Atropisomerism in Medicinal Chemistry: Challenges and Opportunities
Top Cited Papers
- 30 January 2018
- journal article
- research article
- Published by Taylor & Francis in Future Medicinal Chemistry
- Vol. 10 (4) , 409-422
Abstract
Atropisomerism is a dynamic type of axial chirality that is ubiquitous in medicinal chemistry. There are several examples of stable atropisomeric US FDA-approved drugs and experimental compounds, and in each case the atropisomers of these compounds possess drastically different biological activities. Rapidly interconverting atropisomerism is even more prevalent, and while such compounds are typically considered achiral, they bind their protein targets in an atroposelective fashion, with the nonrelevant atropisomer contributing little to the desired activities. It has been recently demonstrated that various properties of an interconverting atropisomer can be modulated through the synthesis of atropisomer stable and pure analogs. Herein we discuss examples of atropisomerism in drug discovery as well as challenges and opportunities moving forward.Keywords
This publication has 78 references indexed in Scilit:
- Biological Stereoselectivity of Atropisomeric Natural Products and DrugsChirality, 2013
- Methyl Effects on Protein–Ligand BindingJournal of Medicinal Chemistry, 2012
- Structural and Spectroscopic Analysis of the Kinase Inhibitor Bosutinib and an Isomer of Bosutinib Binding to the Abl Tyrosine Kinase DomainPLOS ONE, 2012
- Dynamic Kinetic Resolution of Biaryl Atropisomers via Peptide-Catalyzed Asymmetric BrominationScience, 2010
- Bcl-2 Inhibitors: Targeting Mitochondrial Apoptotic Pathways in Cancer TherapyClinical Cancer Research, 2009
- Asymmetric synthesis of biaryl atropisomers by dynamic resolution on condensation of biaryl aldehydes with (−)-ephedrine or a proline-derived diamineBeilstein Journal of Organic Chemistry, 2008
- Structural Requirements for Eszopiclone and Zolpidem Binding to the γ-Aminobutyric Acid Type-A (GABAA) Receptor Are DifferentJournal of Medicinal Chemistry, 2008
- The selectivity of protein kinase inhibitors: a further updateBiochemical Journal, 2007
- Exploiting Ligand Conformation in Selective Inhibition of Non-Ribosomal Peptide Synthetase Amino Acid Adenylation with Designed Macrocyclic Small MoleculesJournal of the American Chemical Society, 2007
- Structure and Chemical Inhibition of the RET Tyrosine Kinase DomainJournal of Biological Chemistry, 2006