Structure‐Atropisomer Stability Relationship in Selective MCL‐1 Inhibitors
Atropisomersm is an emerging feature in recent drug candidates due to the increasing complexity of the targeted protein surfaces. The developability of the drug candidates requires that their atropisomer interconversion is either fast or very slow at ambient temperature therefore the understanding and predictability of the isomerization rate is of great importance. Through a series of selective MCL-1 inhibitors we studied how structural features influence the interconversion of atropisomers. Besides basic observations such as stability in solution, we also carried out NMR kinetics at varying temperatures and a quantum chemical assessment of the isomerization process. The results of our theoretical studies and experimental investigations matched nicely when it came to predicting the presence or absence of isomerization at ambient temperature. For certain compounds we also measured the rotational barrier that fitted nicely the predicted values. The better understanding of how structural elements impact atropisomer stability enables the more efficient optimization of this important feature.
Authors
- Gaëtane Le Toumelin-Braizat
- Zoltán Szlávik (ORCID: https://orcid.org/0000-0002-2781-3795)
- András Stirling (ORCID: https://orcid.org/0000-0002-1696-7932)
- Mihály Kovács (ORCID: https://orcid.org/0000-0001-7977-9114)
- Szabolcs Sipos
- András Kotschy (ORCID: https://orcid.org/0000-0002-7675-3864)
- Barbara Balázs
- Balázs Bálint (ORCID: https://orcid.org/0000-0002-5102-0787)
- Tamás Gáti (ORCID: https://orcid.org/0000-0002-7549-8291)
- James Davidson (ORCID: https://orcid.org/0000-0002-8301-1607)
- Ana-Leticia Maragno
- James B. Murray (ORCID: https://orcid.org/0000-0003-1007-8218)
- Roderick E. Hubbard (ORCID: https://orcid.org/0000-0002-8233-7461)
- Attila Paczal
- Márton Csékei (ORCID: https://orcid.org/0000-0002-5781-1096)
- Olivier Geneste
Institutions
- Eszterhazy Karoly Catholic University (HU)
- Institute of Materials and Environmental Chemistry (HU)
- Granta Design (United Kingdom) (GB)
- Servier (France) (FR)
- Institute of Organic Chemistry (HU)
- Pierre Fabre (France) (FR)
- Institut de Biologie Moléculaire et Cellulaire (FR)
- HUN-REN Research Centre for Natural Sciences (HU)
Publication Details
- Journal
- ChemMedChem
- Published
- 2025-02-03
- DOI
- https://doi.org/10.1002/cmdc.202400970
- Primary Topic
- Axial and Atropisomeric Chirality Synthesis
- Type
- article
- Field-Weighted Citation Impact
- 0.00