SAR studies on hydropentalene derivatives--Important core units of biologically active tetramic acid macrolactams and ptychanolides

Bioorg Med Chem. 2014 Jul 1;22(13):3252-61. doi: 10.1016/j.bmc.2014.04.063. Epub 2014 May 9.

Abstract

Structurally diverse bicyclo[3.3.0]octanes were prepared and tested for their biological activity. Both the antiproliferative activity and the results of phenotypic characterization varied with the substitution patterns. Two derivatives displayed high inhibitory (IC50 ≤3μM) activity against the L-929 cell line, but differed in their mode of action. A cluster analysis with impedance profiling data showed the two compounds in relationship to microtubule interfering compounds. In PtK2 cells treated with both derivatives a perturbing effect on the microtubular network was observed, whereas the actin cytoskeleton in incubated PtK2 cells was disturbed only by one compound. The effects on tubulin and actin polymerization could be confirmed by in vitro polymerization experiments.

Keywords: Biological activity; Click chemistry; Hydropentalene; Structure–activity relationships; Synthesis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology*
  • Bridged Bicyclo Compounds / chemical synthesis
  • Bridged Bicyclo Compounds / chemistry
  • Bridged Bicyclo Compounds / pharmacology*
  • Cell Line
  • Cell Proliferation / drug effects
  • Dose-Response Relationship, Drug
  • Drug Evaluation, Preclinical
  • Humans
  • Lactams, Macrocyclic / chemical synthesis
  • Lactams, Macrocyclic / chemistry
  • Lactams, Macrocyclic / pharmacology*
  • Mice
  • Molecular Conformation
  • Pyrrolidinones / chemical synthesis
  • Pyrrolidinones / chemistry
  • Pyrrolidinones / pharmacology*
  • Structure-Activity Relationship

Substances

  • Antineoplastic Agents
  • Bridged Bicyclo Compounds
  • Lactams, Macrocyclic
  • Pyrrolidinones
  • tetramic acid