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Design, synthesis, radiosynthesis and biological evaluation of fenretinide analogues as anticancer and metabolic syndrome‐preventive agents

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posted on 20.07.2020, 15:43 by Ilaria Patruno, Dawn Thompson, Sergio Dall'Angelo, Albert D Windhorst, Danielle J Vugts, Alex J Poot, Nimesh Mody, Matteo Zanda
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.

Funding

European Union's Horizon 2020 research and innovation programme

Marie Skłodowska-Curie grant. Grant Number: 675417

British Heart Foundation. Grant Number: PG/16/90/32518

History

School

  • Science

Department

  • Chemistry

Published in

ChemMedChem

Volume

15

Issue

16

Pages

1579 - 1590

Publisher

Wiley

Version

AM (Accepted Manuscript)

Rights holder

© Wiley‐VCH Verlag GmbH & Co. KGaA, Weinheim

Publisher statement

This is the peer reviewed version of the following article: Patruno, I., Thompson, D., Dall'Angelo, S., Windhorst, A.D., Vugts, D.J., Poot, A.J., Mody, N. and Zanda, M. (2020), Design, Synthesis, Radiosynthesis and Biological Evaluation of Fenretinide Analogues as Anticancer and Metabolic Syndrome‐Preventive Agents. ChemMedChem, 15 (16), pp.1579-1590, which has been published in final form at https://doi.org/10.1002/cmdc.202000143. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived Versions.

Publication date

2020-07-09

Copyright date

2020

ISSN

1860-7179

eISSN

1860-7187

Language

en

Depositor

Prof Matteo Zanda. Deposit date: 20 July 2020