Synthesis and biological evaluation of indolylglyoxylamide bisphosphonates, antimitotic microtubule-targeting derivatives of indibulin with improved aqueous solubility

Bioorg Med Chem Lett. 2020 Dec 1;30(23):127635. doi: 10.1016/j.bmcl.2020.127635. Epub 2020 Oct 22.

Abstract

Indibulin (D-24851) derivatives with bisphosphonate fragment connected to the N1 atom of imidazole ring were synthesized by alkylation of (indolyl-3)methylglyoxylates with ethylenebisphosphonate. Biological evaluation of targeted compounds 4a-d using the phenotypic sea urchin embryo assay provided evidence that replacing of p-chlorobenzene ring in indibulin by bisphosphonate group did not eliminate antimitotic microtubule destabilizing activity. The most active molecule, tetraacid 5a, at physiological pH formed tetrasodium salt 6a with aqueous solubility value of at least 10 mg/mL. Molecule 5a was more potent in the sea urchin embryo assay than the parent indibulin. This compound also exhibited pronounced cytotoxicity against A549 lung carcinoma and A375 melanoma cell lines.

Keywords: Bisphosphonates; Indibulin; Indolylglyoxylamides; Microtubule destabilization; Sea urchin embryo.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetamides / chemical synthesis
  • Acetamides / pharmacology*
  • Animals
  • Antimitotic Agents / chemical synthesis
  • Antimitotic Agents / pharmacology*
  • Cell Line, Tumor
  • Diphosphonates / chemical synthesis
  • Diphosphonates / pharmacology*
  • Drug Screening Assays, Antitumor
  • Embryo, Nonmammalian / drug effects
  • Humans
  • Indoles / chemical synthesis
  • Indoles / pharmacology*
  • Sea Urchins / drug effects
  • Solubility

Substances

  • Acetamides
  • Antimitotic Agents
  • Diphosphonates
  • Indoles
  • indibulin