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Design, Synthesis, Radiosynthesis and Biological Evaluation of Fenretinide Analogues as Anticancer and Metabolic Syndrome-Preventive Agents.
- Source :
-
ChemMedChem [ChemMedChem] 2020 Aug 19; Vol. 15 (16), pp. 1579-1590. Date of Electronic Publication: 2020 Jul 09. - Publication Year :
- 2020
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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 IC <subscript>50</subscript> 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 [ <superscript>18</superscript> F]3b was successfully developed. Unfortunately, the stability of [ <superscript>18</superscript> F]3b turned out to be insufficient to pursue imaging studies.<br /> (© 2020 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)
- Subjects :
- Animals
Antineoplastic Agents chemical synthesis
Antineoplastic Agents chemistry
Cell Differentiation drug effects
Cell Proliferation drug effects
Cell Survival drug effects
Cells, Cultured
Dose-Response Relationship, Drug
Drug Screening Assays, Antitumor
Fenretinide chemical synthesis
Fenretinide chemistry
Fluorine Radioisotopes
Humans
Lipids antagonists & inhibitors
Mice
Molecular Structure
Positron-Emission Tomography
Retinoids analysis
Structure-Activity Relationship
Antineoplastic Agents pharmacology
Drug Design
Fenretinide pharmacology
Metabolic Syndrome prevention & control
Subjects
Details
- Language :
- English
- ISSN :
- 1860-7187
- Volume :
- 15
- Issue :
- 16
- Database :
- MEDLINE
- Journal :
- ChemMedChem
- Publication Type :
- Academic Journal
- Accession number :
- 32497314
- Full Text :
- https://doi.org/10.1002/cmdc.202000143