%0 Journal Article
%A Garrido García, P.
%A Quirós, I.
%A Milán Rois, P.
%A Ortega Gutiérrez, Silvia
%A Martín-Fontecha Corrales, María Del Mar
%A Campos, L. A.
%A Somoza, A.
%A Fernández López, Israel
%A Rigotti, T.
%A Tortosa, M.
%T Enantioselective photocatalytic synthesis of bicyclo[2.1.1]hexanes as ortho-disubstituted benzene bioisosteres with improved biological activity
%D 2025
%U https://hdl.handle.net/20.500.14352/120135
%X 1,5-Disubstituted bicyclo[2.1.1]hexanes are bridged scaffolds with well-defined exit vectors that are becoming increasingly popular building blocks in medicinal chemistry because they are saturated bioisosteres of ortho-substituted phenyl rings. Here we have developed a Lewis-acid-catalysed [2 + 2] photocycloaddition to obtain these motifs as enantioenriched scaffolds, providing an efficient approach for their incorporation in a variety of drug analogues. Retention of the biological activity of the bicyclo[2.1.1]hexane-containing analogues in the specific proteins targeted by the original drugs has confirmed the suitability of this moiety to serve as a bioisostere of ortho-substituted phenyl rings. Moreover, we have studied the potential of the different enantiomers of the drug analogues to selectively induce cytotoxicity in a panel of tumour cell lines, observing markedly differential effects for the two enantiomers and a substantial improvement over the corresponding sp2-based drugs. This showcases that the control of the absolute configuration and tridimensionality of the drug analogue has a large impact on its biological properties.
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