Design, synthesis, radiosynthesis and biological evaluation of Fenretinide analogues as anticancer and metabolic syndromepreventive agents

Matteo Zanda* (Corresponding Author), Ilaria Patruno, Dawn Thompson, Sergio Dall'angelo, Albert D. Windhorst, Danielle J. Vugts, Alex J. Poot, Nimesh Mody

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

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 IC 50 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
JournalChemMedChem
Volume15
Issue number16
Early online date9 Jul 2020
DOIs
Publication statusPublished - 19 Aug 2020

Keywords

  • retinoic acid
  • Click chemistry
  • cancer
  • fluorine-18
  • diabetes
  • metabolic syndrome
  • radiopharmaceuticals
  • drug discovery
  • fenretinide
  • DIHYDROCERAMIDE DESATURASE
  • APOPTOSIS
  • HIGH-FAT
  • DIET-INDUCED OBESITY
  • DIFFERENTIATION
  • STRESS
  • DERIVATIVES
  • SPHINGOSINE KINASE
  • PET
  • N-(4-HYDROXYPHENYL)RETINAMIDE

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