NMR strategies to support medicinal chemistry workflows for primary structure determination.

Paul Oguadinma (1) , Francois Bilodeau (1) , Steven R Laplante (1, 2)

1 INRS-IAF - Institut Armand Frappier
2 NMX Research and Solutions Inc.

Central to drug discovery is the correct characterization of the primary structures of compounds. In general, medicinal chemists make great synthetic and characterization efforts to deliver the intended compounds. However, there are occasions which incorrect compounds are presented, such as those reported for Bosutinib and TIC10. This may be due to a variety of reasons such as uncontrolled reaction schemes, reliance on limited characterization techniques (LC-MS and/or 1D 1H NMR spectra), or even the lack of availability or knowledge of characterization strategies. Here, we present practical NMR approaches that support medicinal chemist workflows for addressing compound characterization issues and allow for reliable primary structure determinations. These strategies serve to differentiate between regioisomers and geometric isomers, distinguish between N- versus O-alkyl analogues, and identify rotamers and atropisomers. Overall, awareness and application of these available NMR methods (e.g. HMBC/HSQC, ROESY and VT experiments, to name only a few) should help practicing chemists to reveal chemical phenomena and avoid mis-assignment of the primary structures of compounds.

Mots clés: Medicinal chemistry; NMR methods; Primary structure; Regioisomers; Rotamers

Domaines: Sciences du Vivant [q-bio]; Chimie organique

Paul Oguadinma, Francois Bilodeau, Steven R Laplante. NMR strategies to support medicinal chemistry workflows for primary structure determination.. Bioorganic and Medicinal Chemistry Letters, 2017, 27 (2), pp.242-247. ⟨10.1016/j.bmcl.2016.11.066⟩. ⟨pasteur-01421230⟩