Design,Synthesis, Radiosynthesis and Biological Evaluation of Fenretinide Analogues as Anticancer and Metabolic Syndrome-Preventive Agents |
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Authors: | Ilaria Patruno Dr. Dawn Thompson Dr. Sergio Dall'Angelo Prof. Albert D. Windhorst Dr. Danielle J. Vugts Dr. Alex J. Poot Dr. Nimesh Mody Prof. Matteo Zanda |
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Affiliation: | 1. Institute of Medical Sciences, University of Aberdeen, Aberdeen, AB25 2ZD UK;2. Amsterdam UMC, VU University Medical Center, Cancer Center Amsterdam, De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands |
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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 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. |
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Keywords: | cancer drug discovery fenretinide metabolic syndrome radiopharmaceuticals |
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