Garrido García, P.Quirós, I.Milán Rois, P.Ortega Gutiérrez, SilviaMartín-Fontecha Corrales, María Del MarCampos, L. A.Somoza, A.Fernández López, IsraelRigotti, T.Tortosa, M.2025-05-162025-05-162025-02-25Garrido-García, Pablo, et al. «Enantioselective Photocatalytic Synthesis of Bicyclo[2.1.1]Hexanes as Ortho-Disubstituted Benzene Bioisosteres with Improved Biological Activity». Nature Chemistry, vol. 17, n.o 5, mayo de 2025, pp. 734-45. DOI.org (Crossref), https://doi.org/10.1038/s41557-025-01746-7.10.1038/s41557-025-01746-7https://hdl.handle.net/20.500.14352/1201351,5-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.engAttribution-NonCommercial-NoDerivatives 4.0 Internationalhttp://creativecommons.org/licenses/by-nc-nd/4.0/journal articlehttps://doi.org/10.1038/s41557-025-01746-7https://www.nature.com/articles/s41557-025-01746-7restricted access547Química2306 Química Orgánica