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

Ilaria Patruno, Dawn Thompson, Sergio Dall'Angelo, Albert D. Windhorst, Danielle J. Vugts, Alex J. Poot, Nimesh Mody, Matteo Zanda

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2 Citations (Scopus)


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 [18F]3b was successfully developed. Unfortunately, the stability of [18F]3b turned out to be insufficient to pursue imaging studies.
Original languageEnglish
Pages (from-to)1579-1590
Number of pages12
Issue number16
Early online date4 Jun 2020
Publication statusPublished - 19 Aug 2020


  • cancer
  • drug discovery
  • fenretinide
  • metabolic syndrome
  • radiopharmaceuticals

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