoptosis and inhibition of the epithelial to mesenchymal transition. 28 acted as a novel inhibitor of tubulin polymerization by its binding to the colchicine site. SAR analysis revealed that a hydrogen atom at the C-3 position of the β-lactam was required for the potent antiproliferative activity of β-lactam-azide derivatives. Oral administration of compound 28 also effectively inhibited MGC-803 xenograft tumor growth in vivo in nude mice without causing significant loss of body weight. These results suggested that compound 28 is a promising orally active anticancer agent with potential for development of further clinical applications.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Oral
  • Animals
  • Antineoplastic Agents / administration & dosage
  • Antineoplastic Agents / chemistry*
  • Antineoplastic Agents / pharmacology*
  • Apoptosis / drug effects
  • Azides / administration & dosage
  • Azides / chemistry
  • Azides / pharmacology*
  • Cadherins / metabolism
  • Cell Line, Tumor
  • Cell Movement / drug effects
  • Colchicine / chemistry
  • Colchicine / pharmacology*
  • Down-Regulation / drug effects
  • Humans
  • Inhibitory Concentration 50
  • Mice, Inbred BALB C
  • Mice, Nude
  • Structure-Activity Relationship
  • Tubulin / metabolism*
  • Up-Regulation / drug effects
  • Zonula Occludens-1 Protein / metabolism
  • beta-Lactams / administration & dosage
  • beta-Lactams / chemistry*
  • beta-Lactams / pharmacology*

Substances

  • Antineoplastic Agents
  • Azides
  • Cadherins
  • Tubulin
  • Zonula Occludens-1 Protein
  • beta-Lactams
  • Colchicine