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 journalArticle

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 evidenced 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 multi‐target 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. Here 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 3b showed good capacity to reduce the amount of lipid accumulation in 3T3‐L1 adipocytes during differentiation. Furthermore, it showed an IC50 = 0.53±0.8μM in cell viability tests on breast cancer cell line MCF‐7, together with a good selectivity over non‐cancerous HEK293 cells. Thus, 3b 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 for pursuing imaging studies.
Original languageEnglish
Number of pages13
JournalChemMedChem
Early online date9 Jul 2020
DOIs
Publication statusE-pub ahead of print - 9 Jul 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

ASJC Scopus subject areas

  • Drug Discovery
  • Molecular Medicine
  • Biochemistry
  • Pharmacology, Toxicology and Pharmaceutics(all)
  • Pharmacology
  • Organic Chemistry

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