New insights into structure-activity relationship of ipomoeassin F from its bioisosteric 5-oxa/aza analogues

Eur J Med Chem. 2018 Jan 20:144:751-757. doi: 10.1016/j.ejmech.2017.11.022. Epub 2017 Dec 12.

Abstract

Ipomoeassin F, a plant-derived macrolide, exhibited single-digit nanomolar growth inhibition activity against many cancer cell lines. In this report, a series of 5-oxa/aza analogues was prepared and screened for cytotoxicity. Replacement of 5-CH2 with O/NH simplified the synthesis and led to only a small activity loss. N-methylation almost completely restored the potency. Further studies with additional 5-oxa analogues suggested, for the first time, that size and flexibility of the ring also significantly influence the bioactivity of ipomoeassin F.

Keywords: Bioisosteric ester/amide analogues; Cytotoxicity; Ipomoeassin F; Macrolide; Resin glycosides.

MeSH terms

  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology*
  • Aza Compounds / chemistry
  • Aza Compounds / pharmacology*
  • Cell Line
  • Cell Proliferation / drug effects
  • Dose-Response Relationship, Drug
  • Drug Screening Assays, Antitumor
  • Glycoconjugates / chemical synthesis
  • Glycoconjugates / chemistry
  • Glycoconjugates / pharmacology*
  • Humans
  • Molecular Structure
  • Structure-Activity Relationship

Substances

  • Antineoplastic Agents
  • Aza Compounds
  • Glycoconjugates
  • ipomoeassin F