The Preorganization of Atropisomers to Increase Target Selectivity

Christopher J. Nalbandian; David E. Hecht; Jeffrey L. Gustafson

doi:10.1055/s-0035-1561314

Synlett, Table of Contents

Synlett 2016; 27(07): 977-983
DOI: 10.1055/s-0035-1561314

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The Preorganization of Atropisomers to Increase Target Selectivity

Christopher J. Nalbandian

^aDepartment of Chemistry and Biochemistry, San Diego State University, 5500 Campanile Dr., San Diego, CA, 92182-1030, USA Email: JGustafson@mail.sdsu.edu

,

David E. Hecht

^bSchool of Mathematics, Science & Engineering, Southwestern College, 900 Otay Lakes Rd., Chula Vista CA, 91910, USA

,

Jeffrey L. Gustafson*

^aDepartment of Chemistry and Biochemistry, San Diego State University, 5500 Campanile Dr., San Diego, CA, 92182-1030, USA Email: JGustafson@mail.sdsu.edu

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Abstract

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Abstract

Atropisomerism is a form of chirality that arises from differential substitution around a bond that renders the rotational isomers enantiomers. Depending on the degree of hindrance to bond rotation, atropisomers can exist as either stable isolable enantiomers or rapidly racemizing atropisomeric mixtures. Many biologically active small molecules exist as rapidly interconverting atropisomers, however, only one of the possible atropisomers possesses the desired activity. The presence of the nonrelevant atropisomer via spontaneous racemization can result in off-target activities that can lead to side effects. We have hypothesized that preorganizing (locking) a freely interconverting atropisomeric axis in a promiscuous scaffold into the target relevant atropisomer can serve as a general strategy towards more selective small molecule inhibitors. This article outlines recent literature on atropisomerism in drug discovery as well as our recent efforts towards increasing the target selectivity of small molecule kinase inhibitors through ‘atropisomer preorganization’.

Key words

atropisomerism - medicinal chemistry - kinase - inhibitor - preorganization

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References

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