Fluorinated aminopiperidones as non-glutarimide thalidomide analogs : stereodivergent synthesis and validation

Adamlje, Boštjan (author), Tomašič, Tihomir (author), Steinebach, Christian (author), Ebeling, Sebastian (author), Herrmann, Alexander (author), Hartmann, Marcus D. (author), Horner, Jessica L. (author), Bhadresha, Kinjal (author), Sosič, Izidor (author), Cotman, Andrej Emanuel (author)

The glutarimide fragment is a key pharmacophore in cereblon-binding immunomodulatory drugs and proteolysis-targeting chimeras, yet exploration of non-glutarimide scaffolds remains limited. Here, we report the design, synthesis, and evaluation of fluorinated aminopiperidones as three-dimensional, non-glutarimide thalidomide analogs. By replacing a single glutarimide carbonyl with a stereogenic C$^*$–CF$_{3}$ unit, we accessed a previously underexplored chemical space encompassing all regio- and diastereomeric variants of 3- and 5-phthalimido-6-trifluoromethyl-2-piperidones. Stereocontrolled synthetic routes enabled reliable control over relative configurations, and two-dimensional NMR provided unambiguous structural assignment. Experimental profiling of CF$_{3}$-piperidones relative to glutarimides revealed improved aqueous solubility despite increased logD and enhanced membrane interaction characteristics, without substantial changes in plasma protein binding, consistent with sp$^3$ enrichment and escape-from-flatland principles. To assess whether cereblon recognition is retained after carbonyl-to-C$^*$–CF$_{3}$ replacement, the compounds were evaluated by microscale thermophoresis. No measurable cereblon binding was detected for the fluorinated aminopiperidones. Docking studies, performed to rationalize this lack of affinity, suggested disruption of key cereblon–ligand interactions and unfavorable binding poses following carbonyl-to-C$^*$–CF$_{3}$ substitution. Several CF$_{3}$-piperidones, particularly tetrafluorophthalimide derivatives, exhibited potent anti-angiogenic activity in vitro and ex vivo, indicating a cereblon-independent mechanism.

• Language: English
• Keywords: bioisosterism, diastereoselectivity, drug design, fluorine, PROTAC
• Work type: Article
• Typology: 1.01 - Original Scientific Article
• Organization: FFA - Faculty of Pharmacy
• Publication status: Published
• Publication version: Version of Record
• Year: 2026
• Number of pages: 15 str.
• Numbering: Vol. 21, iss. 13, art. e70360
• PID: 20.500.12556/RUL-185196
• UDC: 615.4:54
• ISSN on article: 1860-7187
• DOI: 10.1002/cmdc.70360
• COBISS.SI-ID: 284004099
• Publication date in RUL: 28.07.2026

Record is a part of a journal

• Title: ChemMedChem
• Shortened title: ChemMedChem
• Publisher: Wiley-VCH-Verl..
• ISSN: 1860-7187
• COBISS.SI-ID: 519053337

Licences

• License: CC BY 4.0, Creative Commons Attribution 4.0 International
• Link: http://creativecommons.org/licenses/by/4.0/
• Description: This is the standard Creative Commons license that gives others maximum freedom to do what they want with the work as long as they credit the author.

Secondary language

• Language: Slovenian
• Keywords: bioizosterizem, diastereoselektivnost, načrtovanje zdravil, fluor, PROTAC, zdravila, farmacevtska kemija