Design, Synthesis, Radiosynthesis and Biological Evaluation of Fenretinide Analogues as Anticancer and Metabolic Syndrome-Preventive Agents

ChemMedChem. 2020 Aug 19;15(16):1579-1590. doi: 10.1002/cmdc.202000143. Epub 2020 Jul 9.


Fenretinide (4-HPR) is a synthetic derivative of all-trans-retinoic acid (ATRA) characterised by improved therapeutic properties and toxicological profile relative to ATRA. 4-HPR has been mostly investigated as an anti-cancer agent, but recent studies showed its promising therapeutic potential for preventing metabolic syndrome. Several biological targets are involved in 4-HPR's activity, leading to the potential use of this molecule for treating different pathologies. However, although 4-HPR displays quite well-understood multitarget promiscuity with regards to pharmacology, interpreting its precise physiological role remains challenging. In addition, despite promising results in vitro, the clinical efficacy of 4-HPR as a chemotherapeutic agent has not been satisfactory so far. Herein, we describe the preparation of a library of 4-HPR analogues, followed by the biological evaluation of their anti-cancer and anti-obesity/diabetic properties. The click-type analogue 3 b showed good capacity to reduce the amount of lipid accumulation in 3T3-L1 adipocytes during differentiation. Furthermore, it showed an IC50 of 0.53±0.8 μM in cell viability tests on breast cancer cell line MCF-7, together with a good selectivity (SI=121) over noncancerous HEK293 cells. Thus, 3 b was selected as a potential PET tracer to study retinoids in vivo, and the radiosynthesis of [18 F]3b was successfully developed. Unfortunately, the stability of [18 F]3b turned out to be insufficient to pursue imaging studies.

Keywords: cancer; drug discovery; fenretinide; metabolic syndrome; radiopharmaceuticals.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology*
  • Cell Differentiation / drug effects
  • Cell Proliferation / drug effects
  • Cell Survival / drug effects
  • Cells, Cultured
  • Dose-Response Relationship, Drug
  • Drug Design*
  • Drug Screening Assays, Antitumor
  • Fenretinide / chemical synthesis
  • Fenretinide / chemistry
  • Fenretinide / pharmacology*
  • Fluorine Radioisotopes
  • Humans
  • Lipids / antagonists & inhibitors
  • Metabolic Syndrome / prevention & control*
  • Mice
  • Molecular Structure
  • Positron-Emission Tomography
  • Retinoids / analysis
  • Structure-Activity Relationship


  • Antineoplastic Agents
  • Fluorine Radioisotopes
  • Lipids
  • Retinoids
  • Fenretinide